A NOVEL PHARMACEUTICAL COMPOUND AND METHODS OF MAKING AND USING SAME This application claims benefit of priority to the following U. S. provisional applications which were filed on November 16,2000 and which are herein incorporated by reference in their entirety: 60/248, 607,60/248, 611, 60/248, 609,60/248, 608, 60/248,606, 60/248,604, 60/248, 603, 60/248, 601,60/248, 600, 60/248, 712, 60/248, 711, 60/248, 709, 60/248, 708, 60/248, 707, 60/248, 706, 60/248, 705,60/248, 704,60/248, 703, 60/248,702, 60/248,701, 60/248, 700, 60/248, 699,60/248, 698,60/248, 697, 60/248, 696, 60/248,695, 60/248,694, 60/248,693, 60/248, 692, 60/248, 691,60/248, 710,60/248, 689, 60/248, 688, 60/248, 686,60/248, 720,60/248, 719,60/248, 718, 60/248,717, 60/248,716, 60/248,715, 60/248, 714,60/248, 713,60/248, 536,60/248, 535, 60/248, 733,60/248, 732, 60/248,731, 60/248,730, 60/248,729, 60/248,728, 60/248, 727, 60/248, 726,60/248, 725, 60/248,724, 60/248,723, 60/248, 722,60/248, 721, 60/248, 540,60/248, 539, 60/248, 538, 60/248,537, 60/248, 533, 60/248, 532,60/248, 531,60/248, 530, 60/248, 529,60/248, 528, 60/248,527, 60/248,526, 60/248,525, 60/248,524, 60/248, 670,60/248, 789, 60/248, 599, 60/248,745, 60/248,746, 60/248,747, 60/248,748, 60/248, 744,60/248, 743, 60/248, 756, 60/248,602, 60/248, 598,60/248, 597, 60/248, 596,60/248, 595,60/248, 594,60/248, 858, 60/248,857, 60/248,856, 60/248,855, 60/248, 854, 60/248,853, 60/248, 852, 60/248, 851, 60/248, 850, 60/248, 849, 60/248, 848, 60/248, 792,60/248, 790,60/248, 669,60/248, 668, 60/248,667, 60/248, 666,60/248, 665,60/248, 664,60/248, 793, 60/248, 791, 60/248, 684, 60/248,683, 60/248,682, 60/248, 681,60/248, 680, 60/248, 671,60/248, 679,60/248, 675, 60/248,676, 60/248,677, 60/248,678, 60/248,673, 60/248,674, 60/248,672, 60/248, 784, 60/248,785, 60/248,786, 60/248,775, 60/248, 773, 60/248, 766, 60/248, 765,60/248, 833, 60/248,783, 60/248,781, 60/248, 780, 60/248, 778,60/248, 767, 60/248, 787,60/248, 774, 60/248,764, 60/248, 782, 60/248, 779,60/248, 685,60/248, 772, 60/248, 771,60/248, 777, 60/248,776, 60/248, 770, 60/248, 768, 60/248, 769, 60/248, 796, 60/248, 797,60/248, 795, 60/248,794, 60/248,663, 60/248,662, 60/248,660, 60/248, 659,60/248, 658,60/248, 656, 60/248, 654, 60/248,653, 60/248, 651, 60/248, 650,60/248, 648, 60/248, 647,60/248, 645, 60/248, 643, 60/248, 642, 60/248, 640,60/248, 637, 60/248, 636,60/248, 634, 60/248, 632, 60/248,631, 60/248, 630, 60/248, 629, 60/248, 627, 60/248, 625, 60/248, 763, 60/248, 761,

60/248, 759,60/248, 757, 60/248, 754,60/248, 753, 60/248, 749,60/248, 616, 60/248, 615, 60/248,614, 60/248, 613, 60/248, 612, 60/248, 605, 60/248, 610,60/248, 661,60/248, 657, 60/248,655, 60/248, 652,60/248, 649, 60/248, 646, 60/248, 644, 60/248, 641, 60/248 639, 60/248,638, 60/248,635, 60/248, 633, 60/248, 628, 60/248,626, 60/248, 624, 60/248, 762, 60/248,760, 60/248, 758,60/248, 755,60/248, 752, 60/248, 75. 1, 60/248,750, 60/248,742, 60/248,741, 60/248,740, 60/248,739, 60/248, 736, 60/248, 735,60/248, 734,60/248, 623, 60/248, 622, 60/248, 621, 60/248, 738, 60/248, 737,60/248, 620, 60/248,619, 60/248,618, 60/248, 617 FELD OF THE INVENTION (251) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to leuprolide acetate, as well as methods for protecting and administering leuprolide acetate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(252) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to levocarnitine, as well as methods for protecting and administering levocarnitine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(253) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to levocetirizine, as well as methods for protecting and administering levocetirizine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known

effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(254) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to levofloxacin, as well as methods for protecting and administering levofloxacin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(255) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to levothyroxine, as well as methods for protecting and administering levothyroxine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(256) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to lintuzumab, as well as methods for protecting and administering lintuzumab. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(257) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to lisinopril, as well as methods for protecting and administering lisinopril. This novel compound, referred to as a

CARRERWAVE Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(258) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to lisinopril and hydrochlorothiazide, as well as methods for protecting and administering lisinopril and hydrochlorothiazide.

This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(259) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to carbapenem antibiotic, as well as methods for protecting and administering carbapenem antibiotic. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(260) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to loperamide, as well as methods for protecting and administering loperamide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(261) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to loracarbef, as well as methods for

protecting and administering loracarbef. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(262) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to loratidine, as well as methods for protecting and administering loratidine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(263) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to lorazepam, as well as methods for protecting and administering lorazepam. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(264) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to losartan, as well as methods for protecting and administering losartan. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(265) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to losartan and hydrochlorothiazide, as well as methods for protecting and administering losartan and hydrochlorothiazide.

This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(266) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to lovastatin, as well as methods for protecting and administering lovastatin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(267) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to marimastat, as well as methods for protecting and administering marimastat. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(268) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mecasermin, as well as methods for protecting and administering mecasermin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the

usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(269) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to medroxyprogesterone acetate, as well as methods for protecting and administering medroxyprogesterone acetate. This novel compound, referred to as a CARRERNVAVE Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(270) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mefloquine, as well as methods for protecting and administering mefloquine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(271) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to megestrol acetate, as well as methods for protecting and administering megestrol acetate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(272) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to an adenosine Al receptor antagonist, as well as methods for protecting and administering an adenosine Al receptor antagonist. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that

is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(273) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mercaptopurine, as well as methods for protecting and administering mercaptopurine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(274) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to meropenem, as well as methods for protecting and administering meropenem. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(275) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mesalamine, as well as methods for protecting and administering mesalamine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(276) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mesna, as well as methods for protecting and administering mesna. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known

effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(277) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to metaxalone, as well as methods for protecting and administering metaxalone. This novel compound, referred to as a CARREERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(278) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to Metformin, as well as methods for protecting and administering Metformin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(279) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to an oral nonsteroidal antiestrogen compound, as well as methods for protecting and administering an oral nonsteroidal antiestrogen compound. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(280) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to methylphenidate, as well as methods for protecting and administering methylphenidate. This novel compound,

referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(281) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to methylprednisone (or one of its derivatives, such as methylprednisone acetate), as well as methods for protecting and administering methylprednisone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(282) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to an antifungal agent, as well as methods for protecting and administering an antifungal agent. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(283) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to metolazone, as well as methods for protecting and administering metolazone. This novel compound, referred to as a CARRERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(284) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to metoprolol, as well as methods for protecting and administering metoprolol. This novel compound, referred to as a CARRIlERWAVE Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(285) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a carbapenem antibiotic, as well as methods for protecting and administering a carbapenem antibiotic. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(286) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to metronidazole, as well as methods for protecting and administering metronidazole. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(287) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to milrinone lactate, as well as methods for protecting and administering milrinone lactate. This novel compound, referred to as a CARREERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound

that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(288) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to minocycline, as well as methods for protecting and administering minocycline. This novel compound, referred to as a CARRIIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(289) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mirtazapine, as well as methods for protecting and administering mirtazapine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(290) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to misoprostol, as well as methods for protecting and administering misoprostol. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(291) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mitiglinide, as well as methods for protecting and administering mitiglinide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of

the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(292) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mitoxantrone, as well as methods for protecting and administering mitoxantrone. This novel compound, referred to as a CARREERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(293) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mivacurium, as well as methods for protecting and administering mivacurium. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(294) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to modafinil, as well as methods for protecting and administering modafinil. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(295) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to moexipril, as well as methods for protecting and administering moexipril. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known

effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(296) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to montelukast, as well as methods for protecting and administering montelukast. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(297) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to morphine, as well as methods for protecting and administering morphine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(298) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to mycophenylate mofetil, as well as methods for protecting and administering mycophenylate mofetil. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(299) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nabumetone, as well as methods for protecting and administering nabumetone. This novel compound, referred to as a

CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(300) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nadolol, as well as methods for protecting and administering nadolol. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(301) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to naproxen, as well as methods for protecting and administering naproxen. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(302) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to naratriptan, as well as methods for protecting and administering naratriptan. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(303) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nefazodone, as well as methods for

protecting and administering nefazodone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(304) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nelarabine, as well as methods for protecting and administering nelarabine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(305) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nelfinavir mesylate, as well as methods for protecting and administering nelfinavir mesylate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(306) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nesiritide, as well as methods for protecting and administering nesiritide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(307) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nevirapine, as well as methods for protecting and administering nevirapine. This novel compound, referred to as a CARRERWAVET : Molecular Analogue (CMA), lias the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(308) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nifedipine, as well as methods for protecting and administering nifedipine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(309) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nimodipine, as well as methods for protecting and administering nimodipine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(310) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nisoldipine, as well as methods for protecting and administering nisoldipine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the

usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(311) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nitrofurantoin, as well as methods for protecting and administering nitrofurantoin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(312) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nitroglycerin, as well as methods for protecting and administering nitroglycerin. This novel compound, referred to as a CARRERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(313) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nizatidine, as well as methods for protecting and administering nizatidine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(314) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to norastemizole, as well as methods for protecting and administering norastemizole. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of

the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(315) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to norethindrone, as well as methods for protecting and administering norethindrone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(316) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to norfloxacin, as well as methods for protecting and administering norfloxacin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(317) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to nortriptyline, as well as methods for. protecting and administering nortriptyline. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(318) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to octreotide acetate, as well as methods for protecting and administering octreotide acetate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of

taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(319) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to oxycodone and acetaminophen, as well as methods for protecting and administering oxycodone and acetaminophen. This novel compound, referred to as a CARRIERWAVE"M Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(320) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ofloxacin, as well as methods for protecting and administering ofloxacin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(321) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached. to olanzapine, as well as methods for protecting and administering olanzapine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(322) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to omeprezole, as well as methods for protecting and administering omeprezole. This novel compound, referred to as a

CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(323) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ondansetron, as well as methods for protecting and administering ondansetron. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(324) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to oprelvekin, as well as methods for protecting and administering oprelvekin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(325) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to orlistat, as well as methods for protecting and administering orlistat. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(326) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to orphenadrine citrate, as well as

methods for protecting and administering orphenadrine citrate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(327) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to oxaprozin, as well as methods for protecting and administering oxaprozin. This novel compound, referred to as a CARREERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(328) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to oxazepam, as well as methods for protecting and administering oxazepam. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(329) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to Oxybutynin chloride, as well as methods for protecting and administering Oxybutynin chloride. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(330) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to oxycodone, as well as methods for protecting and administering oxycodone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(331) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a gastroprokinetic compound, as well as methods for protecting and administering a gastroprokinetic compound. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(332) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a macrophage colony stimulating factor, as well as methods for protecting and administering a macrophage colony stimulating factor. This novel compound, referred to as a CARRIIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(333) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pagoclone, as well as methods for protecting and administering pagoclone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the

usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(334) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to palivizumab, as well as methods for protecting and administering palivizumab. This novel compound, referred to as a CARRIERWAVE''' Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(335) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pamidronate, as well as methods for protecting and administering pamidronate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(336) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to paricalcitrol, as well as methods for protecting and administering paricalcitrol. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(337) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to paroxetine, as well as methods for protecting and administering paroxetine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of

the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(338) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pemetrexed, as well as methods for protecting and administering pemetrexed. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(339) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pemoline, as well as methods for protecting and administering pemoline. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(340) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to penicillin V, as well as methods for protecting and administering penicillin V. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(341) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pentosan polysulfate, as well as methods for protecting and administering pentosan polysulfate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of

taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(342) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pentoxifylline, as well as methods for protecting and administering pentoxifylline. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(343) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pergolide, as well as methods for protecting and administering pergolide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(344) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to an orally active carbohydrate, as well as methods for protecting and administering an orally active carbohydrate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(345) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to phenobarbital, as well as methods for protecting and administering phenobarbital. This novel compound, referred to as a

CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(346) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to phenytoin, as well as methods for protecting and administering phenytoin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(347) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pioglitazone, as well as methods for protecting and administering pioglitazone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(348) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to piperacillin, as well as methods for protecting and administering piperacillin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(349) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pleconaril, as well as methods for

protecting and administering pleconaril. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(350) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to poloxamer 188, as well as methods for protecting and administering poloxamer 188. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(351) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to posaconazole, as well as methods for protecting and administering posaconazole. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(352) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to an insulin analogue, as well as methods for protecting and administering an insulin analogue. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(353) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pramipexole, as well as methods for protecting and administering pramipexole. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances thr usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(354) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pravastatin, as well as methods for protecting and administering pravastatin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(355) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to prednisone, as well as methods for protecting and administering prednisone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(356) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pregabalin, as well as methods for protecting and administering pregabalin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the

usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(357) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to primidone, as well as methods for protecting and administering primidone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(358) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to prinomastat, as well as methods for protecting and administering prinomastat. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(359) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to prochlorperazine maleate, as well as methods for protecting and administering prochlorperazine maleate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(360) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to promethazine, as well as methods for protecting and administering promethazine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of

the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(361) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a cholecystokinin antagonist, as well as methods for protecting and administering a cholecystokinin antagonist. This novel compound, referred to as a CARRERWAVE Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(362) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to propoxyphene, as well as to propoxyphene alone, as well as methods for protecting and administering propoxyphene.

This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(363) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to propranolol, as well as methods for protecting and administering propranolol. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(364) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to prourokinase, as well as methods for protecting and administering prourokinase. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known

effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(365) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to quetiapine fumarate, as well as methods for protecting and administering quetiapine fumarate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(366) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to quinapril, as well as methods for protecting and administering quinapril. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(367) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to rabeprazole, as well as methods for protecting and administering rabeprazole. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(368) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to raloxifene, as well as methods for protecting and administering raloxifene. This novel compound, referred to as a

CARRIERWAVET Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(369) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ramipril, as well as methods for protecting and administering ramipril. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(370) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ranitidine, as well as methods for protecting and administering ranitidine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(371) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ranolazine, as well as methods for protecting and administering ranolazine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(372) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to relaxin, as well as methods for

protecting and administering relaxin. This novel compound, referred to as a CARREERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(373) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to remacemide, as well as methods for protecting and administering remacemide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(374) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to repaglinide, as well as methods for protecting and administering repaglinide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(375) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to repinotan, as well as methods for protecting and administering repinotan. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(376) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ribavirin, as well as methods for protecting and administering ribavirin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(377) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to riluzole, as well as methods for protecting and administering riluzole. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(378) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to rimantadine, as well as methods for protecting and administering rimantadine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(379) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to risperidone, as well as methods for protecting and administering risperidone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the

usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(380) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ritonavir, as well as methods for protecting and administering ritonavir. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(381) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to rizatriptan benzoate, as well as methods for protecting and administering rizatriptan benzoate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(382) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to rocuronium, as well as methods for protecting and administering rocuronium. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(383) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to rofecoxib, as well as methods for protecting and administering rofecoxib. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of

the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(384) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ropinirole, as well as methods for protecting and administering ropinirole. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(385) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to rosiglitazone maleate, as well as methods for protecting and administering rosiglitazone maleate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(386) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to goserelin, as well as methods for protecting and administering goserelin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(387) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to rubitecan, as well as methods for protecting and administering rubitecan. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known

effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(388) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sagramostim, as well as methods for protecting and administering sagramostim. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(389) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to saquinavir, as well as methods for protecting and administering saquinavir. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(390) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to docetaxel, as well as methods for protecting and administering docetaxel. This novel compound, referred to as a CARRIERWAVET Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(391) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to satraplatin, as well as methods for protecting and administering satraplatin. This novel compound, referred to as a

CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(392) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to selegiline, as well as methods for protecting and administering selegiline. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(393) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sertraline, as well as methods for protecting and administering sertraline. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(394) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sevelamer, as well as methods for protecting and administering sevelamer. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(395) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sevirumab, as well as methods for

protecting and administering sevirumab. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(396) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sibutramine, as well as methods for protecting and administering sibutramine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(397) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sildenafil citrate, as well as methods for protecting and administering sildenafil citrate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(398) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to simvastatin, as well as methods for protecting and administering simvastatin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(399) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sinapultide, as well as methods for protecting and administering sinapultide. This novel compound, referred to as a CARRERWAVE Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(400) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sitafloxacin, as well as methods for protecting and administering sitafloxacin. This novel compound, referred to as a CARRIERWAVET Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(401) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to polystyrene sulfonate, as well as methods for protecting and administering polystyrene sulfonate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(402) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sotalol, as well as methods for protecting and administering sotalol. This novel compound, referred to as a CARRERWAVE Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the

usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(403) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sparfosic acid, as well as methods for protecting and administering sparfosic acid. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(404) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to spironolactone, as well as methods for protecting and administering spironolactone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(405) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to stavudine, as well as methods for protecting and administering stavudine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(406) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sucralfate, as well as methods for protecting and administering sucralfate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of

the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(407) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to sumatriptan, as well as methods for protecting and administering sumatriptan. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(408) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tabimorelin, as well as methods for protecting and administering tabimorelin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(409) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to Tamoxifen, as well as methods for protecting and administering Tamoxifen. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(410) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tamsulosin, as well as methods for protecting and administering tamsulosin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known

effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(411) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to temazepam, as well as methods for protecting and administering temazepam. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(412) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tenofovir disoproxil, as well as methods for protecting and administering tenofovir disoproxil. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(413) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tepoxalin, as well as methods for protecting and administering tepoxalin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(414) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to terazosin, as well as methods for protecting and administering terazosin. This novel compound, referred to as a

CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(415) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to terbinafine, as well as methods for protecting and administering terbinafine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(416) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to terbutaline sulfate, as well as methods for protecting and administering terbutaline sulfate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(417) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to teriparatide, as well as methods for protecting and administering teriparatide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(418) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tetracycline, as well as methods for

protecting and administering tetracycline. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(419) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to thalidomide, as well as methods for protecting and administering thalidomide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(420) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to theophylline, as well as methods for protecting and administering theophylline. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(421) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to thiotepa, as well as methods for protecting and administering thiotepa. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(422) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to thrombopoetin, as well as methods for protecting and administering thrombopoetin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(423) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tiagabine, as well as methods for protecting and administering tiagabine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(424) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ticlopidine, as well as methods for protecting and administering ticlopidine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(425) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tifacogin, as well as methods for protecting and administering tifacogin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the

usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(426) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tirapazamine, as well as methods for protecting and administering tirapazamine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(427) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tirofiban, as well as methods for protecting and administering tirofiban. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(428) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tizanidine, as well as methods for protecting and administering tizanidine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(429) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tobramycin sulfate, as well as methods for protecting and administering tobramycin sulfate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a

known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(430) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tolterodine, as well as methods for protecting and administering tolterodine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(431) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tomoxetine, as well as methods for protecting and administering tomoxetine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(432) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to topiramate, as well as methods for protecting and administering topiramate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(433) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to topotecan, as well as methods for protecting and administering topotecan. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known

effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(434) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to toresemide, as well as methods for protecting and administering toresemide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(435) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to TPA ANALOGUE, as well as methods for protecting and administering TPA ANALOGUE. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(436) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to tramadol, as well as methods for protecting and administering tramadol. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(437) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to trandolapril, as well as methods for protecting and administering trandolapril. This novel compound, referred to as a

CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(438) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to trastuzumab, as well as methods for protecting and administering trastuzumab. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(439) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to trazadone, as well as methods for protecting and administering trazadone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness (440) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to triamterene, as well as methods for protecting and administering triamterene. This novel compound, referred to as a CARREERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(441) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to troglitazone, as well as methods for

protecting and administering troglitazone. This novel compound, referred to as a CARRERWAVE Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(442) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to trovafloxacin mesylate, as well as methods for protecting and administering trovafloxacin mesylate. This novel compound, referred to as a CARREERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(443) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to urokinase, as well as methods for protecting and administering urokinase. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(444) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ursodiol, as well as methods for protecting and administering ursodiol. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(445) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to valacyclovir, as well as methods for protecting and administering valacyclovir. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(446) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to valdecoxib, as well as methods for protecting and administering valdecoxib. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(447) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to valproic acid, as well as methods for protecting and administering valproic acid. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(448) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to valsartan and hydrochlorothiazide (or valsartan alone), as well as methods for protecting and administering valsartan and hydrochlorothiazide. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical

market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(449) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to valspodar, as well as methods for protecting and administering valspodar. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(450) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to vancomycin, as well as methods for protecting and administering vancomycin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(451) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to vecuronium, as well as methods for protecting and administering vecuronium. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(452) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to venlafaxine, as well as methods for protecting and administering venlafaxine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of

the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(453) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to verapamil, as well as methods for protecting and administering verapamil. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(454) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to vinorelbine tartrate, as well as methods for protecting and administering vinorelbine tartrate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(455) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to vitamin B12, as well as methods for protecting and administering vitamin B 12. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(456) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to vitamin C, as well as methods for protecting and administering vitamin C. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known

effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(457) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to voriconazole, as well as methods for protecting and administering voriconazole. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(458) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to warfarin, as well as methods for protecting and administering warfarin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(459) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to xaliproden, as well as methods for protecting and administering xaliproden. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(460) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to zafirlukast, as well as methods for protecting and administering zafirlukast. This novel compound, referred to as a

CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(461) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to zaleplon, as well as methods for protecting and administering zaleplon. This novel compound, referred to as a CARRERWAVE Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(462) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to zenarestat, as well as methods for protecting and administering zenarestat. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(463) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to zidovudine, as well as methods for protecting and administering zidovudine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(464) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to zolmitriptan, as well as methods

for protecting and administering zolmitriptan. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(465) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to zolpidem, as well as methods for protecting and administering zolpidem. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(466) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to bleomycin, as well as methods for protecting and administering bleomycin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(467) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to phytoseterol, as well as methods for protecting and administering phytoseterol. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(468) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to paclitaxel, as well as methods for protecting and administering paclitaxel. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(469) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to fluticasone, as well as methods for protecting and administering fluticasone. This novel compound, referred to as a CARRERWAVE Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(470) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to flurouracil, as well as methods for protecting and administering flurouracil. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(471) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pseudoephedrine, as well as methods for protecting and administering pseudoephedrine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound

that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness..

(472) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a lipoxygenase inhibitor, as well as methods for protecting and administering a lipoxygenase inhibitor. This novel compound, referred to as a CARREERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(473) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a composite vascular protectant, as well as methods for protecting and administering a composite vascular protectant. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(474) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to an oral neuraminidase inhibitor, as well as methods for protecting and administering an oral neuraminidase inhibitor. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound, that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(475) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to the soluble chimeric protein CTLA4Ig, as well as methods for protecting and administering the soluble chimeric protein CTLA4Ig. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical

agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(476) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a selective endothelin A receptor antagonist, as well as methods for protecting and administering a selective endothelin A receptor antagonist. This novel compound, referred to as a CARRERWAVErM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(477) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a potassium channel modulator, as well as methods for protecting and administering a potassium channel modulator. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(478) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a bactericidal/permeability increasing protein derivative, as well as methods for protecting and administering a bactericidal/permeability increasing protein derivative. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(479) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to humanized monoclonal antibody, hu 1124, directed against CD1 la, as well as methods for protecting and administering

humanized monoclonal antibody, hu 1124, directed against CD1 la. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(480) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a lipid lowering agent, as well as methods for protecting and administering a lipid lowering agent. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(481) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to propofol, as well as methods for protecting and administering propofol. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(482) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a Cholesterol/Triglyceride Reducer, as well as methods for protecting and administering a Cholesterol/Triglyceride Reducer. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(483) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to a recombinant hepatitis B vaccine, as well as methods for protecting and administering a recombinant hepatitis B vaccine.

This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(484) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to an angiotensin II antagonist, as well as methods for protecting and administering an angiotensin lI antagonist. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(485) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to an immunosuppressant protein, as well as methods for protecting and administering an immunosuppr. essant protein. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(486) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to the components of a daily multivitamin, as well as methods for protecting and administering daily multivitamin.

This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a

carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(487) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to erythromycin and sulfx, as well as methods for protecting and administering erythromycin and sulfx. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(488) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ethinyl estradiol and dogestrel, as well as methods for protecting and administering ethinyl estradiol and dogestrel. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(489) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to lithium carbonate, as well as methods for protecting and administering lithium carbonate. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(490) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to LYM 1, as well as methods for protecting and administering LYM 1. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of

the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(491) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to methylprednisolone, as well as methods for protecting and administering methylprednisolone. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(492) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to rotavirus vaccine, as well as methods for protecting and administering rotavirus vaccine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(493) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to saquinavir, as well as methods for protecting and administering saquinavir. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(494) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to arginine, as well as methods for protecting and administering arginine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known

effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(495) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to heparin, as well as methods for protecting and administering heparin. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(496) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to thymosin alpha, as well as methods for protecting and administering thymosin alpha. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(497) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to montelukast and fexofenadine, as well as methods for protecting and administering montelukast and fexofenadine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(498) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to iodothyronine, as well as methods for protecting and administering iodothyronine. This novel compound, referred to as a

CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(499) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to iodothyronine and thyroxine, as well as methods for protecting and administering iodothyronine and thyroxine. This. novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

(500) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to codeine, as well as methods for protecting and administering codeine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

BACKGROUND OF THE INVENTION (251) Leuprolide acetate is a known pharmaceutical agent that is used in the treatment of cancer and endometriosis. Its chemical name is 6-D-leucine-9- (N-ethyl-L- prolinamide)-10-deglycinamide luteinizing hormone-releasing factor (swine). Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to. particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(252) Levocarnitine is a known pharmaceutical agent that is used in the treatment of cardiovascular disease and septic shock. Its chemical name is (R)-3- carboxy-2-hydroxy-N, N, N-trimethyl-l-propanaminiurn hydroxide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples. of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(253) Levocetirizine is a known pharmaceutical agent that is used in the treatment of rhinitis. Its chemical name is [2- [4- [ (R)- (4-chlorophenyl) phenylmethyl]-1- piperazinyl] ethoxy] acetic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In-addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(254) Levofloxacin is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is (S)-9-fluoro-2, 3-dihydro-3-methyl-10- (4- methyl-1-piperazinyl)-7-oxo-7H-pyrido [1, 2, 3-de]-1, 4-benzoxazine-6-carboxylic acid.

Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered

product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several

shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly

or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(255) Levothyroxine is a known pharmaceutical agent that is used in the treatment of hypothyroidism. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of

cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the

gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(256) Lintuzumab is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is immunoglobulin G1 (human-mouse monoclonal HuM195. gamma. 1-chain anti-human antigen CD 33), disulfide with human monoclonal HuM195. kappa. -chain, dimer.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(257) Lisinopril is a known pharmaceutical agent that is used in the treatment of hypertension, heart failure, myocardial infarction, retinopathy, diabetes and kidney disease. Its chemical name is (S)-l-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-prolin.

Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(258) Lisinopril and hydrochlorothiazide are used together in the treatment of hypertension. Lisonopril's chemical name is (S)-l- [N2- (l-carboxy-3-phenylpropyl)-L- lysyl]-L-prolin. Its structure is: The structure of hydrochlorothiazide is

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example,

copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the

active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(259) The carbapenem antibiotic of the present invention is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is [4R- [3 (R*), 4alpha, 5beta, 6beta (R*)]]-6- (l-hydroxyethyl)-4-methyl-7-oxo-3- [ (5- oxo-3-pyrrolidinyl) thio]-1-azabicyclo [3.2. 0] hept-2-ene-2-carboxylic acid (2,2-dimethyl- l-oxopropoxy) methyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(260) Loperamide is a known pharmaceutical agent that is used in the treatment of diarrhea and ophthalmic pain. Its chemical name is 4- (4-chlorophenyi)-4-hydroxy- N, N-dimethyl-alpha, alpha-diphenyl-l-piperidinebutanamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and,, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(261) Loracarbef is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is 7-[(aminophenylacetyl) amino]-3-chloro-8- oxo-l-azabicyclo- [4, 2, 0] oct-2- ene-2-carboxylic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound ; alteration of the release profile of an orally administered

product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several

shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly

or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(262) Loratidine is a known pharmaceutical agent that is used in the treatment of allergy and rhinitis. Its chemical name is ethyl 4-(8-chloro-5, 6-dihydro-l lH- benzo [5,6] cyclohepta [1, 2-b] pyridin-11-ylidene-1-piperidinecarboxylate. Its structure is : The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active

agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(263) Lorazepam is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(264) Losartan is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is 2-butyl-4-chloro-1-[[2'-(lH-tetrazol-5-yl) [l, 1'- biphenyl] -4-yl] methyl]-lH-imidazole-5-methanol. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(265) Losartan and hydrochlorothiazide are used together in the treatment of hypertension. Losartan's chemical name is 2-butyl-4-chloro-1-[[2'-(lH-tetrazol-5- yl) [1, 1'-biphenyl]-4-yl] methyl]-lH-imidazole-5-methanol. Its structure is: The chemical structure of hydrochlorothiazide is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active

agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(266) Lovastatin is a known pharmaceutical agent that is used in the treatment of hyperlipidemia and cancer. Its chemical name is (S) -2-methylbutyric acid, 8-ester with (4R, 6R)-6- [2- [ (lS, 2S, 6R, 8S, 8aR)-1, 2,6, 7,8, 8a-hexahydro-8-hydroxy-2, 6-dimethyl-1- naphthyl] ethyl] tetrahydro-4-hydroxy-2H-pyran-2-one. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(267) Marimastat is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is (2S, 3R)-N4-[(lR)-2, 2-dimethyl-1- [(methylamino) carbonyl] propyl]-N 1"2-dihydroxy-3-(2-methylpropyl) butanediamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(268) Mecasermin is a known pharmaceutical agent that is used in the treatment of hormone disorders, amyotrophic lateral sclerosis, neuropathy, kidney disease and osteoarthritis. Its chemical name is insulin-like growth factor I (human).

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and

aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology

combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(269) Medroxyprogesterone acetate is used orally to reduce the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in postmenopausal women receiving estrogen replacement therapy. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(270) Mefloquine is a known pharmaceutical agent that is used in the treatment and prevention of malaria. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(271) Megestrol acetate is used in the palliative management of recurrent, inoperable, or metastatic endometrial carcinoma or breast cancer. The drug is also used as an adjunct to surgery or radiation. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(272) The adenosine Al receptor antagonist of the present invention is a known pharmaceutical agent that is used in the treatment of hypertension and heart failure. Its chemical name is 3, 7-dihydro-8- (3-oxatricyclo [3.2. 1.0 2,4] oct-6-yl)-1, 3-dipropyl-lH- purine-2,6-dione. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type;

and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the

microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in

the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(273) Mercaptopurine is a known pharmaceutical agent that is used in the treatment of leukemia Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(274) Meropenem is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is (4R, 5S, 6S)-3- [ [ (3S, 5S)-5- [(dimethylamino) carbonyl]-3-pyrrolidinyl] thio]-6-[(lR)-1-hydroxyethyl)-4-methyl-7- oxo-1-azabicyclo [3.2. 0] hept-2-ene-2-carboxylic acid. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(275) Mesalamine is a known pharmaceutical agent that is used in the treatment of inflammatory bowel disease. Its chemical name is 5-amino-2-hydroxybenzoic acid.

Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(276) Mesna is used prophylactically as a uroprotective agent to decrease the incidence of hemorrhagic cystitis in patients receiving ifosfamide. Its structure is: HS-CH-CH-SO The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human

growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide

linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(277) Metaxalone is a known pharmaceutical agent that is used in the treatment of skeletal muscular spasm. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another

invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(278) Metformin is a known pharmaceutical agent that is used in the treatment of diabetes. Its chemical name is N, N-dimethylimidodicarbonimidic diamide. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human

growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide

linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-iinked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(279) The oral nonsteroidal antiestrogen compound of the present invention is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is 2, 2-dimethylpropanoic acid (S)-4- [7- (2, 2-dimethyl-1-oxopropoxy)-4-methyl-2- [4- [2- (1- piperidinyl) ethoxy] phenyl]-2H-l-benzopyran-3-yl] phenyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken

under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(280) Methylphenidate is a known pharmaceutical agent that is used in the treatment of attention deficit disorder. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(281) Methylprednisolone and its derivatives are used principally as anti- inflammatory or immunosuppressant agents. Because methylprednisolone has only minimal mineralocorticoid properties, the drug is inadequate alone for the management of adrenocortical insufficiency. If methylprednisolone is used in the treatment of this condition, concomitant therapy with a mineralocorticoid is also required. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability

of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(282) The antifungal agent of the present invention is a known pharmaceutical agent that is used in the treatment of fungal infections. Its chemical name is 4,5- <BR> <BR> <BR> <BR> dihydroxy-N2- [4- [5- [4- (pentyloxy) phenyl] -3-isoxazolyl] benzoyl] ornithylthreonyl-4-<BR> <BR> <BR> <BR> <BR> <BR> hydroxyprolyl-4-hydroxy-4- [4-hydroxy-3- (sulfooxy) phenyl] threonyl-3- hydroxyglutaminyl-3-hydroxy-4-methylproline cyclic (6-l)-peptide monosodium salt.

Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type;. and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(283) Metolazone is a known pharmaceutical agent that is used in the treatment of edema and hypertension. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(284) Metoprolol is a known pharmaceutical agent that is used in the treatment of angina and hypertension. It is disclosed in U. S. Patent Numbers 4957745 and 5001161, incorporated herein by reference. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release tne active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(285) The carbapenem antibiotic of the present invention is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is [4R- [3 (3S*, 5S*), 4alpha, 5beta, 6beta (R*)]]-3- [ [5- [ [ (3- carboxyphenyl) amino] carbonyl]-3-pyrrolidinyl] thio]-6-(l-hydroxyethyl)-4-methyl-7- oxo-l-azabicyclo [3.2. 0] hept-2-ene-2-carboxylic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of

cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the

gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(286) Metronidazole is used orally in the treatment of symptomatic and asymptomatic trichomoniasis. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(287) Milrinone lactate is a known pharmaceutical agent that is used in the treatment of heart failure. Its chemical name is 1, 6-dihydro-2-methyl-6-oxo- [3, 4'- bipyridine]-5-carbonitrile. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(288) Minocycline is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is 4,7-bis (dimethylamino)-1, 4,4a, 5, 5a, 6, 11, 12a- octahydro-3,10, 12, 12a tetrahydroxy-1, 11-dioxo-2-naphthacenecarboxamide. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(289) Mirtazapine is a known pharmaceutical agent that is used in the treatment of depression. Its chemical name is 1, 2,3, 4,10, 14b-hexahydro-2-methylpyrazino [2, 1- a] pyrido [2,3-c] [2] benzazepine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(290) Misoprostol is a known pharmaceutical agent that is used in the treatment of gastrointestinal ulcer, allergy and labor induction. Its chemical name is (11 alpha, 13E) - (+,-)-11, 16-dihydroxy-16-methyl-9-oxoprost-13-en-1-oic acid methyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent' in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(291) Mitiglinide is a known pharmaceutical agent that is used in the treatment of diabetes. Its chemical name is [2 (S)-cis]-octahydro-gamma-oxo-alpha- (phenylmethyl)-2H-isoindole-2-butanoic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered

product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique., Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several

shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly

or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(292) Mitoxantrone is a known pharmaceutical agent that is used in the treatment of cancer and multiple sclerosis. Its chemical name is 1, 4-dihydroxy-5,8- bis [ [2- [ (2-hydroxyethyl) amino] ethyl] amino]-9, 10-anthracenedione. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product ; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another

invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(293) Mivacurium is a known pharmaceutical agent that is used as a neurolomuscular blocker and muscle relaxant. Its chemical name is [R- [R*, R*- (E)]]- 2, 2'- [ (1, 8-dioxo-4-octene-1, 8-diyl) bis (oxy-3, 1-propanediyl)] bis [ 1, 2,3, 4-tetrahydro-6,7- dimethoxy-2-methyl-l- [ (3, 4,5-trimethoxyphenyl) methyl] -isoquinolinium chloride. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(294) Modafinil is a known pharmaceutical agent that is used in the treatment of neurologic depression. Its chemical name is 2-[(diphenylmethyl) sulfinyl] acetamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(295) Moexipril is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is [3S- [2 [R* (R*), 3R*]]-2-[2-[[1-(ethoxycarbonyl)-3- phenylpropyl] amino]-1-oxopropyl]-1, 2,3, 4-tetrahydro-6,7-dimethoxy-3- isoquinolinecarboxylic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(296) Montelukast is a known pharmaceutical agent that is used in the treatment of asthma. Its chemical name is [R- (E)]- 1- [ [ [l- [3- [2- (7-chloro-2- quinolinyl) ethenyl] phenyl]-3- [2- ( 1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl]- cyclopropaneacetic acid. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(297) Morphine is a known pharmaceutical agent that is used in the treatment of pain. Its structure is : The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(298) Mycophenylate mofetil is a known pharmaceutical agent that is used in the treatment of transplant rejection, rheumatoid arthritis, asthma restenosis, kidney disease, systemic lupus and erythematosus. Its chemical name is (4E)-6- (1, 3-dihydro-4-hydroxy- 6-methoxy-7-methyl-3-oxo-5-isobenzofuran yl) -4-methyl-4-hexenoic acid 2- (4- morpholinyl) ethyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

. (299) Nabumetone is a known pharmaceutical agent that is used in the treatment of pain and inflamation. Its chemical name is 4- (6-methoxy-2-naphthyl)-2-butanone. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound ; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(300) Nadolol is a known pharmaceutical agent that is used in the treatment of hypertension and angina. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(301) Naproxen is a known pharmaceutical agent that is used in the treatment of pain and arthritis. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(302) Naratriptan is a known pharmaceutical agent that is used in the treatment of migraine. Its chemical name is N-methyl-3- (l-methyl-4-piperidinyl)-lH-indole-5- ethanesulfonamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of

cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the

gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(303) Nefazodone is a known pharmaceutical agent that is used in the treatment of depression. Its chemical name is 2- [3- [4- (3-chlorophenyl)-l-piperazinyl] propyl]-5- ethyl-2, 4-dihydro-4- ( 2-phenoxyethyl)-3H-1, 2,4-triazol-3-one. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(304) Nelarabine is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is 9-beta-D-arabinofuranosyl-6-methoxy-9H-purin-2- amine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(305) Nelfinavir mesylate is a known pharmaceutical agent that is used in the treatment of HIV infection. Its chemical name is [3S- [2 (2S*, 3S*), 3alfa, 4abeta, 8abeta]]- <BR> <BR> <BR> N-(1, 1-dimethylethyl) decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino]- 4- (phenylthio) butyl]-3-isoquinolinecarboxamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular rr.--ibranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(306) Nesiritide is a known pharmaceutical agent that is used in the treatment of hypertension and heart failure. Its chemical name is brain natriuretic peptide-32, a natural product.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(307) Nevirapine is a known pharmaceutical agent that is used in the treatment of HIV infection. Its chemical name is 11-cyclopropyl-5, 11-dihydro-4-methyl-6H- dipyrido [3,2-b : 2', 3'-e] [1, 4] diazepin-6-one. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(308) Nifedipine is a known pharmaceutical agent that is used in the treatment of hypertension and angina. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of, the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely. on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of. the intestines is limited to less than 5 microns.

(309) Nimodipine is a known pharmaceutical agent that is used in the treatment of migraine, cognitive defect, Alzheimer disease and brain ischemia. Its chemical name is 1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl)-3, 5-pyridinedicarboxylic acid 2- methoxyethyl 1-methylethyl ester. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(310) Nisoldipine is a known pharmaceutical agent that is used in the treatment of angina and hypertension. Its chemical name is 1,4-dihydro-2, 6-dimethyl-4- (2- nitrophenyl) -3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another

invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme. degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(311) Nitrofurantoin is a known pharmaceutical agent that is used in the treatment of urinary tract infection. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(312) Nitroglycerin is a known pharmaceutical agent that is used in the treatment of angina. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(313) Nizatidine is a known pharmaceutical agent that is used in the treatment of gastrointestinal ulcer. Its chemical name is N- [2- [ [ [2- [ (dimethylamino) methyl] -4- thiazolyl] methyl] thio] ethyl]-N'-methyl-2-nitro-1, 1-ethenediamine. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(314) Norastemizole is a known pharmaceutical agent that is used in the treatment of allergy. Its chemical name is 1- [ (4-fluorophenyl) methyl] -N-4-piperidinyl- lH-benzimidazol-2-amine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn,-was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(315) Norethindrone acetate is used for the treatment of secondary amenorrhea and for the treatment of abnormal uterine bleeding caused by hormonal imbalance in patients without underlying organic pathology such as fibroids or uterine cancer. The drug also is used for the treatment of endometriosis. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of

cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the

gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(316) Norfloxacin is a known pharmaceutical agent that is used in the treatment of gonnorhea and urinary tract infections. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability

of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(317) Nortriptyline is a known pharmaceutical agent that is used in the treatment of depression. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(318) Octreotide acetate is a known pharmaceutical agent that is used in the treatment of Alzheimer disease, cancer, viral infection, psoriasis, diarrhea, diabetes, pain and acromegaly. Its chemical name is [R- (R*, R*) ]-D-phenylalanyl-L-cysteinyl-L- phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1- (hydroxymethyl) propyl]- L-cysteinamide cyclic (2-7) -disulfide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(319) Oxycodone and acetaminophen are used together in the treatment of pain.

The chemical name of acetaminophen is N-acetyl-p-aminophenol. The structure of oxycodone is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(320) Ofloxacin is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is 9-fluoro-2, 3-dihydro-3-methyl-10- (4-methyl-l- piperazinyl) -7-oxo-7H-pyrido [1, 2, 3-de]-1, 4-benzoxazine-6-carboxylic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can . also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(321) Olanzapine is a known pharmaceutical agent that is used in the treatment of schizophrenia and psychosis. Its chemical name is 2-methyl-4- (4-methyl-l- piperazinyl)-10H-thieno [2,3-b] [1, 5] benzodiazepine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of

cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the

gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(322) Omeprezole is a known pharmaceutical agent that is used in the treatment of gastrointestinal ulcer and bacterial infection. Its chemical name is 5-methoxy-2- [ [ (4- methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl]-lH-benzimidazole. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type;

and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the

microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in

the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(323) Ondansetron is a known pharmaceutical agent that is used in the treatment of emesis, cognitive defect and eating disorder. Its chemical name is 1,2, 3,9-tetrahydro- 9-methyl-3-[(2-methyl-1 H-imidazol-l-yl) methyl]-4H-carbazol-4-one. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of

cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the

gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(324) Oprelvekin is a known pharmaceutical agent that is used in the treatment of cancer, HIV infection, mucositis and Crohn disease. It is a recombinant interleukin- 11.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(325) Orlistat is a known pharmaceutical agent that is used in the treatment of obesity, diabetes and hyperlipidemia. Its chemical name is N-formyl-L-leucine [2S- [2alpha (R*), 3beta]]-1-[(3-hexyl-4-oxo-2-oxetanyl) methyl] dodecyl ester. Its structure is : The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(326) Orphenadrine citrate is a known pharmaceutical agent that is used in the treatment of skeletal muscle spasm. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(327) Oxaprozin is a known pharmaceutical agent that is used in the treatment of inflammation. Its chemical name is 4,5-diphenyl-2-oxazolepropanoic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are. often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(328) Oxazepam is a known pharmaceutical agent that is used in the treatment of anxiety. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more. of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid-bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(329) Oxybutynin chloride is used as an antispasmodic in patients with uninhibited neurogenic or reflex neurogenic bladder for the relief of symptoms associated with voiding, such as urgency, urge incontinence, frequency, nocturia, and incontinence.

Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another

invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(330) Oxycodone is a known pharmaceutical agent that is used in the treatment of pain. The structure of oxycodone is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(331) The gastroprokinetic compound of the present invention is a known pharmaceutical agent that is used in the treatment of gastrointestinal motility disease. Its chemical name is 8,9-didehydro-N-demethyl-9-deoxo-6, 11-dideoxy-6, 9-epoxy-12-O- methyl-N-(l-methylethyl)-ll-oxoerythromycin (E) -2-butenedioate (2: 1). Its structure is :

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following : another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(332) The macrophage colony stimulating factor of the present invention is a known pharmaceutical agent that is used in the treatment of mycosis, hyperlipidemia, wounds, and bacterial infection. It is a human clone pcCSF-17 precursor protein that is the subject of European Patent EP 20960. 1 B (1993), which is based on US Patent Application Number 698359 (1985), which is hereby incorporated by reference.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties. to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active

agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(333) Pagoclone is a known pharmaceutical agent that is used in the treatment of anxiety and panic disorder. Its chemical name is (+)-2- (7-chloro-1, 8-naphthyridin-2-yl) - 2, 3-dihydro-3- (5-methyl-2-oxohexyl)-1H-isoindol-1-one. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example,

copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the

active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(334) Palivizumab, a monoclonal antibody, is a known pharmaceutical agent that is used in the treatment of respiratory disease and viral infection. Its chemical name is immunoglobulin G1, anti- (respiratory syncytial virus protein F) (human-mouse monoclonal MEDI-493 gamma 1-chain), disulfide with human-mouse monoclonal MEDI-493 kappa-chain, dimmer. It is the subject of US Patent Number 5585089, which is incorporated herein by reference.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another

invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(335) Pamidronate is a known pharmaceutical agent that is used in the treatment of osteoporosis and cancer. Its chemical name is (3-amino-1-hydroxypropylidene) bisphosphonic acid. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example,

copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be. attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the

active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(336) Paricalcitrol is a known pharmaceutical agent that is used in the treatment of hyperparathyroidism. Its chemical name is (lalpha, 3beta, 7E, 22E) -19-nor-9, 10- secoergosta-5,7, 22-triene-1, 3,25-triol. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken

under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(337) Paroxetine is a known pharmaceutical agent that is used in the treatment of depression, obsessive compulsive disorder, anxiety and panic disorder. Its chemical name is (3S, 4R)-3- [ (1, 3-benzodioxol-5-yloxy) methyl]-4- (4-fluorophenyl) piperidine hydrochloride. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone : A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(338) Pemetrexed is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-lH-pyrrolo [2,3- d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(339) Pemoline is a known pharmaceutical agent that is used in the treatment of attention deficit hyperactivity disorder. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of. the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(340) Penicillin V is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type;

and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the

microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid ; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in

the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(341) Pentosan polysulfate is a known pharmaceutical agent that is used in the treatment of arthritis, angina, hyperlipidemia, rheumatoid arthritis, cancer and cystitis. Its chemical name is (1-4)-beta-D-xylan 2,3-bis (hydrogen sulfate). Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, . unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(342) Pentoxifylline is a known pharmaceutical agent that is used in the treatment of peripheral vascular disease, stroke, atherosclerosis, and rheumatoid arthritis.

Its. chemical name is 3, 7-dimethyl-l- (5-oxo-hexyl) xanthine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered . product ; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(343) Pergolide is a known pharmaceutical agent that is used in the treatment of Parkinson disease and depression. Its chemical name is (8beta)-8-[(methylthio) methyl] - 6-propylergoline. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of

cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the

gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(344) The orally active carbohydrate of the present invention is a known pharmaceutical agent that is used in the treatment of gastrointestinal ulcer. It is a natural product isolated from human breast milk, as disclosed in U. S. Patent Number 5514660, which is incorporated herein by reference.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following : another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(345) Phenobarbital is a known pharmaceutical agent that is used in the treatment of anxiety, epilepsy and insomnia. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active

agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalent attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(346) Phenytoin is a known pharmaceutical agent that is used in the treatment of epilepsy. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(347) Pioglitazone is a known pharmaceutical agent that is used in the treatment of diabetes. Its chemical name is 5- [ [4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl] methy]-2, 4- thiazolidinedione. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(348) Piperacillin is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its structure is :-----

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the-active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active . agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large'oowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(349) Pleconaril is a known pharmaceutical agent that is used in the treatment of viral infection. Its chemical name is 3- [3, 5-dimethyl-4- [3- (3-methyl-5- isoxazolyl) propoxy] phenyl]-5- (trifluoromethyl)-1, 2,4-oxadiazole. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered

product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several

shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested. slowly

or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(350) Poloxamer 188 is a known pharmaceutical agent that is used in the treatment of thrombosis, sickle cell anemia, and respiratory distress syndrome. Its chemical name is methyloxirane, block polymer with oxirane.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(351) Posaconazole is a known pharmaceutical agent that is used in the treatment of mycosis. Its chemical name is 2, 5-anhydro-1, 3, 4-trideoxy-2-C- (2, 4- difluorophenyl) -4- [ [4- [4- [4- [ 1- [ ( 1 S, 2S)-1-ethyl-2-hydroxypropyl]-1, 5-dihydro-5-oxo-4H- 1,2, 4-triazol-4-yl] phenyl]-1-piperazinyl] phenoxy] methyl]-1- (1 H-1, 2, 4-triazol-1-yl)-D- threo-pentitol. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(352) The insulin analogue of the present invention is a known pharmaceutical agent that is used in the treatment of diabetes. Its chemical name is Human 29B-[N6-(1- oxotetradecyl)-L-lysine]- (1 A-21 A), ( lB-29B)-Insulin.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrelytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(353) Pramipexole is a known pharmaceutical agent that is used in the treatment of Parkinson disease and depression. Its chemical name is (S)-2-amino-4, 5,6, 7- tetrahydro-6- (propylamino)-benzothiazole. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered

product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several

shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly

or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(354) Pravastatin is a known pharmaceutical agent that is used in the treatment of hyperlipidemia and myocardial infarction. Its chemical name is [1S- [lalfa (betaS*, deltaS*), 2alfa, 6alfa, 8beta (R*), 8aalfa]]-1, 2,6, 7, 8, 8a-hexahydro-beta, delta, 6- trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalenehe ptanoic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone. has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(355) Prednisone is usually considered the oral glucocorticoid of choice for anti- inflammatory or immunosuppressant effects. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration., It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(356) Pregabalin is a known pharmaceutical agent that is used in the treatment of epilepsy and pain. Its chemical name is (S)-3- (aminomethyl)-5-methyl-hexanoic acid.

Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken

under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone : A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(357) Primidone is a known pharmaceutical agent that is used in the treatment of epilepsy. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(358) Prinomastat is a known pharmaceutical agent that is used in the treatment of cancer and retinopathy. Its chemical name is (3S)-N-hydroxy-2, 2-dimethyl-4- [ [4- (4- pyridinyloxy) phenyl] sulfonyl] -3-thiomorpholinecarboxamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability

of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following : another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(359) Prochlorperazine maleate is a known pharmaceutical agent that is used in the treatment of nausea and psychotic disorders. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(360) Promethazine is used for its sedative and antiemetic effects in surgery and obstetrics (during labor). The drug reduces preoperative tension and anxiety, facilitates sleep, and reduces postoperative nausea and vomiting. As a preanesthetic medication, promethazine is used in conjunction with reduced doses of an opiate analgesic and a belladonna alkaloid. Promethazine may also be used as a routine sedative and as an adjunct to analgesics for control of pain. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(361) The cholecystokinin antagonist of the present invention is a known pharmaceutical agent that is used in the treatment of anxiety. It is a combination of [1 S- [1 alfa, 2beta [S* *(S*)],4alfa]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[ [(1, 7,7- trimethylbicyclo [2.2. 1] hept-2-yl) oxy] carbonyl] amino] propyl] amino]-1- phenylethyl] amino] -4-oxobutanoic acid compound and meglumine (1: 1). Its structure is :

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(362) Propoxyphene is used in the treatment of pain. The structure of propoxyphene is The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(363) Propranolol is a known pharmaceutical agent that is used in the treatment of hypertension and angina. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(364) Prourokinase is a known pharmaceutical agent that is used in the treatment of thrombosis.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase

markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(365) Quetiapine fumarate is a known pharmaceutical agent that is used in the treatment of schizophrenia. Its chemical name is 2- [2- (4-dibenzo [b, f] [1, 4] thiazepin-11- yl-l-piperazinyl) ethoxy] ethanol. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(366) Quinapril is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is [3S- [2 [R* (R*)], 3R*]]-2- [2- [ [l- (ethoxycarbonyl)-3- phenylpropyl] amino]-1-oxopropyl]-1, 2,3, 4-tetrahydro-3-isoquinolinecarboxylic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type;

and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following : another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the

microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in

the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(367) Rabeprazole is a known pharmaceutical agent that is used in the treatment of gastrointestinal ulcer and bacterial infection. Its chemical name is 2- [ [ [4- (3- methoxypropoxy) -3-methyl-2-pyridinyl] methyl] sulfinyl]-1H-ben zimidazole. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid ; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydroiytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(368) Raloxifene is a known pharmaceutical agent that is used in the treatment of osteoporosis and cancer. Its chemical name is [6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl] [4-[2-(1-piperidinyl) ethoxy] phenyl] methanone. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability I of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug. and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(369) Ramipril is a known pharmaceutical agent that is used in the treatment of hypertension and heart failure. Its chemical name is (2S, 3aS, 6åS)-1-[(S)-N-[(S)-1- carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b] pyrrole-2-carboxylic acid 1-ethyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product ; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration : For instance, one would expect patient compliance to increase

markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(370) Ranitidine is a known pharmaceutical agent that is used in the treatment of gastrointestinal ulcer. Its chemical name is N- [2- [ [ [5- [ (dimethylamino) methyl] -2- furanyl] methyl] thio] ethyl]-N'-methyl-2-nitro-l, l-ethenediamine. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even . reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(371) Ranolazine is a known pharmaceutical agent that is used in the treatment of angina and peripheral vascular disease : Its chemical name is (+,-)-N- (2, 6- dimethylphenyl)-4- [2-hydroxy-3- (2-methoxyphenoxy) propyl]-1-piperazineacetamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(372) Relaxin is a known pharmaceutical agent that is used in the treatment of scleroderma, scars, infertility and peripheral vascular disease. It is a recombinant natural protein.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and

aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology

combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypep'tide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(373) Remacemide is a known pharmaceutical agent that is used in the treatment of epilepsy, Parkinson disease, and neurodegeneration. Its chemical name is 2-amino-N- (1-methyl-1, 2-diphenylethyl) acetamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(374) Repaglinide is a known pharmaceutical agent that is used in the treatment of diabetes. Its chemical name is (S)-2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl) phenyl] butyl amino] -2-oxoethyl] benzoic acid. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(375) Repinotan is a known pharmaceutical agent that is used in the treatment of stroke and trauma. Its chemical name is (R)-2- [4- [ [ (3, 4-dihydro-2H-1-benzopyran-2- yl) methyl] amino] butyl]-1, 2-benzisothiazol-3 (2H)-one 1, 1-dioxide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(376) Ribavirin is used via nasal and oral inhalation for the treatment of severe lower respiratory tract infections (i. e. , bronchiolitis, pneumonia) caused by respiratory syncytial virus (RSV) in hospitalized infants and young children. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release. the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(377) Riluzole is a known pharmaceutical agent that is used in the treatment of amyotrophic lateral sclerosis, Alzheimer disease and Parkinson disease. Its chemical name is 6- (trifluoromethoxy)-2-benzothiazolamine. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent, delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and

aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology

combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(378) Rimantadine is a known pharmaceutical agent that is used in the treatment of viral infection and trypanosomiasis. Its chemical name is alpha-methyl-1- adamantanemethylamine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase

markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(379) Risperidone is a known pharmaceutical agent that is used in the treatment of schizophrenia. Its chemical name is 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3- yl) piperidinyl] ethyl]-6, 7, 8, 9-tet rahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(380) Ritonavir is a known pharmaceutical agent that is used in the treatment of HIV infection. Its chemical name is [5S- (5R*, 8R*, 10R*, 11R*)]- 10-Hydroxy-2-methyl- 5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3, 6-dioxo-8, 11-bis (phenylmethyl) - 2,4, 7.12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(381) Rizatriptan benzoate is a known pharmaceutical agent that is used in the treatment of migraine. Its chemical name is N, N-dimethyl-5-(lH-1, 2, 4-triazol-1- ylmethyl)-lH-indole-3-ethanamine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacteriai hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(382) Rocuronium is a known pharmaceutical agent that is used as muscle relaxant and neuromuscular blocker. Its chemical name is 1- [ (2beta, 3alfa, 5alfa, 16beta, 17beta)-17- (acetyloxy)-3-hydroxy-2- (4- morpholinyl) androstan-16-yl]-1-(2-propenyl) pyrrolidinium bromide. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following : another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(383) Rofecoxib is a known pharmaceutical agent that is used in the treatment of inflammation, rheumatoid arthritis, osteoarthritis, pain, and Alzheimer disease. Its <BR> <BR> <BR> chemical name is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H)-furanone. Its structure is : The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken

under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(384) Ropinirole is a known pharmaceutical agent that is used in the treatment of Parkinson disease. Its chemical name is (4-2 (-dipropylamino) ethyl)-1, 3-dihydro-2H- indol-2-one monohydrochloride. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(385) Rosiglitazone maleate is a known pharmaceutical agent that is used in the treatment of diabetes. Its chemical name is 5- [ [4- [2- (methyl-2- pyridinylamino) ethoxy] phenyl] methyl] -2, 4-thiazolidi nedione. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(386) Goserelin is a known pharmaceutical agent that is used in the treatment of cancer, endometriosis and infertility. Its chemical name is 6- [O- (1, 1-dimethylethyl)-D- serine]-1-9-luteinizing hormone-releasing factor (swine) 2- (aminocarbonyl) hydrazide.

Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be. quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(387) Rubitecan is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is (4S)-4-ethyl-4-hydroxy-10-nitro-lH- pyrano [3', 4' : 6,7] indolizino [1, 2-b] quinoline-3, 14 (4H, 12H) -dione. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability

of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(388) Sagramostim is a known pharmaceutical agent that is a granulocyte macrophage-colony stimulating factor used in the treatment of cancer and HIV infection.

Its chemical name is 23-L-leucine colony-stimulating factor 2 (human clone pHG25 protein moiety).

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be. quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(389) Saquinavir is a known pharmaceutical agent that is used in the treatment of HIV infection. Its chemical name is [3S-[2 [1R* (R*), 2S*], 3alpha, 4abeta, 8abeta]]-N1- [3- [3- [ [ (1, 1-dimethyleth yl) amino] carbonyl] octahydro-2 (lH)-isoquinolinyl]-2-hydroxy- 1- (phenylmethyl) prop y 1]-2-[(2-quinolinylcarbonyl) aminobutanediamide. Its structure is :

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(390) Docetaxel is a known pharmaceutical agent that is used in the treatment of cancer and malaria. Its chemical name is beta-[[(1, 1-dimethylethoxy) carbonyl] amino] - alpha-hydroxybenzenepropano ic acid [2aR- [2aalpha, 4beta, 4abeta, 6beta, 9alpha (alphaR*, betaS*)-l alpha, 12alpha, 12a alpha, 12balpha]]-12b-(acetyloxy)-12- (benzoyloxy) -2a, 3,4, 4a, 5,6, 9,10, 11, 12,12a, 12b-do d ecahydro-4,6, 11-trihydroxy- 4a, 8, 13,13-tetramethyl-5-oxo-7, 11-methano-lH-cyclodec a [3,4] benz [1, 2-b] oxet-9-yl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability

of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(391) Satraplatin is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is Satraplatin. Its structure is : The novel pharmaceutical compound of the present invention is useful in. accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(392) Selegiline is a known pharmaceutical agent that is used in the treatment of Parkinson disease. Its chemical name is (R) -N, alpha-dimethyl-N-2- propynylbenzeneethanamine. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human

growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide

linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(393) Sertraline is a known pharmaceutical agent that is used in the treatment of depression, obsessive compulsive disorder, anxiety, panic disorder, sexual dysfunction and obesity. Its chemical name is (lS, 4S)-4-(3, 4-dichlorophenyl)-1, 2,3, 4-tetrahydro-N- methyl-1-naphthaleneamine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase

markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(394) Sevelamer is a known pharmaceutical agent that is used in the treatment of kidney disease. Its chemical name is 2-propen-1-amine, polymer with (chloromethyl) oxirane. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(395) Sevirumab is a known pharmaceutical agent that is used in the treatment of cytomegalic inclusion disease. Its chemical name is immunoglobulin G1, anti- (cytomegalovirus) (human monoclonal EV2-7. gamma. 1-chain), disulfide with human monoclonal EV2-7. kappa. -chain, dimer.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(396) Sibutramine is a known pharmaceutical agent that is used in the treatment of obesity. Its chemical name is 1- (4-chlorophenyl)-N, N-dimethyl-alpha- (2- methylpropyl) cyclobutanemethanamine hydrochloride monohydrate. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(397) Sildenafil citrate is a known pharmaceutical agent that is used in the treatment of sexual dysfunction. Its chemical name is 1- [ [3- (4, 7-dihydro-1-methyl-7- oxo-3-propyl-lH-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methyl- piperazine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membru ies. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified . amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(398) Simvastatin is a known pharmaceutical agent that is used in the treatment of hyperlipidemia and osteoporosis. Its chemical name is 2,2-dimethylbutanoic acid [1S- [lalfa, 3alfa, 7beta, 8beta (2S*, 4S*) 8abeta]]-1, 2,3, 7, 8, 8a-hexahydro-3, 7-dimethyl-8- [2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl]-1-naphthalenyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(399) Sinapultide is a known pharmaceutical agent that is used in the treatment of respiratory distress syndrome. It is a mimic of human surfactant B protein, for the treatment of meconium aspiration syndrome. Its structure is: Lys-Leu-Leu-Leu-Leu- Lys-Leu-Leu-Leu-Leu-Lys-Leu-Leu-Leu-Leu-Lys-Leu-Leu-Leu-Leu- Lys.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(400) Sitafloxacin is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is [lR-[lalfa (S*), 2alfa]]-7- (7-amino-5- azaspiro [2,4] hept-5-yl)-8-chloro-6-fluoro-1-(2-fluorocyclopropyl)-1, 4-dihydro-4-oxo-3- quinoline carboxylic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following : another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of

cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the

gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(401) Sodium polystyrene sulfonate is a sulfonated cation-exchange resin prepared in the sodium phase and used for the removal of excess potassium. Each gram of the resin has an in vitro exchange capacity of about 3.1 mEq (range: 2. 81-3. 45 mEq) of potassium. Sodium polystyrene sulfonate occurs as a golden brown, fine powder that is odorless and tasteless and is insoluble in water. Each gram of the powdered resin contains approximately 4.1 mEq of sodium. Sodium polystyrene sulfonate is commercially available as the powder or as a suspension. The commercially available suspension occurs as a brown, slightly viscous suspension of the resin in a 33% sorbitol vehicle; the vehicle also contains purifiedwater, propylene glycol, magnesium aluminum silicate (Veegum°), saccharin sodium, and parabens as a preservative. Each 100 mL of the

commercially available suspension contains 25 g of sodium polystyrene sulfonate, 33 g of sorbitol, and 108 mEq of sodium.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stabiiity of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release

through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(402) Sotalol is a known pharmaceutical agent that is used in the treatment of arrhythmia. Its chemical name is N- [4- [1-hydroxy-2- [ (1-methylethyl) amino] ethyl] phenyl] methanesulfonamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(403) Sparfosic acid is a known pharmaceutical agent that is used in the treatment of cancer.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(404) Spironolactone is a known pharmaceutical agent that is used in the treatment of edema. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken

under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating-enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(405) Stavudine is a known pharmaceutical agent that is used in the treatment of HIV infection. Its chemical name is 2', 3'-didehydro-3'-deoxythymidine. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(406) Sucralfate is a known pharmaceutical agent that is used in the treatment of gastrointestinal ulcer and ulcerative colitis. Its chemical name is sucrose octakis (hydrogen sulfate), aluminum complex. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of, pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(407) Sumatriptan is a known pharmaceutical agent that is used in the treatment of migraine. Its chemical name is 3- [2- (dimethylamino) ethyl]-N-methyl-lH-indole-5- methanesulfonamide. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid ; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(408) Tabimorelin is a known pharmaceutical agent that is used in the treatment of hormone deficiency. Its chemical name is N-[(2E)-5-amino-5-methyl-1-oxo-2- hexenyl]-N-methyl-3- (2-naphthalenyl)-D-alanyl-N, Nalpha-dimethyl-D- phenylalaninamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(409) Tamoxifen is a known pharmaceutical agent that is used in the treatment of breast cancer. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(410) Tamsulosin is a known pharmaceutical agent that is used in the treatment of benign prostate hypertrophy. Its chemical name is R- (-)-5- [2- [ [2- (2- ethoxyphenoxy) ethyl] amino] propyl]-2-methoxybenzenesulfonamide. Its structure is : The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability

of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(411) Temazepam is a known pharmaceutical agent that is used in the treatment of insomnia. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(412) Tenofovir disoproxil is a known pharmaceutical agent that is used in the treatment of HIV infection. Its chemical name is [[(lR)-2-(6-amino-9H-purin-9-yl)-1- methylethoxy] methyl] phosphonic acid. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(413) Tepoxalin is a known pharmaceutical agent that is used in the treatment of asthma, inflammation, and inflammatory bowel disease. Its chemical name is 5- (4- <BR> <BR> <BR> <BR> chlorophenyl)-N-hydroxy-1- (4-methoxyphenyl)-N-methyl-1 H-pyrazole-3-propanamide.

Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product ; enhanced digestion or absorption; targeted delivery to particular tissue/cell type;

and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the

microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in

the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(414) Terazosin is a known pharmaceutical agent that is used in the treatment of benign prostate hypertrophy and hypertension. Its chemical name is 1-(4-amino-6, 7- dimethoxy-2-quinazolinyl)-4- [ (tetrahydro-2-furanyl) carbonyl] piperazine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(415) Terbinafine is a known pharmaceutical agent that is used in the treatment of mycosis. Its chemical name is (E)-N- (6, 6-dimethyl-2-hepten-4-ynyl)-N-methyl-l- naphthalenemethanamine. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(416) Terbutaline sulfate is a known pharmaceutical agent that is used in the treatment of asthma and bronchitis. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(417) Teriparatide is a known pharmaceutical agent that is used in the treatment of thyroid deficiency. It is a parathyroid hormone.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(418) Tetracycline is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another

invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(419) Thalidomide is a known pharmaceutical agent that is used in the treatment of cachexia, diarrhea, leprosy, rheumatoid arthritis, transplant rejection, cancer and Crohn disease. Its chemical name is N- (2, 6-dioxo-3-piperidyl) phthalimide. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human

growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide

linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(420) Theophylline is a known pharmaceutical agent that is used in the treatment of asthma. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid ; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(421) Thiotepa is a known pharmaceutical agent that is used in the treatment of cancer. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(422) Thrombopoetin is a human protein that is used in the treatment of thrombocytopenia.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(423) Tiagabine is a known pharmaceutical agent that is used in the treatment of epilepsy. Its chemical name is (R)-l- [4, 4-bis (3-methyi-2-thienyl)-3-butenyl]-3- piperidinecarboxylic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(424) Ticlopidine is a known pharmaceutical agent that is used in the treatment of stroke and thrombosis. Its chemical name is 5-[(2-chlorophenyl) methyl]-4, 5,6, 7- tetrahydrothieno [3, 2-c] pyridine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(425) Tifacogin, a tissue factor pathway inhibitor, is a known pharmaceutical agent that is used in the treatment of thrombosis and septic shock. Its structure is N-L- alanyl-blood coagulation factor LACI (human clone lambdaP9 protein moiety reduced).

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(426) Tirapazamine is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is 3-amino-1, 2, 4-benzotriazine-1, 4 dioxide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microsphe : es swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include : linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-'specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(427) Tirofiban is a known pharmaceutical agent that is used in the treatment of thrombosis and angina. Its chemical name is N- (butylsulfonyl)-O- [4- (4- piperidinyl) butyl] -L-tyrosine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active, agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(428) Tizanidine is a known pharmaceutical agent that is used in the treatment of muscle spasm. Its chemical name is 5-chloro-N-(4, 5-dihydro-lH-imidazol-2-yl)-2, 1, 3- benzothiadiazol-4-amine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(429) Tobramycin sulfate is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(430) Tolterodine is a known pharmaceutical agent that is used in the treatment of urinary incontinence. Its chemical name is (R)-2- [3- [bis (l-methylethyl) amino]-l- phenylpropyl]-4-methyl-phenol. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following : another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and

aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology

combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(431) Tomoxetine is a known pharmaceutical agent that is used in the treatment of attention deficit disorder. Its chemical name is (gamma. R)-N-methyl-gamma- (2- methylphenoxy) benzenepropanamine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken

under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicaboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(432) Topiramate is a known pharmaceutical agent that is used in the treatment of epilepsy, psychosis and depression. Its chemical name is 2,3 : 4, 5-bis-O- (1- methylethylidene)-beta-D-fructopyranose sulfamate. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(433) Topotecan is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is (S)-10-[(dimethylamino) methyl] -4-ethyl-4, 9-dihydroxy-lH- pyrano [3', 4' : 6,7] indolizino [1, 2-b] quinoline-3,14 (4H, 12H) -dione. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(434) Toresemide is a known pharmaceutical agent that is used in the treatment of hypertension and heart failure. Its chemical name is N- [ [ (1- methylethyl) amino] carbonyl]-4- [ (3-methylphenyl) amino]-3-pyridinesulfonamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(435) TPA ANALOGUE is a known pharmaceutical agent that is used in the treatment of acute myocardial infarction. It is related to naturally occurring tissue plasminogen activator and is disclosed in EP 293934 B 1994, priority US 58217 1987, herein incorporated by reference.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(436) Tramadol is a known pharmaceutical agent that is used in the treatment of pain. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug-conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(437) Trandolapril is a known pharmaceutical agent that is used in the treatment of hypertension, heart failure, and myocardial infarction-. Its chemical name is [2S- [1 [R* (R*) ], 2alpha, 3aalpha, 7abeta]]-1-[2-[[1-(ethoxycarbonyl)-3-phe nylpropyl3amino]- 1-oxopropyl] octahydro-lH-indole-2-carboxylic acid. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include : linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(438) Trastuzumab is a monoclonal antibody used in the treatment of metatstatic breast cancer. Trastuzumab is the subject of U. S. Patent Number 5677171, herein incorporated by reference, which describes how to make that drug.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(439) Trazadone is a known pharmaceutical agent that is used in the treatment of depression. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(440) Triamterene is a known pharmaceutical agent that is used in the treatment of edema. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(441) Troglitazone is a known pharmaceutical agent that is used in the treatment of diabetes. Its chemical name is 5- [ [4- [ (3, 4-dihydro-6-hydroxy-2,5, 7, 8-tetramethyl-2H- l-benzopyran-2-yl) methoxy] phenyl] methyl]-2, 4-thiazolidinedione. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example,

copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid ; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the

active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(442) Trovafloxacin mesylate is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is (l : alpha., 5. alpha. , 6. alpha.)-7- (6-amino-3-azabicyclo [3. 1. 0] hex-3-yl)-1-(2, 4-difluorophenyl) -6-fluoro-1,4-dihydro-4- oxo-1, 8-naphthyridine-3-carboxylic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(443) Urokinase is used for the lysis of acute massive pulmonary emboli (obstruction or substantial filling defects involving 2 or more lobar pulmonary arteries or an equivalent amount of emboli in other vessels) and for lysis of emboli accompanied by unstable hemodynamics (i. e. , failure to maintain blood pressure without supportive measures) in adults. The drug is generally most effective in lysing recently formed thrombi. Urokinase is an enzyme produced by the kidneys and excreted in urine.

Commercially available urokinase is isolated from human kidney tissue cultures and contains both 55,000 dalton high molecular weight and 34,000 dalton low molecular weight forms of urokinase. The drug is soluble in water. Urokinase is commercially available as a lyophilized white powder which also contains albumin human, mannitol, and sodium chloride or gelatin, mannitol, sodium chloride, and monobasic sodium phosphate anhydrous The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(444) Ursodiol is a known pharmaceutical agent that is used in the treatment of gall stones. Its chemical name is 3a, 7p-dihydroxy-5p-cholan-24-oic acid.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble. microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(445) Valacyclovir is a known pharmaceutical agent that is used in the treatment of viral infection. Its chemical name is 2-[(2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy]-L-valine ethyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(446) Valdecoxib is a known pharmaceutical agent that is used in the treatment of arthritis and pain. Its chemical name is 4- (5-methyl-3-phenyl-4- isoxazolyl) benzenesulfonamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability

of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(447) Valproic acid is a known pharmaceutical agent that is used in the treatment of epilepsy. Its structure is: CH3CH2CH2CHCOOH CHaCIs2H The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(448) Valsartan and hydrochlorothiazide are used together in the treatment of hypertension. Its chemical name is N-(1-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl) [1, 1- biphenyl]-4-yl] meth yl]-L-valine. Its structure is: The chemical structure of hydrochlorothiazide is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(449) Valspodar is a known pharmaceutical-agent that is used in the treatment of cancer. Its chemical name is 6- [ [R- (E)]-6, 7-didehydro-N, 4-dimethyl-3-oxo-L-2- aminooctanoic acid]-7-L-valine-cyclosporin A. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product ; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another-active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(450) Vancomycin is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or. another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine.. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(451) Vecuronium is a known pharmaceutical agent that is used for skeletal muscle relaxation. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(452) Venlafaxine is a known pharmaceutical agent that is used in the treatment of anxiety and depression. Its chemical name is (+,-)-1- [2- (dimethylamino)-1- (4- methoxyphenyl) ethyl] cyclohexanol. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery-systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(453) Verapamil is a known pharmaceutical agent that is used in the treatment of hypertension. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(454) Vinorelbine tartrate is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is 3', 4'-didehydro-4'deoxy-C'- norvincaleukoblastine. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(455) Vitamin B 12 is a known pharmaceutical agent that is used in the treatment of Vitamin B 12 deficiency. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another

invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(456) Vitamin C is a known pharmaceutical agent that is used in the treatment of vitamin C deficiency. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted'delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(457) Voriconazole is a known pharmaceutical agent that is used in the treatment of mycosis. Its chemical name is alpha- (2, 4-difluorophenyl) -5-fluoro-. beta.- methyl-. alpha.- (lH-1, 2,4-triazol-1-ylmethyl)-4-pyrimidineethanol [R- (R*, S*)]. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability

of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(458) Warfarin is a known pharmaceutical agent that is used in the treatment of thrombosis and myocardial infarction. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids-enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(459) Xaliproden is a known pharmaceutical agent that is used in the treatment of Alzheimer disease and amyotrophic lateral sclerosis. Its chemical name is 1,2, 3,6- tetrahydro-1- [2- (I-naphthalenyl) ethyl] -4- [3- (trifluoromethyl) phenyl] pyridine. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product ; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(460) Zafirlukast is a known pharmaceutical agent that is used in the treatment of asthma and rhinitis. Its chemical name is [3- [ [2-methoxy-4- [ [ [ (2- methylphenyl) sulfonyl] amino] carbonyl] phenyl] met hyl]-l-methyl-lH-indol-5- yl] carbamic acid, cyclopentyl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include : linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(461) Zaleplon is a known pharmaceutical agent that is used in the treatment of insomnia. Its chemical name is N- [3- (3-cyanopyrazolo [1, 5-a] pyrimidin-7-yl) phenyl] -N- ethylacetamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(462) Zenarestat is a known pharmaceutical agent that is used in the treatment of diabetes, retinopathy and neuropathy. Its chemical name is 3- [ (4-bromo-2- fluorophenyl) methyl]-7-chloro-3, 4-dihydro-2,4-dioxo-1 (2H)-quinazolineacetic acid. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(463) Zidovudine is a known pharmaceutical agent that is used in the treatment of HIV infection. Its chemical name is 3'-azido-3'-deoxythymidine. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(464) Zolmitriptan is a known pharmaceutical agent that is used in the treatment of migraine. Its chemical name is (4S)-4-[[3-[2-(dimethylamino) ethyl]-lH-indol-5- yl] methyl] -2-oxazolidinone. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(465) Zolpidem is a known pharmaceutical agent that is used in the treatment of insomnia. Its chemical name is N, N, 6-trimethyl-2- methylphenyl)-imidazol [1, 2- a] pyridine-3-acetamide. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited . to less than 5 microns.

(466) Bleomycin is a known pharmaceutical agent that is used in the treatment of cancer. Its structure is: (M@@ comgonent: @leomyein @2, in wnich R is (CH@)2S#C#eCH@CH@-) The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(467) Phytoseterol is a plant-derived product with potential for the treatment and prevention of hypercholesterolemia. The product comprises a mixture of four

phytosterols and is thought to act by competing with dietary cholesterol for absorption in the intestine.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release

through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(468) Paclitaxel is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is [2aR [2aalpha, 4beta, 4abeta, 6beta, 9alpha (alphaR*, betaS*), 1 lbeta, 12alpha, 12alpha, 12balpha]]-beta-(benzoylamino)-alpha- hydroxybenzenpropanoic acid 6,12b-bis (acetyloxy)-12-(benzoyloxy)- 2a, 3,4, 4a, 5,6, 9,10, 11,12, 12a, 12b-dodecahydro-4, 11-dihydroxy-4a, 8, 13,13-tetramethyl-5- oxo-7, 11-methano-lH-cyclodeca [3,4] benz [1, 2-b] oxet-9-yl ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following : another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorptibn of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(469) Fluticasone is a known pharmaceutical agent that is used in the treatment of dermatitis, rhinitis, asthma, pulmonary obstructive disease and skin disease. Its chemical name is (6alfa, llbeta, 16alfa, 17alfa)-6, 9-difluoro-11-hydroxy-16-methyl-3-oxo- 1 7- (1-oxopropoxy)-androsta-1, 4-diene-17-carbothioic acid, S- (fluoromethyl) ester. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(470) Flurouracil is a known pharmaceutical agent that is used in the treatment of actinic keratoses. Its structure is:

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres,

liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide

spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(471) Pseudoephedrine is a known pharmaceutical agent that is used in the treatment of allergy. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type;

and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the

microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in

the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(472) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to pseudoephedrine, as well as methods for protecting and administering pseudoephedrine. This novel compound, referred to as a CARRIERWAVETM Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.

CDLXXIII The lipoxygenase inhibitor of the present invention is a known pharmaceutical agent with the chemical name (R)-2-chloro-5- (2- azetidinylmethoxy) pyridine.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active

agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(474) The composite vascular protectant of the present invention is a known pharmaceutical agent that is used in the treatment of atherosclerosis and restenosis. The compound, AGI 1067, is a composite vascular protectant and blocks the production of VCAM-1 and MCP-1 inflammatory genes implicated in the initiation and progression of the condition.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(475) The oral neuraminidase inhibitor of the present invention is a known pharmaceutical agent that is used in the treatment of viral infection. It is referred to as chemical name is BCX1812.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(476) The soluble chimeric protein CTLA4Ig is a known pharmaceutical agent that is used in the treatment of psoriasis and transplant rejection.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include : linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attache, to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(477) The selective endothelin A receptor antagonist of the present invention is a known pharmaceutical agent that is used in the treatment of heart failure. It is known as BMS193884).

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The

released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(478) The potassium channel modulator is a known pharmaceutical agent that is used in the treatment of stroke. It is referred to as BMS 204352.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(479) The bactericidal/permeability increasing (BPI) protein derivative of the present invention, specifically the BPI-21 derivative, is a known pharmaceutical agent that is used in the treatment of septic shock. BPI was isolated from human blood cells.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(480) Humanized monoclonal antibody, hu 1124, directed against CD1 la is a known pharmaceutical agent that is used in the treatment of psoriasis and transplant rejection.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of

cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral

administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(481) The lipid lowering agent is a known pharmaceutical agent that is used in the treatment of hyperlipidemia. It is called CEB 925, a cholesterol ester hydrolase inhibitor produced by American Home Products.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include : linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(482) Propofol is a known pharmaceutical agent that is used as an anesthetic. Its chemical name is 2,6-diisopropylphenol. As part of the present invention, it is provided as a sustained release oral version of the anesthetic with decreased toxicity and increased patient compliance.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme

degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(483) The Cholesterol/Triglyceride Reducer of the present invention is a known pharmaceutical agent that is used in the treatment of hyperlipidemia. It is a second generation nonabsorbed polymer, known as GT 102279, that produces a the reduction of LDL cholesterol.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these

systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some

technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(484) The recombinant hepatitis B vaccine of the present invention is used for immunization against hepatitis B virus infection.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release

through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(485) The angiotensin II antagonist of the present invention is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is N- [ [4'- [ (2-ethyl-5, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] [1, 1'-biphenyl]-2- yl] sulfonyl]-benzamide.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active

agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(486) An immunosuppressant protein of the present invention is a known pharmaceutical agent that is used in the treatment of psoriasis. It is a recombinant human fusion protein, LFA3TIP.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals : enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered

product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several

shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly

or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(487) A daily multivitamin is a known pharmaceutical agent that is used in the treatment of vitamin deficiency. It is made up of one or more of the known vitamins and minerals, including Vitamins A, B1 through B12, C, D, E, K and iron, magnesium and copper, among others well known as components of multivitamins.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(488) Erythromycin and sulfx together make up a known pharmaceutical agent that is used in the treatment of bacterial infection. The chemical name of erythromycin is (3R*, 4S*, 55*, 6R*, 7R*, 9R*, l lR*, 12R*, 13S*, 14R*)-4-((2, 6-Dideoxy-3-C-methyl-3- 0-methyl-a-L-ribo-hexopyranosyl)-oxy)-14-ethyl-7, 12, 13- trihydroxy-3, 5,7, 9, 11, 13- hexa methyl-6- ( (3, 4, 6-trideoxy-3- (dimethylamino)-b-D-xylo- hexopyran osyl) oxy) oxacyclotetradecane-2, 10-dine.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical

compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage

reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high

moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(489) Ethinyl estradiol and dogestrel are used together as a contraceptive.

Ethinyl estradiol's chemical name is (17alpha)-19-norpregna-1 ; 2, 5 (10)-trien-20-yne- 3,17-diol. Its structure is:

Desogestrel's chemical name is (17alpha)-13-ethyl-11-methylene-1S, 19- dinorpregn-4-en-20-yn-17-ol. Its structure is : The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(490) Lithium carbonate is a known pharmaceutical agent that is used in the treatment of depression.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(491) LYM 1 is an antibody that is used in the treatment of cancer.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of

cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the

gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(492) Methylprednisolone, a steroid, is a known pharmaceutical agent that is used in the reatment of spinal cord injuries. Its chemical name is pregna-1, 4-diene-3, 20 -dione, 11, 17, 21-trihydroxy-6-methyl-, (6a, lip)-.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor :

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble

microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR

application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(493) Rotavirus vaccine is a known pharmaceutical agent that is used in the prevention of viral infection The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example,

copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the

active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(494) Saquinavir is a known pharmaceutical agent that is used in the treatment of HIV infection. Its chemical name is butanediamide, Nl- [ (lS, lR)]-3- [ (3S, 4aS, 8aS)-3- [ [1, 1-dimethylethyl) amino] carbonyl] octahydro-2 (1 H)-isoquinolinyl]-2-hydroxy-1- (phenylmethyl) propyl]-2-[(2-quinolinylcarbonyl) amino]-, (2S) -.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf

life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances, Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(495) Arginine is a known pharmaceutical agent that is used as a nutritional supplement and as a source of nitrogen.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(496) Heparin is a known pharmaceutical agent that is used in the treatment of blood clots. Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans having anticoagulant properties.

Although others may be present, the main sugars occurring in heparin are: (1) a-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-a-D-glucose 6-sulfate, (3) b-D-glucuronic acid, (4) 2-acetamido-2-deoxy-a-D-glucose, and (5) a-L-iduronic acid.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken

under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted'to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns. Thymosin alpha is a known pharmaceutical agent that is used in the treatment of hepatitis B.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered . product ; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified

amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that

incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(497) Montelukast is a known pharmaceutical agent that is used in the treatment of asthma. Its chemical name is [R- (E)]- 1- [ [ [l- [3- [2- (7-chloro-2- quinolinyl) ethenyl] phenyl]-3-[2-(1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl]- cyclopropaneacetic acid. Its structure is: Fexofenadine is a known pharmaceutical agent that is used in the treatment of seasonal allergic rhinitis. Its chemical name is 4- [1-hydroxy-4- [4- (hydroxydiphenylmethyl)-1-piperidinyl] butyl]- alpha, alpha-dimethylbenzeneacetic acid. Its structure is: The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability

of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent, conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns. Iodothyronine is a known pharmaceutical agent that is used in the treatment of hypothyroidism.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the

active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently

attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(498) Iodothyronine is a known pharmaceutical agent that is used in the treatment of hypothyroidism.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following : another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken

under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is

unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral. administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

(499) Iodothyronine and thyroxine are known pharmaceutical agents used in the treatment of hypothyroidism.

The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to-particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.

Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release

through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that the concept of attaching an active ingredient to a polypeptide pendant group sted delivery into the bloodstream via oral administration. also important to control the molecular weight, molecular size and particle active agent delivery system. Variable molecular weights have unpredictable ates and pharmacokinetics. High molecular weight carriers are digested slowly in the case of naproxen-linked dextran, which is digested almost exclusively in by bacterial enzymes. High molecular weight microspheres usually have high content which may present a problem with water labile active ingredients. size not only becomes a problem with injectable drugs, as in the HAR don, but absorption through the brush-border membrane of the intestines is limited than 5 microns.

(500) Codeine is a known pharmaceutical agent that is used in the treatment of Its structure is shown in Figure 1.

The novel pharmaceutical compound of the present invention is useful in nplishing one or more of the following goals: enhancement of the chemical stability B original compound; alteration of the release profile of an orally administered jet ; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; provision for an oral dosage form when none exists. The novel pharmaceutical ) ound may contain one or more of the following: another active pharmaceutical t, an adjuvant, or an inhibitor.

Active agent delivery systems are often critical for the effective delivery of a , gically active agent (active agent) to the appropriate target. The importance of these ms becomes magnified when patient compliance and active agent stability are taken r consideration. For instance, one would expect patient compliance to increase edly if an active agent is administered orally in lieu of an injection or another ive technique. Increasing the stability of the active agent, such as prolonging shelf survival in the stomach, will assure dosage reproducibility and perhaps even number of dosages required which could improve patient compliance. absorption of an orally administered active agent is often blocked by the harshly ch milieu, powerful digestive enzymes in the GI tract, permeability of anes and transport across lipid bilayers. Incorporating adjuvants such as

resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.

Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.

Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.

In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous

pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.

This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.

It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients.

Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.

SUMMARY OF THE INVENTION CCLI The present invention provides covalent attachment of the active agent (leuprolide acetate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching leuprolide acetate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising leuprolide acetate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and leuprolide acetate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Leuprolide acetate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The

microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting leuprolide acetate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering leuprolide acetate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, leuprolide acetate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, leuprolide acetate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and leuprolide acetate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, leuprolide acetate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, leuprolide acetate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching leuprolide acetate to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, leuprolide acetate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLII The present invention provides covalent attachment of the active agent (levocarnitine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching levocarnitine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by

the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising levocarnitine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and levocarnitine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Levocarnitine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting levocarnitine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering levocarnitine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, levocarnitine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, levocarnitine is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and levocarnitine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, levocarnitine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, levocarnitine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching levocarnitine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, levocarnitine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular

transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLIIIThe present invention provides covalent attachment of the active agent (levocetirizine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching levocetirizine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising levocetirizine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and levocetirizine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Levocetirizine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently'attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting levocetirizine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering levocetirizine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, levocetirizine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, levocetirizine is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and levocetirizine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment,

levocetirizine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, levocetirizine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching levocetirizine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, levocetirizine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLIV The present invention provides covalent attachment of the active agent (levofloxacin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching levofloxacin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising levofloxacin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and levofloxacin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Levofloxacin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting levofloxacin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering levofloxacin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, levofloxacin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, levofloxacin is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and levofloxacin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, levofloxacin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, levofloxacin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching levofloxacin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, levofloxacin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLV The present invention provides covalent attachment of the active agent (levothyroxine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching levothyroxine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising levothyroxine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and levothyroxine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Levothyroxine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting levothyroxine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering levothyroxine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, levothyroxine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, levothyroxine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and levothyroxine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, levothyroxine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, levothyroxine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching levothyroxine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, levothyroxine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLVI The present invention provides covalent attachment of the active agent (lintuzumab) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching lintuzumab to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising lintuzumab microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and lintuzumab covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Lintuzumab preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting lintuzumab from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering lintuzumab to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, lintuzumab is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, lintuzumab is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and lintuzumab is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, lintuzumab is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, lintuzumab is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching lintuzumab to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, lintuzumab and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLVII The present invention provides covalent attachment of the active agent (lisinopril) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching lisinopril to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising lisinopril microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and lisinopril covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Lisinopril preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another

preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting lisinopril from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering lisinopril to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, lisinopril is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, lisinopril is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and lisinopril is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, lisinopril is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, lisinopril is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching lisinopril to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, lisinopril and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an- amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLVIII The present invention provides covalent attachment of the active agent (lisinopril and hydrochlorothiazide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching lisinopril and hydrochlorothiazide to the N-terminus, the C-terminus or directly

to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising lisinopril and hydrochlorothiazide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and lisinopril and hydrochlorothiazide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Lisinopril and hydrochlorothiazide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The. active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting lisinopril and hydrochlorothiazide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering lisinopril and hydrochlorothiazide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, lisinopril and hydrochlorothiazide are released from the composition by an enzyme-catalyzed release. In another preferred embodiment, lisinopril and hydrochlorothiazide are released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and lisinopril and hydrochlorothiazide are released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, lisinopril and hydrochlorothiazide are released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, lisinopril and hydrochlorothiazide are released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching lisinopril and hydrochlorothiazide to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, lisinopril and hydrochlorothiazide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLIX The present invention provides covalent attachment of the active agent (carbapenem antibiotic) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching carbapenem antibiotic to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.

In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry

into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising carbapenem antibiotic microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and carbapenem antibiotic covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Carbapenem antibiotic preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting carbapenem antibiotic from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering carbapenem antibiotic to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, carbapenem antibiotic is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, carbapenem antibiotic is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and carbapenem antibiotic is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, carbapenem antibiotic is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, carbapenem antibiotic is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching carbapenem antibiotic to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, carbapenem antibiotic and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLX The present invention provides covalent attachment of the active agent (loperamide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching loperamide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising loperamide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and loperamide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Loperamide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting loperamide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering loperamide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, loperamide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, loperamide is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and loperamide is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, loperamide is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, loperamide is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching loperamide to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, loperamide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXI The present invention provides covalent attachment of the active agent (loracarbef) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching loracarbef to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the-polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising loracarbef microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and loracarbef covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Loracarbef preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another

preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting loracarbef from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering loracarbef to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, loracarbef is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, loracarbef is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and loracarbef is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, loracarbef is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, loracarbef is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching loracarbef to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, loracarbef and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXII The present invention provides covalent attachment of the active agent (loratidine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching loratidine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or

polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising loratidine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and loratidine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic * amino acids.

Loratidine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting loratidine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering loratidine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, loratidine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, loratidine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and loratidine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, loratidine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, loratidine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching loratidine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second

agent, loratidine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXIII The present invention provides covalent attachment of the active agent (lorazepam) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching lorazepam to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising lorazepam microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and lorazepam covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide,

(ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Lorazepam preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is. covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting lorazepam from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering lorazepam to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, lorazepam is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, lorazepam is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed

release. In another preferred embodiment, the composition further comprises a microencapsulating agent and lorazepam is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, lorazepam is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, lorazepam is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching lorazepam to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, lorazepam and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXIV The present invention provides covalent attachment of the active agent (losartan) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching losartan to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising losartan microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and losartan covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Losartan preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another

preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting losartan from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering losartan to a patient, the patient being a human or a non-human animal, comprising administering to the patient-a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, losartan is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, losartan is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and losartan is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, losartan is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, losartan is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching losartan to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, losartan and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXV The present invention provides covalent attachment of the active agent (losartan and hydrochlorothiazide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching losartan and hydrochlorothiazide to the N-terminus, the C-terminus or directly

to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising losartan and hydrochlorothiazide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and losartan and hydrochlorothiazide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Losartan and hydrochlorothiazide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting losartan and hydrochlorothiazide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering losartan and hydrochlorothiazide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, losartan and hydrochlorothiazide are released from the composition by an enzyme-catalyzed release. In another preferred embodiment, losartan and hydrochlorothiazide are released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and losartan and hydrochlorothiazide are released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, losartan and hydrochlorothiazide are released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, losartan and hydrochlorothiazide are released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching losartan and hydrochlorothiazide to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, losartan and hydrochlorothiazide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXVI The present invention provides covalent attachment of the active agent (lovastatin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching lovastatin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the

upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising lovastatin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and lovastatin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Lovastatin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting lovastatin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering lovastatin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, lovastatin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, lovastatin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and lovastatin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, lovastatin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, lovastatin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching lovastatin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, lovastatin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXVII The present invention provides covalent attachment of the active agent (marimastat) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching marimastat to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising marimastat microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and marimastat covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Marimastat preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting marimastat from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering marimastat to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, marimastat is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, marimastat is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and marimastat is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, marimastat is

released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, marimastat is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching marimastat to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, marimastat and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXVIII The present invention provides covalent attachment of the active agent (mecasermin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching mecasermin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mecasermin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mecasermin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mecasermin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mecasermin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mecasermin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mecasermin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mecasermin is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mecasermin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, mecasermin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, mecasermin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching mecasermin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mecasermin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXIX The present invention provides covalent attachment of the active agent (medroxyprogesterone acetate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching medroxyprogesterone acetate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications,

delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising medroxyprogesterone acetate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and medroxyprogesterone acetate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Medroxyprogesterone acetate preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In

another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting medroxyprogesterone acetate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering medroxyprogesterone acetate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, medroxyprogesterone acetate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, medroxyprogesterone acetate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and medroxyprogesterone acetate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, medroxyprogesterone acetate is released from the composition by a pH-dependent unfolding of the polypeptide.

In another preferred embodiment, medroxyprogesterone acetate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching medroxyprogesterone acetate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, medroxyprogesterone acetate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethana, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXX The present invention provides covalent attachment of the active agent (mefloquine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching mefloquine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mefloquine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mefloquine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mefloquine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mefloquine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mefloquine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mefloquine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mefloquine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mefloquine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, mefloquine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, mefloquine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching mefloquine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mefloquine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine,

cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXI The present invention provides covalent attachment of the active agent (megestrol acetate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching megestrol acetate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising megestrol acetate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and megestrol acetate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Megestrol acetate preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting megestrol acetate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering megestrol acetate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, megestrol acetate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, megestrol acetate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and megestrol acetate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, megestrol acetate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, megestrol acetate is

released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching megestrol acetate to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, megestrol acetate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXII The present invention provides covalent attachment of the active agent (an adenosine A1 receptor antagonist) to a polymer of peptides or amino acids.

The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching an adenosine Al receptor antagonist to the N-terminus, the C- terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.

In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising an adenosine A1 receptor antagonist microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and an adenosine Al receptor antagonist covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

An adenosine Al receptor antagonist preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting an adenosine Al receptor antagonist from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering an adenosine Al receptor antagonist to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, an adenosine Al receptor antagonist is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, an adenosine Al receptor antagonist is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and an adenosine Al receptor antagonist is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, an adenosine Al receptor antagonist is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, an adenosine A1 receptor antagonist is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching an adenosine Al receptor antagonist to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, an adenosine Al receptor antagonist and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXIII The present invention provides covalent attachment of the active agent (mercaptopurine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching

mercaptopurine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mercaptopurine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mercaptopurine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mercaptopurine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mercaptopurine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mercaptopurine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mercaptopurine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mercaptopurine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mercaptopurine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, mercaptopurine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, mercaptopurine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching mercaptopurine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mercaptopurine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXXIV The present invention provides covalent attachment of the active agent (meropenem) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching meropenem to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising meropenem microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and meropenem covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Meropenem preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting meropenem from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering meropenem to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, meropenem is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, meropenem is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and meropenem is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, meropenem is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, meropenem is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching meropenem to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, meropenem and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine,

cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXV The present invention provides covalent attachment of the active agent (mesalamine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching mesalamine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mesalamine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mesalamine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mesalamine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mesalamine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mesalamine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mesalamine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mesalamine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mesalamine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, mesalamine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, mesalamine is released from the

composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching mesalamine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mesalamine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXXVI The present invention provides covalent attachment of the active agent (mesna) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching mesna to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mesna microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mesna covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mesna preferably is covalently attached to a side chain, the N-terminus or the C- terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mesna from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mesna to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mesna is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mesna is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mesna is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, mesna is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, mesna is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching mesna to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mesna and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXXVII The present invention provides covalent attachment of the active agent (metaxalone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching metaxalone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising metaxalone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and metaxalone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Metaxalone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting metaxalone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering metaxalone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, metaxalone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, metaxalone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and metaxalone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, metaxalone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, metaxalone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching metaxalone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, metaxalone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released

from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXVIII The present invention provides covalent attachment of the active agent (Metformin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching Metformin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising Metformin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and Metformin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Metformin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting Metformin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering Metformin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, Metformin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, Metformin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and Metformin is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, Metformin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, Metformin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant. from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching Metformin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, Metformin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXIX The present invention provides covalent attachment of the active agent (an oral nonsteroidal antiestrogen compound) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching an oral nonsteroidal antiestrogen compound to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.

In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising an oral nonsteroidal antiestrogen compound microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and an oral nonsteroidal antiestrogen compound covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

An oral nonsteroidal antiestrogen compound preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N- terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-

terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting an oral nonsteroidal antiestrogen compound from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering an oral nonsteroidal antiestrogen compound to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, an oral nonsteroidal antiestrogen compound is released from the composition by an enzyme- catalyzed release. In another preferred embodiment, an oral nonsteroidal antiestrogen compound is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and an oral nonsteroidal antiestrogen compound is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, an oral nonsteroidal antiestrogen compound is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, an oral nonsteroidal antiestrogen compound is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The

adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching an oral nonsteroidal antiestrogen compound to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, an oral nonsteroidal antiestrogen compound and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXX The present invention provides covalent attachment of the active agent (methylphenidate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching methylphenidate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising methylphenidate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and methylphenidate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Methylphenidate preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino

acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting methylphenidate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering methylphenidate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, methylphenidate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, methylphenidate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and methylphenidate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, methylphenidate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, methylphenidate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching methylphenidate to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, methylphenidate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXXXI The present invention provides covalent attachment of the active agent (methylprednisone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching methylprednisone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper, intestinal tract, indigenous enzymes release the active ingredient for

absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising methylprednisone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and methylprednisone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Methylprednisone preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting methylprednisone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering methylprednisone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, methylprednisone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, methylprednisone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and methylprednisone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, methylprednisone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, methylprednisone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

. The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching methylprednisone to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, methylprednisone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular

transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXXII The present invention provides covalent attachment of the active agent (an antifungal agent) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching an antifungal agent to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising an antifungal agent microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and an antifungal agent covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or

(vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

An antifungal agent preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus. of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent : In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting an antifungal agent from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering an antifungal agent to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, an antifungal agent is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, an antifungal agent is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and an antifungal agent is released from the composition by dissolution of the microencapsulating agent. In another

preferred embodiment, an antifungal agent is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, an antifungal agent is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching an antifungal agent to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, an antifungal agent and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXXXIII The present invention provides covalent attachment of the active agent (metolazone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching metolazone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising metolazone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and metolazone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Metolazone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting metolazone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering metolazone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, metolazone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, metolazone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and metolazone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, metolazone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, metolazone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching metolazone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, metolazone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXXIV The present invention provides covalent attachment of the active agent (metoprolol) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching metoprolol to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising metoprolol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and metoprolol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Metoprolol preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting metoprolol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering metoprolol to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, metoprolol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, metoprolol is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and metoprolol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, metoprolol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, metoprolol is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching metoprolol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, metoprolol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino'acid is glutamic acid and the active agent is released

from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXXXV The present invention provides covalent attachment of the active agent (a carbapenem antibiotic) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a carbapenem antibiotic to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.

In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a carbapenem antibiotic microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a carbapenem antibiotic covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a

homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A carbapenem antibiotic preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a carbapenem antibiotic from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a carbapenem antibiotic to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a carbapenem antibiotic is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, a carbapenem antibiotic is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a carbapenem

antibiotic is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a carbapenem antibiotic is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a carbapenem antibiotic is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching a carbapenem antibiotic to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a carbapenem antibiotic and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXXVI The present invention provides covalent attachment of the active agent (metronidazole) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching metronidazole to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

. Alternatively, the present invention provides a pharmaceutical composition comprising metronidazole microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and metronidazole covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Metronidazole preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another

preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting metronidazole from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering metronidazole to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, metronidazole is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, metronidazole is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and metronidazole is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, metronidazole is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, metronidazole is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching metronidazole to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, metronidazole and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXXVII The present invention provides covalent attachment of the active agent (milrinone lactate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching milrinone lactate to the N-terminus, the C-terminus or directly to the amino acid side

chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising milrinone lactate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and milrinone lactate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Milrinone lactate preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting milrinone lactate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering milrinone lactate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, milrinone lactate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, milrinone lactate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and milrinone lactate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, milrinone lactate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, milrinone lactate. is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching milrinone lactate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, milrinone lactate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCLXXXVIII The present invention provides covalent attachment of the active agent (minocycline) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching minocycline to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising minocycline microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and minocycline covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Minocycline preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting minocycline from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering minocycline to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, minocycline is released from the composition

by an enzyme-catalyzed release. In another preferred embodiment, minocycline is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and minocycline is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, minocycline is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, minocycline is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching minocycline to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, minocycline and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a

carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCLXXXIX The present invention provides covalent attachment of the active agent (mirtazapine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching mirtazapine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mirtazapine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mirtazapine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mirtazapine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In

another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and-a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mirtazapine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mirtazapine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mirtazapine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mirtazapine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mirtazapine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, mirtazapine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, mirtazapine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The

adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching mirtazapine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mirtazapine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCXC The present invention provides covalent attachment of the active agent (misoprostol) to a polymer of peptides or amino acids. The invention is distinguished

from the above-mentioned technologies by virtue of covalently attaching misoprostol to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising misoprostol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and misoprostol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Misoprostol preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting misoprostol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering misoprostol to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, misoprostol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, misoprostol is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and misoprostol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, misoprostol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, misoprostol is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching misoprostol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, misoprostol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the, active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCXCI The present invention provides covalent attachment of the active agent (mitiglinide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching mitiglinide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mitiglinide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mitiglinide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mitiglinide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mitiglinide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mitiglinide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mitiglinide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mitiglinide is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mitiglinide is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, mitiglinide is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, mitiglinide is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching mitiglinide to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mitiglinide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine,

cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCXCII The present invention provides covalent attachment of the active agent (mitoxantrone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching mitoxantrone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mitoxantrone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mitoxantrone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mitoxantrone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mitoxantrone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mitoxantrone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mitoxantrone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mitoxantrone is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mitoxantrone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, mitoxantrone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, mitoxantrone is released from the

composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching mitoxantrone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mitoxantrone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCXCIII The present invention provides covalent attachment of the active agent (mivacurium) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching mivacurium to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mivacurium microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mivacurium covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mivacurium preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mivacurium from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mivacurium to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mivacurium is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mivacurium is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mivacurium is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, mivacurium is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, mivacurium is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching mivacurium to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mivacurium and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCXCIV The present invention provides covalent attachment of the active agent (modafinil) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching modafinil to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising modafinil microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and modafinil covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Modafinil preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting modafinil from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering modafinil to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, modafinil is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, modafinil is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and modafinil is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, modafinil is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, modafinil is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching modafinil to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, modafinil and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCXCV The present invention provides covalent attachment of the active agent (moexipril) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching moexipril to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively,. the present invention provides a pharmaceutical composition comprising moexipril microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and moexipril covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Moexipril preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting moexipril from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering moexipril to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, moexipril is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, moexipril is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and moexipril is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, moexipril is released

from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, moexipril is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching moexipril to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, moexipril and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCXCVI The present invention provides covalent attachment of the active agent (montelukast) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching montelukast to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising montelukast microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and montelukast covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Montelukast preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting montelukast from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering montelukast to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, montelukast is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, montelukast is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and montelukast is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, montelukast is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, montelukast is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching montelukast to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, montelukast and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCXCVII The present invention provides covalent attachment of the active agent (morphine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching morphine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising morphine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and morphine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Morphine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting morphine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering morphine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, morphine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, morphine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and morphine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, morphine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, morphine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching morphine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, morphine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCXCVIII The present invention provides covalent attachment of the active agent (mycophenylate mofetil) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching mycophenylate mofetil to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.

In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising mycophenylate mofetil microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and mycophenylate mofetil covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more

synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Mycophenylate mofetil preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting mycophenylate mofetil from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering mycophenylate mofetil to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, mycophenylate mofetil is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, mycophenylate mofetil is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and mycophenylate mofetil is released from the composition by dissolution of the microencapsulating agent. In another

preferred embodiment, mycophenylate mofetil is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, mycophenylate mofetil is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching mycophenylate mofetil to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, mycophenylate mofetil and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCXCIX The present invention provides covalent attachment of the active agent (nabumetone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nabumetone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nabumetone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nabumetone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nabumetone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nabumetone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nabumetone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nabumetone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nabumetone is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nabumetone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nabumetone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nabumetone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching nabumetone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agentlamino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nabumetone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCC The present invention provides covalent attachment of the active agent (nadolol) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nadolol to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nadolol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nadolol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nadolol preferably is covalently attached to a side chain, the N-terminus or the C- terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nadolol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nadolol to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nadolol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nadolol is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and nadolol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nadolol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nadolol is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nadolol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nadolol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCI The present invention provides covalent attachment of the active agent (naproxen) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching naproxen to. the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising naproxen microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and naproxen covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Naproxen preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting naproxen from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering naproxen to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, naproxen is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, naproxen is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and naproxen is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, naproxen is released

from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, naproxen is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching naproxen to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with-a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, naproxen and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCII The present invention provides covalent attachment of the active agent (naratriptan) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching naratriptan to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising naratriptan microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and naratriptan covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Naratriptan preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

* The invention also provides a method for protecting naratriptan from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering naratriptan to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, naratriptan is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, naratriptan is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and naratriptan is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, naratriptan is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, naratriptan is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching naratriptan to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, naratriptan and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCIII The present invention provides covalent attachment of the active agent (nefazodone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nefazodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nefazodone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nefazodone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nefazodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active. agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nefazodone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nefazodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nefazodone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nefazodone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nefazodone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nefazodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nefazodone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nefazodone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nefazodone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released

from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCIV The present invention provides covalent attachment of the active agent (nelarabine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nelarabine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nelarabine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nelarabine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nelarabine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nelarabine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nelarabine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nelarabine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nelarabine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nelarabine is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, nelarabine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nelarabine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nelarabine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nelarabine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCV The present invention provides covalent attachment of the active agent (nelfinavir mesylate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nelfinavir mesylate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nelfinavir mesylate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nelfinavir mesylate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nelfinavir mesylate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nelfinavir mesylate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nelfinavir mesylate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nelfinavir mesylate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nelfinavir mesylate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nelfinavir mesylate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nelfinavir mesylate is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, nelfinavir mesylate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching nelfinavir mesylate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nelfinavir mesylate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCVI The present invention provides covalent attachment of the active agent (nesiritide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nesiritide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nesiritide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nesiritide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nesiritide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another. preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nesiritide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nesiritide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nesiritide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nesiritide is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and nesiritide is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nesiritide is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nesiritide is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nesiritide to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nesiritide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCVII The present invention provides covalent attachment of the active agent (nevirapine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nevirapine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nevirapine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nevirapine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nevirapine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nevirapine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nevirapine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nevirapine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nevirapine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nevirapine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nevirapine is released

from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nevirapine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nevirapine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nevirapine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCVIII The present invention provides covalent attachment of the active agent (nifedipine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nifedipine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nifedipine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nifedipine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nifedipine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nifedipine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nifedipine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nifedipine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nifedipine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nifedipine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nifedipine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nifedipine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to. the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching nifedipine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nifedipine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCIX The present invention provides covalent attachment of the active agent (nimodipine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nimodipine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nimodipine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nimodipine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nimodipine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another. preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nimodipine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nimodipine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nimodipine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nimodipine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nimodipine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nimodipine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nimodipine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nimodipine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nimodipine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released

from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCX The present invention provides covalent attachment of the active agent (nisoldipine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nisoldipine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nisoldipine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nisoldipine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nisoldipine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nisoldipine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nisoldipine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nisoldipine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nisoldipine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nisoldipine is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, nisoldipine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nisoldipine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nisoldipine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nisoldipine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXI The present invention provides covalent attachment of the active agent (nitrofurantoin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nitrofurantoin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nitrofurantoin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nitrofurantoin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nitrofurantoin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another

preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nitrofurantoin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nitrofurantoin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nitrofurantoin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nitrofurantoin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nitrofurantoin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nitrofurantoin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nitrofurantoin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The. adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nitrofurantoin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nitrofurantoin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the. following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXII The present invention provides covalent attachment of the active agent (nitroglycerin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nitroglycerin to the N-terminus, the C-terminus or directly to the amino acid side chain of

an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nitroglycerin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nitroglycerin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nitroglycerin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nitroglycerin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nitroglycerin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nitroglycerin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nitroglycerin is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nitroglycerin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nitroglycerin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nitroglycerin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nitroglycerin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nitroglycerin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXIII The present invention provides covalent attachment of the active agent (nizatidine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nizatidine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nizatidine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nizatidine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nizatidine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nizatidine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nizatidine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nizatidine is released from the composition by

an enzyme-catalyzed release. In another preferred embodiment, nizatidine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nizatidine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nizatidine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nizatidine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nizatidine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nizatidine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the

glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXIV The present invention provides covalent attachment of the active agent (norastemizole) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching norastemizole to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising norastemizole microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and norastemizole covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Norastemizole preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to

the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting norastemizole from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering norastemizole to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, norastemizole is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, norastemizole is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and norastemizole is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, norastemizole is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, norastemizole is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The

adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching norastemizole to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, norastemizole and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXV The present invention provides covalent attachment of the active agent (norethindrone) to a polymer of peptides or amino acids. The invention is

distinguished from the above-mentioned technologies by virtue of covalently attaching norethindrone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising norethindrone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and norethindrone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Norethindrone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting norethindrone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering norethindrone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, norethindrone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, norethindrone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and norethindrone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, norethindrone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, norethindrone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching norethindrone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, norethindrone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXVI The present invention provides covalent attachment of the active agent (norfloxacin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching norfloxacin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising norfloxacin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and norfloxacin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Norfloxacin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting norfloxacin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering norfloxacin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, norfloxacin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, norfloxacin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and norfloxacin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, norfloxacin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, norfloxacin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching norfloxacin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, norfloxacin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine,

cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXVII The present invention provides covalent attachment of the active agent (nortriptyline) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching nortriptyline to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising nortriptyline microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and nortriptyline covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Nortriptyline preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting nortriptyline from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering nortriptyline to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, nortriptyline is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, nortriptyline is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and nortriptyline is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, nortriptyline is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, nortriptyline is released from the

composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching nortriptyline to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, nortriptyline and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXVIII The present invention provides covalent attachment of the active agent (octreotide acetate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching octreotide acetate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising octreotide acetate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and octreotide acetate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Octreotide acetate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting octreotide acetate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering octreotide acetate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, octreotide acetate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, octreotide acetate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and octreotide acetate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, octreotide acetate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, octreotide acetate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching octreotide acetate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, octreotide acetate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXIX The present invention provides covalent attachment of the active agent (oxycodone and acetaminophen) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching oxycodone and acetaminophen to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications,

delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising oxycodone and acetaminophen microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and oxycodone and acetaminophen covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Oxycodone and acetaminophen preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In

another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting oxycodone and acetaminophen from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering oxycodone and acetaminophen to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, oxycodone and acetaminophen are released from the composition by an enzyme- catalyzed release. In another preferred embodiment, oxycodone and acetaminophen are released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and oxycodone and acetaminophen are released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, oxycodone and acetaminophen are released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, oxycodone and acetaminophen are released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching oxycodone and acetaminophen to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, oxycodone and acetaminophen and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXX The present invention provides covalent attachment of the active agent (ofloxacin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ofloxacin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ofloxacin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ofloxacin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ofloxacin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ofloxacin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ofloxacin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ofloxacin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ofloxacin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and ofloxacin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ofloxacin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ofloxacin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ofloxacin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ofloxacin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side

chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXI The present invention provides covalent attachment of the active agent (olanzapine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching olanzapine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising olanzapine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and olanzapine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Olanzapine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a

carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting olanzapine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering olanzapine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, olanzapine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, olanzapine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and olanzapine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, olanzapine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, olanzapine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the

composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching olanzapine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, olanzapine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXII The present invention provides covalent attachment of the active agent (omeprezole) to a polymer of peptides or amino acids. The invention is

distinguished from the above-mentioned technologies by virtue of covalently attaching omeprezole to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising omeprezole microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and omeprezole covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Omeprezole preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting omeprezole from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering omeprezole to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, omeprezole is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, omeprezole is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and omeprezole is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, omeprezole is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, omeprezole is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching omeprezole to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, omeprezole and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXIII The present invention provides covalent attachment of the active agent (ondansetron) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ondansetron to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ondansetron microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ondansetron covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ondansetron preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ondansetron from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ondansetron to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ondansetron is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ondansetron is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and ondansetron is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ondansetron is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ondansetron is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ondansetron to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ondansetron and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine,

cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXIV The present invention provides covalent attachment of the active agent (oprelvekin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching oprelvekin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising oprelvekin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and oprelvekin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Oprelvekin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting oprelvekin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering oprelvekin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, oprelvekin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, oprelvekin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and oprelvekin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, oprelvekin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, oprelvekin is released from the composition in a sustained

release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching oprelvekin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, oprelvekin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXXV The present invention provides covalent attachment of the active agent (orlistat) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching orlistat to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising orlistat microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and orlistat covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Orlistat preferably is covalently attached to a side chain, the N-terminus or the C- terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino

acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting orlistat from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering orlistat to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, orlistat is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, orlistat is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and orlistat is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, orlistat is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, orlistat is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching orlistat to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, orlistat and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXXVI The present invention provides covalent attachment of the active agent (orphenadrine citrate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching orphenadrine citrate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising orphenadrine citrate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and orphenadrine citrate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Orphenadrine citrate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting orphenadrine citrate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering orphenadrine citrate to a patient, the patient being a human or a non-human animal, comprising administering to

the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, orphenadrine citrate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, orphenadrine citrate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and orphenadrine citrate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, orphenadrine citrate is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, orphenadrine citrate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching orphenadrine citrate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, orphenadrine citrate and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine,

cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXXVII The present invention provides covalent attachment of the active agent (oxaprozin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching oxaprozin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising oxaprozin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and oxaprozin covalently attached to. the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Oxaprozin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting oxaprozin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering oxaprozin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, oxaprozin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, oxaprozin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and oxaprozin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, oxaprozin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, oxaprozin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide. and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching oxaprozin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, oxaprozin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference. *

CCCXXVIII The present invention provides covalent attachment of the active agent (oxazepam) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching oxazepam to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising oxazepam microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and oxazepam covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Oxazepam preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino

acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting oxazepam from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering oxazepam to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, oxazepam is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, oxazepam is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and oxazepam is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, oxazepam is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, oxazepam is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching oxazepam to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, oxazepam and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXIX The present invention provides covalent attachment of the active agent (Oxybutynin chloride) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching Oxybutynin chloride to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising Oxybutynin chloride microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and Oxybutynin chloride covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Oxybutynin chloride preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting Oxybutynin chloride from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering Oxybutynin chloride to a patient, the patient being a human or a non-human animal, comprising administering to

the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, Oxybutynin chloride is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, Oxybutynin chloride is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and Oxybutynin chloride is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, Oxybutynin chloride is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, Oxybutynin chloride is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching Oxybutynin chloride to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, Oxybutynin chloride and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine,

cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXXX The present invention provides covalent attachment of the active agent (oxycodone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching oxycodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising oxycodone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and oxycodone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Oxycodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting oxycodone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering oxycodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, oxycodone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, oxycodone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and oxycodone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, oxycodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, oxycodone is released from the composition in a

sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching oxycodone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, oxycodone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonirie, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXXI The present invention provides covalent attachment of the active agent (a gastroprokinetic compound) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a gastroprokinetic compound to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a gastroprokinetic compound microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a gastroprokinetic compound covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A gastroprokinetic compound preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a gastroprokinetic compound from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a gastroprokinetic compound to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a gastroprokinetic compound is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, a gastroprokinetic compound is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a gastroprokinetic compound is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a gastroprokinetic compound is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a gastroprokinetic compound is released from the composition, in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching a gastroprokinetic compound to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a gastroprokinetic compound and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXXII The present invention provides covalent attachment of the active agent (a macrophage colony stimulating factor) to a polymer of peptides or amino acids.

The invention is distinguished from the above-mentioned technologies by virtue of

covalently attaching a macrophage colony stimulating factor to the N-terminus, the C- terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.

In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a macrophage colony stimulating factor microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a macrophage colony stimulating factor covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more-naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A macrophage colony stimulating factor preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N- terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C- terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a macrophage colony stimulating factor from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a macrophage colony stimulating factor to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a macrophage colony stimulating factor is released from the composition by an enzyme- catalyzed release. In another preferred embodiment, a macrophage colony stimulating factor is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a macrophage colony stimulating factor is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a macrophage colony stimulating factor is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a macrophage colony stimulating factor is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching a macrophage colony stimulating factor to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a macrophage colony stimulating factor and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXXIII The present invention provides covalent attachment of the active agent (pagoclone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pagoclone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the

upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pagoclone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pagoclone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pagoclone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pagoclone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pagoclone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pagoclone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pagoclone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pagoclone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pagoclone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pagoclone is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching pagoclone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pagoclone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXXXIV The present invention provides covalent attachment of the active agent (palivizumab) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching palivizumab to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising palivizumab microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and palivizumab covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Palivizumab preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting palivizumab from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering palivizumab to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, palivizumab is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, palivizumab is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and palivizumab is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment,

palivizumab is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, palivizumab is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of (a) attaching palivizumab to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, palivizumab and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXXV The present invention provides covalent attachment of the active agent (pamidronate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pamidronate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pamidronate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pamidronate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pamidronate preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pamidronate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pamidronate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pamidronate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pamidronate is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pamidronate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pamidronate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pamidronate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching pamidronate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pamidronate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incorporated herein by reference.

CCCXXXVI The present invention provides covalent attachment of the active agent (paricalcitrol) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching paricalcitrol to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising paricalcitrol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and paricalcitrol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Paricalcitrol preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting paricalcitrol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering paricalcitrol to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, paricalcitrol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, paricalcitrol is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and paricalcitrol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, paricalcitrol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, paricalcitrol is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching paricalcitrol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, paricalcitrol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXXXVII The present invention provides covalent attachment of the active agent (paroxetine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching paroxetine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising paroxetine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and paroxetine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Paroxetine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting paroxetine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering paroxetine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, paroxetine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, paroxetine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and paroxetine is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, paroxetine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, paroxetine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching paroxetine to a side chain of an amino acid to form an active agentlamino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, paroxetine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXXXVIIIThe present invention provides covalent attachment of the active agent (pemetrexed) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pemetrexed to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pemetrexed microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pemetrexed covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pemetrexed preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pemetrexed from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pemetrexed to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pemetrexed is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pemetrexed is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pemetrexed is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pemetrexed is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pemetrexed is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching pemetrexed to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pemetrexed and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXXXIX The present invention provides covalent attachment of the active agent (pemoline) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pemoline to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pemoline microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pemoline covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pemoline preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pemoline from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pemoline to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pemoline is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pemoline is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and pemoline is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pemoline is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pemoline is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching pemoline to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pemoline and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXL The present invention provides covalent attachment of the active agent (penicillin V) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching- penicillin V to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising penicillin V microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and penicillin V covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Penicillin V preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting penicillin V from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering penicillin V to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, penicillin V is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, penicillin V is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and penicillin V is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, penicillin

V is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, penicillin V is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching penicillin V to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, penicillin V and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXLI The present invention provides covalent attachment of the active agent (pentosan polysulfate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pentosan polysulfate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pentosan polysulfate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pentosan polysulfate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pentosan polysulfate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pentosan polysulfate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pentosan polysulfate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pentosan polysulfate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pentosan polysulfate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pentosan polysulfate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pentosan polysulfate is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, pentosan polysulfate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching pentosan polysulfate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pentosan polysulfate and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXLII The present invention provides covalent attachment of the active agent (pentoxifylline) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pentoxifylline to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pentoxifylline microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pentoxifylline covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pentoxifylline preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet. another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pentoxifylline from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pentoxifylline to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pentoxifylline is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pentoxifylline is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pentoxifylline is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pentoxifylline is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pentoxifylline is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching pentoxifylline to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pentoxifylline and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXLIII The present invention provides covalent attachment of the active agent (pergolide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pergolide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pergolide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pergolide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pergolide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pergolide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pergolide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pergolide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pergolide is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and pergolide is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, pergolide is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pergolide is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of- (a) attaching pergolide to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pergolide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXLIV The present invention provides covalent attachment of the active agent (an orally active carbohydrate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching an orally active carbohydrate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising an orally active carbohydrate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and an orally active carbohydrate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

An orally active carbohydrate preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet

another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting an orally active carbohydrate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering an orally active carbohydrate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, an orally active carbohydrate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, an orally active carbohydrate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and an orally active carbohydrate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, an orally active carbohydrate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, an orally active carbohydrate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching an orally active carbohydrate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, an orally active carbohydrate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXLV The present invention provides covalent attachment of the active agent (phenobarbital) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching

phenobarbital to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising phenobarbital microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and phenobarbital covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Phenobarbital preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting phenobarbital from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering phenobarbital to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, phenobarbital is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, phenobarbital is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and phenobarbital is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, phenobarbital is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, phenobarbital is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching phenobarbital to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, phenobarbital and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXLVI The present invention provides covalent attachment of the active agent (phenytoin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching phenytoin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising phenytoin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and phenytoin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Phenytoin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting phenytoin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering phenytoin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, phenytoin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, phenytoin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and phenytoin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, phenytoin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, phenytoin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching phenytoin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, phenytoin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side

chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXLVII The present invention provides covalent attachment of the active agent (pioglitazone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pioglitazone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pioglitazone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pioglitazone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pioglitazone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a

carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pioglitazone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pioglitazone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pioglitazone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pioglitazone is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pioglitazone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pioglitazone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pioglitazone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and

release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching pioglitazone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pioglitazone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the. side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXLVIII The present invention provides covalent attachment of the active agent (piperacillin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching piperacillin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising piperacillin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and piperacillin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Piperacillin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino

acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting piperacillin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering piperacillin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, piperacillin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, piperacillin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and piperacillin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, piperacillin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, piperacillin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching piperacillin to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, piperacillin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXLIX The present invention provides covalent attachment of the active agent (pleconaril) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pleconaril to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by

the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pleconaril microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pleconaril covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pleconaril preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pleconaril from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pleconaril to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pleconaril is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pleconaril is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pleconaril is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pleconaril is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pleconaril is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching pleconaril to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pleconaril and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an

amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCL The present invention provides covalent attachment of the active agent (poloxamer 188) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching poloxamer 188 to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising poloxamer 188 microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and poloxamer 188 covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Poloxamer 188 preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting poloxamer 188 from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering poloxamer 188 to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, poloxamer 188 is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, poloxamer 188 is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and poloxamer 188 is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, poloxamer 188 is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, poloxamer 188 is

released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching poloxamer 188 to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, poloxamer 188 and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLIThe present invention provides covalent attachment of the active agent (posaconazole) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching posaconazole to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising posaconazole microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and posaconazole covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Posaconazole preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting posaconazole from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering posaconazole to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, posaconazole is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, posaconazole is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and posaconazole is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, posaconazole is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, posaconazole is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching posaconazole to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, posaconazole and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLII The present invention provides covalent attachment of the active agent (an insulin analogue) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching an insulin analogue to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active

agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising an insulin analogue microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and an insulin analogue covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

An insulin analogue preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting an insulin analogue from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering an insulin analogue to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, an insulin analogue is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, an insulin analogue is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and an insulin analogue is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, an insulin analogue is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, an insulin analogue is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the. polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching an insulin analogue to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, an insulin analogue and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLIII The present invention provides covalent attachment of the active agent (pramipexole) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pramipexole to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pramipexole microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pramipexole covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pramipexole preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

. Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pramipexole from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pramipexole to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pramipexole is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pramipexole is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pramipexole is released from the composition by

dissolution of the microencapsulating agent. In another preferred embodiment, pramipexole is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pramipexole is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching pramipexole to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pramipexole and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLIV The present invention provides covalent attachment of the active agent (pravastatin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pravastatin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pravastatin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pravastatin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pravastatin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another

preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pravastatin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pravastatin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pravastatin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pravastatin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pravastatin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pravastatin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pravastatin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further. comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching pravastatin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pravastatin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLV The present invention provides covalent attachment of the active agent (prednisone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching prednisone to the N-terminus, the C-terminus or directly to the amino acid side chain of

an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising prednisone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and prednisone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Prednisone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting prednisone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering prednisone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, prednisone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, prednisone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and prednisone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, prednisone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, prednisone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching prednisone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, prednisone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLVI The present invention provides covalent attachment of the active agent (pregabalin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pregabalin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pregabalin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pregabalin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pregabalin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pregabalin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pregabalin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pregabalin is released from the composition by

an enzyme-catalyzed release. In another preferred embodiment, pregabalin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a . microencapsulating agent and pregabalin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, pregabalin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pregabalin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching pregabalin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pregabalin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the

glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLVII The present invention provides covalent attachment of the active agent (primidone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching primidone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising primidone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and primidone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Primidone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to

the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting primidone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering primidone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, primidone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, primidone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and primidone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, primidone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, primidone is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching primidone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, primidone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLVIII The present invention provides covalent attachment of the active agent (prinomastat) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching prinomastat to the N-terminus, the C-terminus or directly to the amino acid side chain of

an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising prinomastat microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and prinomastat covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Prinomastat preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting prinomastat from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering prinomastat to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, prinomastat is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, prinomastat is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and prinomastat is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, prinomastat is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, prinomastat is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching prinomastat to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, prinomastat and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLIX The present invention provides covalent attachment of the active agent (prochlorperazine maleate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching prochlorperazine maleate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.

In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising prochlorperazine maleate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and prochlorperazine maleate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Prochlorperazine maleate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting prochlorperazine maleate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering prochlorperazine maleate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, prochlorperazine maleate is

released from the composition by an enzyme-catalyzed release. In another preferred embodiment, prochlorperazine maleate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and prochlorperazine maleate is released from the composition by dissolution of the microencapsulating agent.

In another preferred embodiment, prochlorperazine maleate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, prochlorperazine maleate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching prochlorperazine maleate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, prochlorperazine maleate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an

ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLX The present invention provides covalent attachment of the active agent (promethazine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching promethazine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising promethazine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and promethazine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Promethazine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a

carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting promethazine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering promethazine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, promethazine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, promethazine is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and promethazine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, promethazine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, promethazine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and

release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching promethazine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, promethazine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXI The present invention provides covalent attachment of the active agent (a cholecystokinin antagonist) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a cholecystokinin antagonist to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a cholecystokinin antagonist microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a cholecystokinin antagonist covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A cholecystokinin antagonist preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The

microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a cholecystokinin antagonist from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a cholecystokinin antagonist to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a cholecystokinin antagonist is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, a cholecystokinin antagonist is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a cholecystokinin antagonist is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a cholecystokinin antagonist is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a cholecystokinin antagonist is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method compnses the steps of :

(a) attaching a cholecystokinin antagonist to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a cholecystokinin antagonist and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXII The present invention provides covalent attachment of the active agent (propoxyphene) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching propoxyphene to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach,

through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising propoxyphene microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and propoxyphene covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Propoxyphene preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In

another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting propoxyphene from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering propoxyphene to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, propoxyphene is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, propoxyphene is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and propoxyphene is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, propoxyphene is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, propoxyphene is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching propoxyphene to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second

agent, propoxyphene and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642 ; 820, filed August 22,2000, incorporated herein by reference.

CCCLXIII The present invention provides covalent attachment of the active agent (propranolol) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching propranolol to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising propranolol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and propranolol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide,

(ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Propranolol preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting propranolol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering propranolol to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, propranolol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, propranolol is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed

release. In another preferred embodiment, the composition further comprises a microencapsulating agent and propranolol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, propranolol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, propranolol is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching propranolol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, propranolol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the

glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXIV The present invention provides covalent attachment of the active agent (prourokinase) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching prourokinase to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising prourokinase microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and prourokinase covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Prourokinase preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to

the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting prourokinase from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering prourokinase to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, prourokinase is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, prourokinase is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and prourokinase is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, prourokinase is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, prourokinase is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The

adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching prourokinase to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, prourokinase and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXV The present invention provides covalent attachment of the active agent (quetiapine fumarate) to a polymer of peptides or amino acids. The invention is

distinguished from the above-mentioned technologies by virtue of covalently attaching quetiapine fumarate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising quettapine fumarate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and quetiapine fumarate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Quetiapine fumarate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting quetiapine fumarate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering quetiapine fumarate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, quetiapine fumarate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, quetiapine fumarate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and quetiapine fumarate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, quetiapine fumarate is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, quetiapine fumarate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching quetiapine fumarate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, quetiapine fumarate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXVI The present invention provides covalent attachment of the active agent (quinapril) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching quinapril to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising quinapril microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and quinapril covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Quinapril preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting quinapril from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering quinapril to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, quinapril is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, quinapril is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and quinapril is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, quinapril is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, quinapril is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching quinapril to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, quinapril and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side j

chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXVII The present invention provides covalent attachment of the active agent (rabeprazole) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching rabeprazole to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising rabeprazole microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and rabeprazole covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Rabeprazole preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a

carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is . an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting rabeprazole from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering rabeprazole to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, rabeprazole is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, rabeprazole is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and rabeprazole is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, rabeprazole is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, rabeprazole is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and

release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching rabeprazole to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, rabeprazole and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXVIII The present invention provides covalent attachment of the active agent (raloxifene) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching raloxifene to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising raloxifene microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and raloxifene covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Raloxifene preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino

acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting raloxifene from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering raloxifene to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, raloxifene is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, raloxifene is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and raloxifene is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, raloxifene is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, raloxifene is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching raloxifene to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, raloxifene and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the-active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXIX The present invention provides covalent attachment of the active agent (ramipril) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ramipril to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ramipril microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ramipril covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ramipril preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ramipril from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ramipril to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ramipril is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ramipril is released in a . time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and ramipril is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ramipril is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ramipril is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ramipril to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ramipril and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side

chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXX The present invention provides covalent attachment of the active agent (ranitidine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ranitidine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ranitidine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ranitidine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ranitidine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a

carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ranitidine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ranitidine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ranitidine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ranitidine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and ranitidine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ranitidine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ranitidine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is

controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ranitidine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ranitidine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester,. an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXXI The present invention provides covalent attachment of the active agent (ranolazine) to a polymer of peptides or amino acids. The invention is

distinguished from the above-mentioned technologies by virtue of covalently attaching ranolazine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ranolazine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ranolazine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ranolazine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ranolazine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ranolazine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ranolazine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ranolazine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and ranolazine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ranolazine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ranolazine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ranolazine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ranolazine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXXII The present invention provides covalent attachment of the active agent (relaxin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching relaxin to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising relaxin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and relaxin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Relaxin preferably is covalently attached to a side chain, the N-terminus or the C- terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting relaxin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering relaxin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, relaxin is released from the composition by an

enzyme-catalyzed release. In another preferred embodiment, relaxin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and relaxin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, relaxin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, relaxin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching relaxin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, relaxin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the

glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXXIII The present invention provides covalent attachment of the active agent (remacemide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching remacemide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising remacemide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and remacemide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Remacemide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to

the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting remacemide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering remacemide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, remacemide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, remacemide is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and remacemide is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, remacemide is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, remacemide is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The

adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching remacemide to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, remacemide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXXIV The present invention provides covalent attachment of the active agent (repaglinide) to a polymer of peptides or amino acids. The invention is

distinguished from the above-mentioned technologies by virtue of covalently attaching repaglinide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising repaglinide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and repaglinide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Repaglinide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting repaglinide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering repaglinide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, repaglinide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, repaglinide is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and repaglinide is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, repaglinide is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, repaglinide is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching repaglinide to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, repaglinide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXV The present invention provides covalent attachment of the active agent (repinotan) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching repinotan to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising repinotan microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and repinotan covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Repinotan preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting repinotan from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering repinotan to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, repinotan is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, repinotan is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and repinotan is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, repinotan is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, repinotan is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching repinotan to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, repinotan and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side

chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXXVI The present invention provides covalent attachment of the active agent (ribavirin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ribavirin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ribavirin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ribavirin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ribavirin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a

carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ribavirin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ribavirin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ribavirin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ribavirin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and ribavirin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ribavirin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ribavirin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is

controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ribavirin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ribavirin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXVII The present invention provides covalent attachment of the active agent (riluzole) to a polymer of peptides or amino acids. The invention is distinguished

from the above-mentioned technologies by virtue of covalently attaching riluzole to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selecitively hydrolyzing the peptide bondes of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising riluzole microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and riluzole covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Riluzole preferably is covalently attached to a side chain, the N-terminus or the C- terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting riluzole from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering riluzole to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, riluzole is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, riluzole is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and riluzole is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, riluzole is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, riluzole is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching riluzole to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, riluzole and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXVIII The present invention provides covalent attachment of the active agent (rimantadine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching rimantadine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising rimantadine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and rimantadine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Rimantadine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting rimantadine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering rimantadine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, rimantadine is released from the composition by

an enzyme-catalyzed release. In another preferred embodiment, rimantadine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and rimantadine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, rimantadine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, rimantadine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be inicroencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching rimantadine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, rimantadine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a

carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXXIX The present invention provides covalent attachment of the active agent (risperidone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching risperidone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising risperidone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and risperidone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Risperidone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In

another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting risperidone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering risperidone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, risperidone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, risperidone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and risperidone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, risperidone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, risperidone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be

microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching risperidone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, risperidone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester,. an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXX The present invention provides covalent attachment of the active agent (ritonavir) to a polymer of peptides or amino acids. The invention is distinguished

from the above-mentioned technologies by virtue of covalently attaching ritonavir to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ritonavir microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ritonavir covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ritonavir preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ritonavir from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ritonavir to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ritonavir is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ritonavir is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and ritonavir is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ritonavir is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ritonavir is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ritonavir to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ritonavir and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXXI The present invention provides covalent attachment of the active agent (rizatriptan benzoate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching rizatriptan benzoate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising rizatriptan benzoate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and rizatriptan benzoate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Rizatriptan benzoate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting rizatriptan benzoate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering rizatriptan benzoate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, rizatriptan benzoate is released

from the composition by an enzyme-catalyzed release. In another preferred embodiment, rizatriptan benzoate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and rizatriptan benzoate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, rizatriptan benzoate is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, rizatriptan benzoate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching rizatriptan benzoate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, rizatriptan benzoate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a

carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXXXII The present invention provides covalent attachment of the active agent (rocuronium) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching rocuronium to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising rocuronium microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and rocuronium covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Rocuronium preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In

another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting rocuronium from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering rocuronium to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, rocuronium is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, rocuronium is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and rocuronium is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, rocuronium is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, rocuronium is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The

adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching rocuronium to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, rocuronium and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXXIII The present invention provides covalent attachment of the active agent (rofecoxib) to a polymer of peptides or amino acids. The invention is distinguished

from the above-mentioned technologies by virtue of covalently attaching rofecoxib to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising rofecoxib microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and rofecoxib covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Rofecoxib preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting rofecoxib from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering rofecoxib to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, rofecoxib is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, rofecoxib is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and rofecoxib is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, rofecoxib is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, rofecoxib is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching rofecoxib to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, rofecoxib and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXXIV The present invention provides covalent attachment of the active agent (ropinirole) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ropinirole to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ropinirole microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ropinirole covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ropinirole preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ropinirole from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ropinirole to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ropinirole is released from the composition by

an enzyme-catalyzed release. In another preferred embodiment, ropinirole is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and ropinirole is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ropinirole is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ropinirole is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ropinirole to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ropinirole and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the

glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXXV The present invention provides covalent attachment of the active agent (rosiglitazone maleate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching rosiglitazone maleate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising rosiglitazone maleate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and rosiglitazone maleate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Rosiglitazone maleate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached

to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting rosiglitazone maleate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering rosiglitazone maleate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, rosiglitazone maleate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, rosiglitazone maleate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and rosiglitazone maleate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, rosiglitazone maleate is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, rosiglitazone maleate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the

polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching rosiglitazone maleate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, rosiglitazone maleate and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXXXVI The present invention provides covalent attachment of the active agent (goserelin) to a polymer of peptides or amino acids. The invention is distinguished

from the above-mentioned technologies by virtue of covalently attaching goserelin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising goserelin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and goserelin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Goserelin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting goserelin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering goserelin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, goserelin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, goserelin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and goserelin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, goserelin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, goserelin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier, peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching goserelin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, goserelin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCLXXXVII The present invention provides covalent attachment of the active agent (rubitecan) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching rubitecan to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising rubitecan microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and rubitecan covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Rubitecan preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting rubitecan from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering rubitecan to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, rubitecan is released from the composition by

an enzyme-catalyzed release. In another preferred embodiment, rubitecan is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and rubitecan is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, rubitecan is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, rubitecan is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching rubitecan to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, rubitecan and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the

glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXXVIII The present invention provides covalent attachment of the active agent (sagramostim) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sagramostim to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sagramostim microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sagramostim covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sagramostim preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to

the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sagramostim from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sagramostim to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sagramostim is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sagramostim is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sagramostim is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sagramostim is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sagramostim is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The

adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sagramostim to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sagramostim and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, . an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCLXXXIX The present invention provides covalent attachment of the active agent (saquinavir) to a polymer of peptides or amino acids. The invention is

distinguished from the above-mentioned technologies by virtue of covalently attaching saquinavir to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising saquinavir microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and saquinavir covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Saquinavir preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting saquinavir from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering saquinavir to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, saquinavir is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, saquinavir is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and saquinavir is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, saquinavir is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, saquinavir is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching saquinavir to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, saquinavir and a second active agent can be copolymerized in step (c). In another . preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXC The present invention provides covalent attachment of the active agent (docetaxel) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching docetaxel to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising docetaxel microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and docetaxel covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Docetaxel preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting docetaxel from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering docetaxel to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, docetaxel is released from the composition by

an enzyme-catalyzed release. In another preferred embodiment, docetaxel is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and docetaxel is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, docetaxel is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, docetaxel is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching docetaxel to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, docetaxel and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the

glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXCI The present invention provides covalent attachment of the active agent (satraplatin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching satraplatin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising satraplatin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and satraplatin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Satraplatin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to

the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting satraplatin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering satraplatin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, satraplatin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, satraplatin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and satraplatin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, satraplatin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, satraplatin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching satraplatin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, satraplatin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXCII The present invention provides covalent attachment of the active agent (selegiline) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching selegiline to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or

polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising selegiline microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and selegiline covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Selegiline preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting selegiline from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering selegiline to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide : In a preferred embodiment, selegiline is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, selegiline is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and selegiline is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, selegiline is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, selegiline is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching selegiline to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second

agent, selegiline and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXCIII The present invention provides covalent attachment of the active agent (sertraline) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sertraline to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sertraline microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sertraline covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide,

(ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sertraline preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sertraline from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sertraline to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sertraline is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sertraline is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and sertraline is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sertraline is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sertraline is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sertraline to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sertraline and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXCIV The present invention provides covalent attachment of the active agent (sevelamer) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sevelamer to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sevelamer microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sevelamer covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sevelamer preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another

preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodifnent, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sevelamer from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sevelamer to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sevelamer is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sevelamer is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sevelamer is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sevelamer is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sevelamer is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sevelamer to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sevelamer and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXCV The present invention provides covalent attachment of the active agent (sevirumab) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sevirumab to the N-terminus, the C-terminus or directly to the amino acid side chain of

an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sevirumab microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sevirumab covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sevirumab preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition, in a pH-dependent manner.

The invention also provides a method for protecting sevirumab from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sevirumab to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sevirumab is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sevirumab is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sevirumab is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sevirumab is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sevirumab is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sevirumab to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second

agent, sevirumab and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXCVI The present invention provides covalent attachment of the active agent (sibutramine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sibutramine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sibutramine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sibutramine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide,

(ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sibutramine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sibutramine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sibutramine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sibutramine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sibutramine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed

release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sibutramine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sibutramine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sibutramine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sibutramine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sibutramine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the

glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CCCXCVII The present invention provides covalent attachment of the active agent (sildenafil citrate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sildenafil citrate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sildenafil citrate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sildenafil citrate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sildenafil citrate preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to

the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sildenafil citrate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sildenafil citrate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sildenafil citrate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sildenafil citrate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sildenafil citrate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sildenafil citrate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sildenafil citrate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the

polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sildenafil citrate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sildenafil citrate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a-urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXCVIII The present invention provides covalent attachment of the active agent (simvastatin) to a polymer of peptides or amino acids. The invention is

distinguished from the above-mentioned technologies by virtue of covalently attaching simvastatin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising simvastatin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and simvastatin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Simvastatin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting simvastatin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering simvastatin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, simvastatin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, simvastatin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and simvastatin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, simvastatin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, simvastatin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching simvastatin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, simvastatin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CCCXCIX The present invention provides covalent attachment of the active agent (sinapultide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sinapultide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sinapultide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sinapultide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sinapultide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner : The invention also provides a method for protecting sinapultide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sinapultide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sinapultide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sinapultide is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sinapultide is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sinapultide is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sinapultide is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sinapultide to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sinapultide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine,

cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CD The present invention provides covalent attachment of the active agent (sitafloxacin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sitafloxacin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sitafloxacin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sitafloxacin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sitafloxacin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sitafloxacin from degradation comprising covalently attaching it to a polypeptide.

The. invention also provides a method for delivering sitafloxacin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sitafloxacin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sitafloxacin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sitafloxacin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sitafloxacin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sitafloxacin is released from the

composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sitafloxacin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sitafloxacin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDI The present invention provides covalent attachment of the active agent (polystyrene sulfonate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching polystyrene sulfonate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising polystyrene sulfonate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and polystyrene sulfonate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Polystyrene sulfonate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting polystyrene sulfonate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering polystyrene sulfonate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, polystyrene sulfonate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, polystyrene sulfonate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and polystyrene sulfonate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, polystyrene sulfonate is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, polystyrene sulfonate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching polystyrene sulfonate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agentlamino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, polystyrene sulfonate and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDII The present invention provides covalent attachment of the active agent (sotalol) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sotalol to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.

In these applications, delivery of the active agent is controlled, in part, by the kinetics of

unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical, composition comprising sotalol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sotalol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sotalol preferably is covalently attached to a side chain, the N-terminus or the C- terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sotalol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sotalol to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sotalol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sotalol is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sotalol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sotalol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sotalol is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sotalol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sotalol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDIII The present invention provides covalent attachment of the active agent (sparfosic acid) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sparfosic acid to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sparfosic acid microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sparfosic acid covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or

(vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sparfosic acid preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sparfosic acid from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sparfosic acid to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sparfosic acid is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sparfosic acid is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sparfosic acid is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sparfosic

acid is released from the composition by a pH-dependent unfolding of the polypeptide.

In another preferred embodiment, sparfosic acid is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sparfosic acid to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sparfosic acid and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDIV The present invention provides covalent attachment of the active agent (spironolactone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching spironolactone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising spironolactone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and spironolactone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Spironolactone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting spironolactone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering spironolactone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, spironolactone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, spironolactone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and spironolactone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, spironolactone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, spironolactone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching spironolactone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, spironolactone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDV The present invention provides covalent attachment of the active agent (stavudine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching stavudine to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising stavudine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and stavudine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Stavudine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting stavudine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering stavudine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, stavudine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, stavudine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and stavudine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, stavudine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, stavudine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching stavudine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, stavudine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination.. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDVI The present invention provides covalent attachment of the active agent (sucralfate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sucralfate to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the. carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sucralfate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sucralfate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sucralfate preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sucralfate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sucralfate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sucralfate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sucralfate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and sucralfate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sucralfate is released

from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sucralfate is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching sucralfate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sucralfate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDVII The present invention provides covalent attachment of the active agent (sumatriptan) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching sumatriptan to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising sumatriptan microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and sumatriptan covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Sumatriptan preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting sumatriptan from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering sumatriptan to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, sumatriptan is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, sumatriptan is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and sumatriptan is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, sumatriptan is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, sumatriptan is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching sumatriptan to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, sumatriptan and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDVIII The present invention provides covalent attachment of the active agent (tabimorelin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tabimorelin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tabimorelin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tabimorelin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tabimorelin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tabimorelin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tabimorelin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tabimorelin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tabimorelin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and tabimorelin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tabimorelin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tabimorelin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tabimorelin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tabimorelin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released

from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is. attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDIX The present invention provides covalent attachment of the active agent (Tamoxifen) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching Tamoxifen to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising Tamoxifen microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and Tamoxifen covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tamoxifen preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting Tamoxifen from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering Tamoxifen to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, Tamoxifen is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, Tamoxifen is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and Tamoxifen is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, Tamoxifen is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, Tamoxifen is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a. composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching Tamoxifen to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, Tamoxifen and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDX The present invention provides covalent attachment of the active agent (tamsulosin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tamsulosin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tamsulosin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tamsulosin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tamsulosin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another

preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tamsulosin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tamsulosin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tamsulosin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tamsulosin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and tamsulosin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tamsulosin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tamsulosin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tamsulosin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tamsulosin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXI The present invention provides covalent attachment of the active agent (temazepam) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching temazepam to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide

or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising temazepam microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and temazepam covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Temazepam preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or ari oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting temazepam from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering temazepam to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, temazepam is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, temazepam is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and temazepam is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, temazepam is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, temazepam is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching temazepam to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, temazepam and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXII The present invention provides covalent attachment of the active agent (tenofovir disoproxil) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tenofovir disoproxil to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tenofovir disoproxil microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tenofovir disoproxil covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tenofovir disoproxil preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tenofovir disoproxil from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tenofovir disoproxil to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tenofovir disoproxil is released

from the composition by an enzyme-catalyzed release. In another preferred embodiment, tenofovir disoproxil is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and tenofovir disoproxil is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tenofovir disoproxil is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, tenofovir disoproxil is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tenofovir disoproxil to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tenofovir disoproxil and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a

carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXIII The present invention provides covalent attachment of the active agent (tepoxalin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tepoxalin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tepoxalin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tepoxalin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tepoxalin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In

another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tepoxalin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tepoxalin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tepoxalin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tepoxalin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and tepoxalin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tepoxalin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tepoxalin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is

controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tepoxalin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tepoxalin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular trarisamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXIV The present invention provides covalent attachment of the active agent (terazosin) to a polymer of peptides or amino acids. The invention is distinguished

from the above-mentioned technologies by virtue of covalently attaching terazosin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising terazosin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and terazosin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Terazosin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting terazosin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering terazosin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, terazosin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, terazosin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and terazosin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, terazosin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, terazosin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching terazosin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, terazosin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXV The present invention provides covalent attachment of the active agent (terbinafine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching terbinafine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising terbinafine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and terbinafine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Terbinafine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting terbinafine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering terbinafine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, terbinafine is released from the composition by

an enzyme-catalyzed release. In another preferred embodiment, terbinafine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and terbinafine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, terbinafine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, terbinafine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching terbinafine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, terbinafine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the

glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXVI The present invention provides covalent attachment of the active agent (terbutaline sulfate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching terbutaline sulfate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising terbutaline sulfate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and terbutaline sulfate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Terbutaline sulfate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached

to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting terbutaline sulfate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering terbutaline sulfate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, terbutaline sulfate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, terbutaline sulfate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and terbutaline sulfate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, terbutaline sulfate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, terbutaline sulfate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the

polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching terbutaline sulfate to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, terbutaline sulfate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXVII The present invention provides covalent attachment of the active agent (teriparatide) to a polymer of peptides or amino acids. The invention is

distinguished from the above-mentioned technologies by virtue of covalently attaching teriparatide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising teriparatide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and teriparatide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Teriparatide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting teriparatide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering teriparatide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, teriparatide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, teriparatide is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and teriparatide is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, teriparatide is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, teriparatide is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching teriparatide to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agentlamino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, teriparatide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid-functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXVIII The present invention provides covalent attachment of the active agent (tetracycline) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tetracycline to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tetracycline microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tetracycline covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tetracycline preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tetracycline from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tetracycline to a patient, the patient being a human or a non-human animal, comprising administering to the patient a

composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tetracycline is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tetracycline is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and tetracycline is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tetracycline is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tetracycline is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tetracycline to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tetracycline and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine,

cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXIX The present invention provides covalent attachment of the active agent (thalidomide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching thalidomide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising thalidomide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and thalidomide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Thalidomide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting thalidomide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering thalidomide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, thalidomide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, thalidomide is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and thalidomide is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, thalidomide is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, thalidomide is released from the

composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching thalidomide to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, thalidomide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXX The present invention provides covalent attachment of the active agent (theophylline) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching theophylline to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising theophylline microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and theophylline covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Theophylline preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting theophylline from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering theophylline to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, theophylline is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, theophylline is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and theophylline is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, theophylline is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, theophylline is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching theophylline to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, theophylline and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXI The present invention provides covalent attachment of the active agent (thiotepa) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching thiotepa to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising thiotepa microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and thiotepa covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Thiotepa preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting thiotepa from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering thiotepa to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, thiotepa is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, thiotepa is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and thiotepa is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, thiotepa is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, thiotepa is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching thiotepa to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, thiotepa and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXII The present invention provides covalent attachment of the active agent (thrombopoetin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching thrombopoetin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising thrombopoetin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and thrombopoetin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or

(vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Thrombopoetin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt : When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting thrombopoetin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering thrombopoetin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, thrombopoetin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, thrombopoetin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and thrombopoetin is released from the composition by dissolution of the microencapsulating agent. In another preferred

embodiment, thrombopoetin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, thrombopoetin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching thrombopoetin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, thrombopoetin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXIII The present invention provides covalent attachment of the active agent (tiagabine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tiagabine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tiagabine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tiagabine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tiagabine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tiagabine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tiagabine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tiagabine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tiagabine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and tiagabine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tiagabine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tiagabine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching tiagabine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tiagabine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are. not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXIV The present invention provides covalent attachment of the active agent (ticlopidine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ticlopidine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ticlopidine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ticlopidine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ticlopidine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ticlopidine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ticlopidine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ticlopidine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ticlopidine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and ticlopidine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ticlopidine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ticlopidine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ticlopidine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ticlopidine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXV The present invention provides covalent attachment of the active agent (tifacogin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tifacogin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tifacogin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tifacogin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tifacogin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tifacogin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tifacogin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tifacogin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tifacogin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and tifacogin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tifacogin is released

from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tifacogin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tifacogin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tifacogin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXVI The present invention provides covalent attachment of the active agent (tirapazamine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tirapazamine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tirapazamine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tirapazamine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tirapazamine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tirapazamine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tirapazamine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tirapazamine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tirapazamine is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and tirapazamine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tirapazamine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tirapazamine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching tirapazamine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tirapazamine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXXVII The present invention provides covalent attachment of the active agent (tirofiban) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tirofiban to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tirofiban microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tirofiban covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino-acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tirofiban preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tirofiban from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tirofiban to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tirofiban is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tirofiban is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and tirofiban is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tirofiban is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tirofiban is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tirofiban to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tirofiban and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXXVIII The present invention provides covalent attachment of the active agent (tizanidine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tizanidine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tizanidine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tizanidine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tizanidine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tizanidine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tizanidine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tizanidine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tizanidine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and tizanidine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tizanidine is released

from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tizanidine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tizanidine to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tizanidine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXIX The present invention provides covalent attachment of the active agent (tobramycin sulfate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tobramycin sulfate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tobramycin sulfate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tobramycin sulfate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tobramycin sulfate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tobramycin sulfate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tobramycin sulfate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tobramycin sulfate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tobramycin sulfate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and tobramycin sulfate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tobramycin sulfate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tobramycin sulfate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching tobramycin sulfate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tobramycin sulfate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXXX The present invention provides covalent attachment of the active agent (tolterodine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tolterodine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tolterodine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tolterodine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino'acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tolterodine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tolterodine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tolterodine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tolterodine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tolterodine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and tolterodine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tolterodine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tolterodine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tolterodine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tolterodine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXXXI The present invention provides covalent attachment of the active agent (tomoxetine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tomoxetine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tomoxetine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tomoxetine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tomoxetine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tomoxetine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tomoxetine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tomoxetine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tomoxetine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and tomoxetine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tomoxetine is

released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tomoxetine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tomoxetine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tomoxetine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXXII The present invention provides covalent attachment of the active agent (topiramate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching topiramate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising topiramate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and topiramate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Topiramate preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising topotecan microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and topotecan covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Topotecan preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting topotecan from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering topotecan to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, topotecan is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, topotecan is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and topotecan is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, topotecan is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, topotecan is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching topotecan to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, topotecan and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXXIV The present invention provides covalent attachment of the active agent (toresemide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching toresemide to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising toresemide microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and toresemide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Toresemide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent : In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting toresemide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering toresemide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, toresemide is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, toresemide is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and toresemide is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, toresemide is

released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, toresemide is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching toresemide to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, toresemide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXXV The present invention provides covalent attachment of the active agent (TPA ANALOGUE) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching TPA ANALOGUE to the N-terminus, the'C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising TPA ANALOGUE microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and TPA ANALOGUE covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

TPA ANALOGUE preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting TPA ANALOGUE from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering TPA ANALOGUE to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, TPA ANALOGUE is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, TPA ANALOGUE is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and TPA ANALOGUE is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, TPA ANALOGUE is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, TPA ANALOGUE is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invehtion also provides a method for protecting topiramate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering topiramate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, topiramate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, topiramate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and topiramate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, topiramate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, topiramate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching topiramate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, topiramate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXXIII The present invention provides covalent attachment of the active agent (topotecan) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching topotecan to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

(a) attaching TPA ANALOGUE to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, TPA ANALOGUE and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are. not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXXVI The present invention provides covalent attachment of the active agent (tramadol) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching tramadol to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising tramadol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and tramadol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Tramadol preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting tramadol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering tramadol to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, tramadol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, tramadol is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and tramadol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, tramadol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, tramadol is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching tramadol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, tramadol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXXXVII The present invention provides covalent attachment of the active agent (trandolapril) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching trandolapril to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising trandolapril microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and trandolapril covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Trandolapril preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting trandolapril from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering trandolapril to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, trandolapril is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, trandolapril is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and trandolapril is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment,

trandolapril is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, trandolapril is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of (a) attaching trandolapril to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, trandolapril and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXXVIII The present invention provides covalent attachment of the active agent (trastuzumab) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching trastuzumab to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising trastuzumab microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and trastuzumab covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Trastuzumab preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting trastuzumab from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering trastuzumab to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, trastuzumab is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, trastuzumab is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and trastuzumab is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, trastuzumab is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, trastuzumab is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching trastuzumab to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, trastuzumab and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXXXIX The present invention provides covalent attachment of the active agent (trazadone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching trazadone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This . enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising trazadone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and trazadone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino'acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Trazadone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting trazadone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering trazadone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, trazadone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, trazadone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and trazadone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, trazadone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, trazadone is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching trazadone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, trazadone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXL The present invention provides covalent attachment of the active agent (triamterene) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching triamterene to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising triamterene microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and triamterene covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Triamterene preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting triamterene from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering triamterene to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, triamterene is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, triamterene is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and triamterene is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, triamterene is

released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, triamterene is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching triamterene to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, triamterene and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXLI The present invention provides covalent attachment of the active agent (troglitazone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching troglitazone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising troglitazone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and troglitazone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Troglitazone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invehtion also provides a method for protecting troglitazone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering troglitazone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, troglitazone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, troglitazone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and troglitazone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, troglitazone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, troglitazone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching troglitazone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, troglitazone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an, anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXLII The present invention provides covalent attachment of the active agent (trovafloxacin mesylate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching trovafloxacin mesylate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.

In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active

agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising trovafloxacin mesylate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and trovafloxacin mesylate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Trovafloxacin mesylate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting trovafloxacin mesylate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering trovafloxacin mesylate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, trovafloxacin mesylate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, trovafloxacin mesylate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and trovafloxacin mesylate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, trovafloxacin mesylate is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, trovafloxacin mesylate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :.

(a) attaching trovafloxacin mesylate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, trovafloxacin mesylate and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXLIII The present invention provides covalent attachment of the active agent (urokinase) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching urokinase to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising urokinase microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and urokinase covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Urokinase preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting urokinase from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering urokinase to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, urokinase is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, urokinase is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and urokinase is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, urokinase is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, urokinase is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching urokinase to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, urokinase and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXLIV The present invention provides covalent attachment of the active agent (ursodiol) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ursodiol to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ursodiol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ursodiol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ursodiol preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ursodiol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ursodiol to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ursodiol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ursodiol is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and ursodiol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ursodiol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ursodiol is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching ursodiol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ursodiol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are. not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXLV The present invention provides covalent attachment of the active agent (valacyclovir) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching valacyclovir to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising valacyclovir microencapsulated by a polypeptide.' The invention provides a composition comprising a polypeptide and valacyclovir covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Valacyclovir preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting valacyclovir from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering valacyclovir to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, valacyclovir is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, valacyclovir is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and valacyclovir is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, valacyclovir is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, valacyclovir is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching valacyclovir to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, valacyclovir and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXLVI The present invention provides covalent attachment of the active agent (valdecoxib) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching valdecoxib to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising valdecoxib microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and valdecoxib covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Valdecoxib preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting valdecoxib from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering valdecoxib to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, valdecoxib is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, valdecoxib is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and valdecoxib is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, valdecoxib is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, valdecoxib is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching valdecoxib to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, valdecoxib and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXLVII The present invention provides covalent attachment of the active agent (valproic acid) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ) valproic acid to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising valproic acid microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and valproic acid covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Valproic acid preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another

preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting valproic acid from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering valproic acid to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, valproic acid is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, valproic acid is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and valproic acid is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, valproic acid is released from the composition by a pH-dependent unfolding of the polypeptide.

In another preferred embodiment, valproic acid is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching valproic acid to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-earboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, valproic acid and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXLVIII The present invention provides covalent attachment of the active agent (valsartan and hydrochlorothiazide) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching valsartan and hydrochlorothiazide to the N-terminus, the C-terminus or directly

to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising valsartan and hydrochlorothiazide microencapsulated by a polypeptide.

The invehtion provides a composition comprising a polypeptide and valsartan and hydrochlorothiazide covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Valsartan and hydrochlorothiazide preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting valsartan and hydrochlorothiazide from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering valsartan and hydrochlorothiazide to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, valsartan and hydrochlorothiazide are released from the composition by an enzyme-catalyzed release. In another preferred embodiment, valsartan and hydrochlorothiazide are released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and valsartan and hydrochlorothiazide are released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, valsartan and hydrochlorothiazide are released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, valsartan and hydrochlorothiazide are released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching valsartan and hydrochlorothiazide to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, valsartan and hydrochlorothiazide and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXLIX The present invention provides covalent attachment of the active agent (valspodar) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching valspodar to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the

upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising valspodar microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and valspodar covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Valspodar preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting valspodar from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering valspodar to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, valspodar is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, valspodar is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and valspodar is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, valspodar is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, valspodar is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching valspodar to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, valspodar and a second active agent can be copolymerized in step (c). In another. preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDL The present invention provides covalent attachment of the active agent (vancomycin) to a polymer of peptides or amino acids. The'invention is distinguished from the above-mentioned technologies by virtue of covalently attaching vancomycin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising vancomycin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and vancomycin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Vancomycin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting vancomycin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering vancomycin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, vancomycin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, vancomycin is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and vancomycin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment,

vancomycin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, vancomycin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching vancomycin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, vancomycin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLI The present invention provides covalent attachment of the active agent (vecuronium) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching vecuronium to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising vecuronium microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and vecuronium covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Vecuronium preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting vecuronium from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering vecuronium to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, vecuronium is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, vecuronium is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and vecuronium is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, vecuronium is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, vecuronium is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching vecuronium to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, vecuronium and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLII The present invention provides covalent attachment of the active agent (venlafaxine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching venlafaxine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising venlafaxine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and venlafaxine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Venlafaxine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting venlafaxine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering venlafaxine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, venlafaxine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, venlafaxine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and venlafaxine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, venlafaxine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, venlafaxine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching venlafaxine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, venlafaxine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released

from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLIIIThe present invention provides covalent attachment of the active agent (verapamil) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching verapamil to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising verapamil microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and verapamil covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Verapamil preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting verapamil from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering verapamil to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, verapamil is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, verapamil is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and verapamil is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, verapamil is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, verapamil is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching verapamil to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, verapamil and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLIV The present invention provides covalent attachment of the active agent (vinorelbine tartrate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching vinorelbine tartrate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising vinorelbine tartrate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and vinorelbine tartrate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Vinorelbine tartrate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting vinorelbine tartrate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering vinorelbine tartrate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, vinorelbine tartrate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, vinorelbine tartrate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and vinorelbine tartrate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, vinorelbine tartrate is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, vinorelbine tartrate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching vinorelbine tartrate to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, vinorelbine tartrate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLV The present invention provides covalent attachment of the active agent (vitamin B 12) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching vitamin B12 to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising vitamin B 12 microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and vitamin B12 covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Vitamin B12 preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino . acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting vitamin B12 from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering vitamin B12 to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, vitamin B 12 is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, vitamin B 12 is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and vitamin B12 is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, vitamin B 12 is released from the composition by a pH-dependent unfolding of the polypeptide.

In another preferred embodiment, vitamin B12 is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching vitamin B12 to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, vitamin B 12 and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLVI The present invention provides covalent attachment of the active agent (vitamin C) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching vitamin C to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising vitamin C microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and vitamin C covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Vitamin C preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting vitamin C from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering vitamin C to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, vitamin C is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, vitamin C is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and vitamin C is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, vitamin C is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, vitamin C is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching vitamin C to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, vitamin C and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLVII The present invention provides covalent attachment of the active agent (voriconazole) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching voriconazole to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising voriconazole microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and voriconazole covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Voriconazole preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting voriconazole from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering voriconazole to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, voriconazole is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, voriconazole is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and voriconazole is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, voriconazole is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, voriconazole is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching voriconazole to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, voriconazole and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLVIII The present invention provides covalent attachment of the active agent (warfarin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching warfarin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising warfarin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and warfarin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Warfarin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting warfarin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering warfarin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, warfarin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, warfarin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and warfarin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, warfarin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, warfarin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching warfarin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, warfarin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLIX The present invention provides covalent attachment of the active agent (xaliproden) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching xaliproden to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising xaliproden microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and xaliproden covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Xaliproden preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting xaliproden from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering xaliproden to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, xaliproden is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, xaliproden is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and xaliproden is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, xaliproden is

released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, xaliproden is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching xaliproden to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, xaliproden and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLX The present invention provides covalent attachment of the active agent (zafirlukast) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching zafirlukast to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising zafirlukast microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and zafirlukast covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Zafirlukast preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting zafirlukast from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering zafirlukast to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, zafirlukast is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, zafirlukast is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and zafirlukast is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, zafirlukast is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, zafirlukast is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching zafirlukast to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, zafirlukast and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXI The present invention provides covalent attachment of the active agent (zaleplon) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching zaleplon to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising zaleplon microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and zaleplon covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Zaleplon preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment,-the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting zaleplon from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering zaleplon to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, zaleplon is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, zaleplon is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and zaleplon is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, zaleplon is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, zaleplon is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching zaleplon to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, zaleplon and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXII The present invention provides covalent attachment of the active agent (zenarestat) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching zenarestat to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising zenarestat microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and zenarestat covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Zenarestat preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting zenarestat from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering zenarestat to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, zenarestat is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, zenarestat is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and zenarestat is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, zenarestat is released

from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, zenarestat is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching zenarestat to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, zenarestat and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXIII The present invention provides covalent attachment of the active agent (zidovudine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching zidovudine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising zidovudine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and zidovudine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Zidovudine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting zidovudine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering zidovudine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, zidovudine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, zidovudine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and zidovudine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, zidovudine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, zidovudine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching zidovudine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, zidovudine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXIV The present invention provides covalent attachment of the active agent (zolmitriptan) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching zolmitriptan to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising zolmitriptan microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and zolmitriptan covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino'acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Zolmitriptan preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting zolmitriptan from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering zolmitriptan to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, zolmitriptan is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, zolmitriptan is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and zolmitriptan is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, zolmitriptan is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, zolmitriptan is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching zolmitriptan to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, zolmitriptan and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXV The present invention provides covalent attachment of the active agent (zolpidem) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching zolpidem to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising zolpidem microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and zolpidem covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Zolpidem preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

-Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting zolpidem from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering zolpidem to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, zolpidem is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, zolpidem is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and zolpidem is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, zolpidem is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, zolpidem is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching zolpidem to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, zolpidem and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXVI The present invention provides covalent attachment of the active agent (bleomycin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching bleomycin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising bleomycin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and bleomycin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Bleomycin preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine'and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can-be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting bleomycin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering bleomycin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, bleomycin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, bleomycin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a . microencapsulating agent and bleomycin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, bleomycin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, bleomycin is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching bleomycin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, bleomycin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid'is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22, 2000, incorporated herein by reference.

CDLXVII The present invention provides covalent attachment of the active agent (phytoseterol) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching phytoseterol to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising phytoseterol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and phytoseterol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Phytoseterol preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting phytoseterol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering phytoseterol to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, phytoseterol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, phytoseterol is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and phytoseterol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, phytoseterol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, phytoseterol is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching phytoseterol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, phytoseterol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is

released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXVIII The present invention provides covalent attachment of the active agent (paclitaxel) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching paclitaxel to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising paclitaxel microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and paclitaxel covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Paclitaxel preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting paclitaxel from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering paclitaxel to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, paclitaxel is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, paclitaxel is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and paclitaxel is released from the composition by dissolution

of the microencapsulating agent. In another preferred embodiment, paclitaxel is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, paclitaxel is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching paclitaxel to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, paclitaxel and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXIX The present invention provides covalent attachment of the active agent (fluticasone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching fluticasone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising fluticasone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and fluticasone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Fluticasone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting fluticasone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering fluticasone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, fluticasone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, fluticasone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and fluticasone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, fluticasone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, fluticasone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching fluticasone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, fluticasone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXX The present invention provides covalent attachment of the active agent (flurouracil) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching flurouracil to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is

controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising flurouracil microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and flurouracil covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Flurouracil preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting flurouracil from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering flurouracil to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, flurouracil is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, flurouracil is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and flurouracil is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, flurouracil is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, flurouracil is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching flurouracil to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, flurouracil and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the

active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXXI The present invention provides covalent attachment of the active agent (pseudoephedrine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching pseudoephedrine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising pseudoephedrine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and pseudoephedrine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or

(vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Pseudoephedrine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting pseudoephedrine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering pseudoephedrine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, pseudoephedrine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, pseudoephedrine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and pseudoephedrine is released from the composition by dissolution of the microencapsulating agent. In another preferred

embodiment, pseudoephedrine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, pseudoephedrine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching pseudoephedrine to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, pseudoephedrine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXXII The present invention provides covalent attachment of the active agent (a lipoxygenase inhibitor) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a lipoxygenase inhibitor to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.

In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a lipoxygenase inhibitor microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a lipoxygenase inhibitor covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A lipoxygenase inhibitor preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a lipoxygenase inhibitor from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a lipoxygenase inhibitor to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a lipoxygenase inhibitor is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, a lipoxygenase inhibitor is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a lipoxygenase inhibitor is released from the composition by dissolution of the microencapsulating agent.

In another preferred embodiment, a lipoxygenase inhibitor is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a lipoxygenase inhibitor is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching a lipoxygenase inhibitor to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex ; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a lipoxygenase inhibitor and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXXIII The present invention provides covalent attachment of the active agent (a composite vascular protectant) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a composite vascular protectant to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent,

primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a composite vascular protectant microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a composite vascular protectant covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A composite vascular protectant preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In

another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a composite vascular protectant from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a composite vascular protectant to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a composite vascular protectant is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, a composite vascular protectant is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a composite vascular protectant is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a composite vascular protectant is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a composite vascular protectant is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching a composite vascular protectant to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a composite vascular protectant and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXIV The present invention provides covalent attachment of the active agent (an oral neuraminidase inhibitor) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching an oral neuraminidase inhibitor to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising an oral neuraminidase inhibitor microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and an oral neuraminidase inhibitor covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

An oral neuraminidase inhibitor preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol- and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting an oral neuraminidase inhibitor from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering an oral neuraminidase inhibitor to a patient, the patient being a human or a non-human animal, comprising

administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, an oral neuraminidase inhibitor is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, an oral neuraminidase inhibitor is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and an oral neuraminidase inhibitor is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, an oral neuraminidase inhibitor is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, an oral neuraminidase inhibitor is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching an oral neuraminidase inhibitor to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, an oral neuraminidase inhibitor and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is

replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXV The present invention provides covalent attachment of the active agent (the soluble chimeric protein CTLA4Ig) to a polymer of peptides or amino acids.

The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching the soluble chimeric protein CTLA4Ig to the N-terminus, the C- terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.

In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising the soluble chimeric protein CTLA4Ig microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and the soluble chimeric protein CTLA4Ig covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more

synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

The soluble chimeric protein CTLA4Ig preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting the soluble chimeric protein CTLA4Ig from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering the soluble chimeric protein CTLA4Ig to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, the soluble chimeric protein CTLA4Ig is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, the soluble chimeric protein CTLA4Ig is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and the soluble chimeric protein CTLA4Ig is released from the

composition by dissolution of the microencapsulating agent. In another preferred embodiment, the soluble chimeric protein CTLA4Ig is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, the soluble chimeric protein CTLA4Ig is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching the soluble chimeric protein CTLA4Ig to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, the soluble chimeric protein CTLA4Ig and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXXVI The present invention provides covalent attachment of the active agent (a selective endothelin A receptor antagonist) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a selective endothelin A receptor antagonist to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.

In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a selective endothelin A receptor antagonist microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a selective endothelin A receptor antagonist covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A selective endothelin A receptor antagonist preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N- terminus of the polypeptide. In another preferred embodiment, the active agent is an

amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C- terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a selective endothelin A receptor antagonist from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a selective endothelin A receptor antagonist to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a selective endothelin A receptor antagonist is released. from the composition by an enzyme-catalyzed release. In another preferred embodiment, a selective endothelin A receptor antagonist is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a selective endothelin A receptor antagonist is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a selective endothelin A receptor antagonist is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a selective endothelin A receptor antagonist is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached

to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching a selective endothelin A receptor antagonist to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a selective endothelin A receptor antagonist and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXVII The present invention provides covalent attachment of the active agent (a potassium channel modulator) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a potassium channel modulator to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a potassium channel modulator microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a potassium channel modulator covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A potassium channel modulator preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The

microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a potassium channel modulator from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a potassium channel modulator to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a potassium channel modulator is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, a potassium channel modulator is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a potassium channel modulator is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a potassium channel modulator is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a potassium channel modulator is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching a potassium channel modulator to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a potassium channel modulator and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXXVIII The present invention provides covalent attachment of the active agent (a bactericidal/permeability increasing protein derivative) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a bactericidal/permeability increasing protein derivative to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain

applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a bactericidal/permeability increasing protein derivative microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a bactericidal/permeability increasing protein derivative covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A bactericidal/permeability increasing protein derivative preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C- terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a bactericidal/permeability increasing protein derivative from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a bactericidal/permeability increasing protein derivative to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a bactericidal/permeability increasing protein derivative is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, a bactericidal/permeability increasing protein derivative is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a bactericidal/permeability increasing protein derivative is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a bactericidal/permeability increasing protein derivative is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a bactericidal/permeability increasing protein derivative is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching a bactericidal/permeability increasing protein derivative to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a bactericidal/permeability increasing protein derivative and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXIX The present invention provides covalent attachment of the active agent (humanized monoclonal antibody, hu 1124, directed against CD 11 a) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching humanized monoclonal antibody, hu 1124, directed against CD 11 a to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.

In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active

agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising humanized monoclonal antibody, hu 1124, directed against CD 11 a microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and humanized monoclonal antibody, hu 1124, directed against CD1 la covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Humanized monoclonal antibody, hu 1124, directed-against CD1 la preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.

In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.

In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In

another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting humanized monoclonal antibody, hu 1124, directed against CD1 la from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering humanized monoclonal antibody, hu 1124, directed against CD 11 a to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, humanized monoclonal antibody, hu 1124, directed against CD 11 a is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, humanized monoclonal antibody, hu 1124, directed against CD1 la is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and humanized monoclonal antibody, hu 1124, directed against CD1 la is released from the composition by dissolution of the microencapsulating agent.

In another preferred embodiment, humanized monoclonal antibody, hu 1124, directed against CD1 la is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, humanized monoclonal antibody, hu 1124, directed against CD1 la is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching humanized monoclonal antibody, hu 1124, directed against CD la to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, humanized monoclonal antibody, hu 1124, directed against CD1 la and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXX The present invention provides covalent attachment of the active agent (a lipid lowering agent) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a lipid lowering agent to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for

absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a lipid lowering agent microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a lipid lowering agent covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A lipid lowering agent preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a lipid lowering agent from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a lipid lowering agent to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a lipid lowering agent is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, a lipid lowering agent is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a lipid lowering agent is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a lipid lowering agent is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, a lipid lowering agent is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching a lipid lowering agent to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a lipid lowering agent and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular

transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXXXI The present invention provides covalent attachment of the active agent (propofol) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching propofol to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising propofol microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and propofol covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Propofol preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting propofol from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering propofol to a patient, the patient being a human or a non-human animal, comprising. administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, propofol is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, propofol is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and propofol is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, propofol is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, propofol is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching propofol to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, propofol and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXXII The present invention provides covalent attachment of the active agent (a Cholesterol/Triglyceride Reducer) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a Cholesterol/Triglyceride Reducer to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a Cholesterol/Triglyceride Reducer microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a Cholesterol/Triglyceride Reducer covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A Cholesterol/Triglyceride Reducer preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the

polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a Cholesterol/Triglyceride Reducer from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a Cholesterol/Triglyceride Reducer to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a Cholesterol/Triglyceride Reducer is released from the composition by an enzyme- catalyzed release. In another preferred embodiment, a Cholesterol/Triglyceride Reducer is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a Cholesterol/Triglyceride Reducer is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a Cholesterol/Triglyceride Reducer is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a

Cholesterol/Triglyceride Reducer is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching a Cholesterol/Triglyceride Reducer to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a Cholesterol/Triglyceride Reducer and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXXXIII The present invention provides covalent attachment of the active agent (a recombinant hepatitis B vaccine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching a recombinant hepatitis B vaccine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising a recombinant hepatitis B vaccine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and a recombinant hepatitis B vaccine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

A recombinant hepatitis B vaccine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred

embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting a recombinant hepatitis B vaccine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering a recombinant hepatitis B vaccine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, a recombinant hepatitis B vaccine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, a recombinant hepatitis B vaccine is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and a recombinant hepatitis B vaccine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, a recombinant hepatitis B vaccine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, a recombinant hepatitis B vaccine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached

to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of, (a) attaching a recombinant hepatitis B vaccine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, a recombinant hepatitis B vaccine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is

described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXXIV The present invention provides covalent attachment of the active agent (an angiotensin II antagonist) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching an angiotensin II antagonist to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising an angiotensin II antagonist microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and an angiotensin II antagonist covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

An angiotensin II antagonist preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet

another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting an angiotensin II antagonist from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering an angiotensin II antagonist to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, an angiotensin II antagonist is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, an angiotensin II antagonist is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and an angiotensin II antagonist is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, an angiotensin II antagonist is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, an angiotensin II antagonist is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The

adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching an angiotensin II antagonist to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, an angiotensin II antagonist and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXXXV The present invention provides covalent attachment of the active agent (an immunosuppressant protein) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching an immunosuppressant protein to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising an immunosuppressant protein microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and an immunosuppressant protein covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

An immunosuppressant protein preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting an immunosuppressant protein from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering an immunosuppressant protein to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, an immunosuppressant protein is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, an immunosuppressant protein is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and an immunosuppressant protein is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, an immunosuppressant protein is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, an immunosuppressant protein is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching an immunosuppressant protein to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, an immunosuppressant protein and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDLXXXVI The present invention provides covalent attachment of the active agent (daily multivitamin) to a polymer of peptides or amino acids. The invention is

distinguished from the above-mentioned technologies by virtue of covalently attaching the components of the multivitamin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising daily multivitamin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and daily multivitamin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Daily multivitamin preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The

microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting daily multivitamin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering daily multivitamin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, daily multivitamin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, daily multivitamin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and daily multivitamin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, daily multivitamin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, daily multivitamin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of :

(a) attaching daily multivitamin to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, daily multivitamin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXXVII The present invention provides covalent attachment of the active agent (erythromycin and sulfx) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching erythromycin and sulfx to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.

In certain applications, the polypeptide will stabilize the active agent, primarily in the

stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising erythromycin and sulfx microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and erythromycin and sulfx covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Erythromycin and sulfx preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting erythromycin and sulfx from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering erythromycin and sulfx to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, erythromycin and sulfx is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, erythromycin and sulfx is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and erythromycin and sulfx is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, erythromycin and sulfx is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, erythromycin and sulfx is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching erythromycin and sulfx to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, erythromycin and sulfx and a second active agent can be copolymerized in step (c).

In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXXVIII The present invention provides covalent attachment of the active agent (ethinyl estradiol and dogestrel) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ethinyl estradiol and dogestrel to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the

carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising ethinyl estradiol and dogestrel microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and ethinyl estradiol and dogestrel covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Ethinyl estradiol and dogestrel preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be

conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting ethinyl estradiol and dogestrel from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering ethinyl estradiol and dogestrel to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ethinyl estradiol and dogestrel is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ethinyl estradiol and dogestrel is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and ethinyl estradiol and dogestrel is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ethinyl estradiol and dogestrel is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ethinyl estradiol and dogestrel is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching ethinyl estradiol and dogestrel to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and

(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ethinyl estradiol and dogestrel and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDLXXXIX The present invention provides covalent attachment of the active agent (lithium carbonate) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching lithium carbonate to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for

absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising lithium carbonate microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and lithium carbonate covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Lithium carbonate preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In

another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting lithium carbonate from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering lithium carbonate to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, lithium carbonate is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, lithium carbonate is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and lithium carbonate is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, lithium carbonate is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, lithium carbonate is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching lithium carbonate to a side chain of an amino acid to form an active agent/amino acid complex ; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, lithium carbonate and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXC The present invention provides covalent attachment of the active agent (LYM 1) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching LYM 1 to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising LYM 1 microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and LYM 1 covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

LYM 1 preferably is covalently attached to a side chain, the N-terminus or the C- terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting LYM 1 from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering LYM 1 to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, LYM 1 is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, LYM 1 is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and LYM 1 is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, LYM 1 is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, LYM 1 is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching LYM 1 to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, LYM 1 and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released

from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXCI The present invention provides covalent attachment of the active agent (methylprednisolone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching methylprednisolone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising methylprednisolone microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and methylprednisolone covalently attached to the polypeptide. Preferably, the polypeptide is

(i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Methylprednisolone preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting methylprednisolone from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering methylprednisolone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently

attached to the polypeptide. In a preferred embodiment, methylprednisolone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, methylprednisolone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and methylprednisolone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, methylprednisolone is released from the composition by a pH- dependent unfolding of the polypeptide. In another preferred embodiment, methylprednisolone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching methylprednisolone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, methylprednisolone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side

chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXCII The present invention provides covalent attachment of the active agent (rotavirus vaccine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching rotavirus vaccine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising rotavirus vaccine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and rotavirus vaccine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Rotavirus vaccine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting rotavirus vaccine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering rotavirus vaccine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, rotavirus vaccine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, rotavirus vaccine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and rotavirus vaccine is released from the composition by dissolution of the microencapsulating agent. In another preferred

embodiment, rotavirus vaccine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, rotavirus vaccine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching rotavirus vaccine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, rotavirus vaccine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXCIII The present invention provides covalent attachment of the active agent (saquinavir) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching saquinavir to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising saquinavir microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and saquinavir covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Saquinavir preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to

the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting saquinavir from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering saquinavir to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, saquinavir is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, saquinavir is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and saquinavir is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, saquinavir is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, saquinavir is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is

controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching saquinavir to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, saquinavir and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXCIV The present invention provides covalent attachment of the active agent (arginine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching arginine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising arginine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and arginine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Arginine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting arginine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering arginine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, arginine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, arginine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and arginine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, arginine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, arginine is released from the composition in a sustained release.

In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching arginine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, arginine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXCV The present invention provides covalent attachment of the active agent (heparin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching heparin to the

N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising heparin microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and heparin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Heparin preferably is covalently attached to a side chain, the N-terminus or the C- terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino

acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting heparin from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering heparin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, heparin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, heparin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and heparin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, heparin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, heparin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching heparin to a side chain of an amino acid to form an active agent/amino acid complex;

(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, heparin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXCVI The present invention provides covalent attachment of the active agent (thymosin alpha) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching thymosin alpha to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the

upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising thymosin alpha microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and thymosin alpha covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Thymosin alpha preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In

another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting thymosin alpha from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering thymosin alpha to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, thymosin alpha is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, thymosin alpha is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and thymosin alpha is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, thymosin alpha is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, thymosin alpha is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching thymosin alpha to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, thymosin alpha and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXCVII The present invention provides covalent attachment of the active agent (montelukast and fexofenadine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching montelukast and fexofenadine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising montelukast and fexofenadine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and montelukast and fexofenadine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Montelukast and fexofenadine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting montelukast and fexofenadine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering montelukast and fexofenadine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, montelukast and fexofenadine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, montelukast and fexofenadine is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and montelukast and fexofenadine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, montelukast and fexofenadine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, montelukast and fexofenadine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching montelukast and fexofenadine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second

agent, montelukast and fexofenadine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

CDXCVIII The present invention provides covalent attachment of the active agent (iodothyronine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching iodothyronine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising iodothyronine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and iodothyronine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Iodothyrtnine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting iodothyronine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering iodothyronine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, iodothyronine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, iodothyronine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and iodothyronine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, iodothyronine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, iodothyronine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching iodothyronine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, iodothyronine and a second active agent can be copolymerized in step (c). In

another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

CDXCIX The present invention provides covalent attachment of the active agent (iodothyronine and thyroxine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching iodothyronine and thyroxine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising iodothyronine and thyroxine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and iodothyronine and thyroxine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Iodothyronine and thyroxine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.

In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting iodothyronine and thyroxine from degradation comprising covalently attaching it to a polypeptide.

The invention also provides a method for delivering iodothyronine and thyroxine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, iodothyronine and thyroxine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, iodothyronine and thyroxine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and iodothyronine and thyroxine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, iodothyronine and thyroxine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, iodothyronine and thyroxine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching iodothyronine and thyroxine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, iodothyronine and thyroxine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide

and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642, 820, filed August 22,2000, incorporated herein by reference.

D The present invention provides covalent attachment of the active agent (codeine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue. of covalently attaching codeine to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.

Alternatively, the present invention provides a pharmaceutical composition comprising codeine microencapsulated by a polypeptide.

The invention provides a composition comprising a polypeptide and codeine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide,

(ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Codeine preferably is covalently attached to a side chain, the N-terminus or the C- terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.

The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.

Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.

The invention also provides a method for protecting codeine from degradation comprising covalently attaching it to a polypeptide.' The invention also provides a method for delivering codeine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the

polypeptide. In a preferred embodiment, codeine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, codeine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.

In another preferred embodiment, the composition further comprises a microencapsulating agent and codeine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, codeine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, codeine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.

The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of : (a) attaching codeine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).

In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, codeine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a

carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.

The general applications of this invention to other active pharmaceutical agents is described in U. S. Patent Application Serial Number 09/642,820, filed August 22,2000, incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION Proteins, oligopeptides and polypeptides are polymers of amino acids that have primary, secondary and tertiary structures. The secondary structure of the protein is the local conformation of the polypeptide chain and consists of helices, pleated sheets and turns. The protein's amino acid sequence and the structural constraints on the conformations of the chain determine the spatial arrangement of the molecule. The folding of the secondary structure and the spatial arrangement of the side chains constitute the tertiary structure.

Proteins fold because of the dynamics associated between neighboring atoms on the protein and solvent molecules. The thermodynamics of protein folding and unfolding are defined by the free energy of a particular condition of the protein that relies on a particular model. The process of protein folding involves, amongst other things, amino acid residues packing into a hydrophobic core. The amino acid side chains inside the protein core occupy the same volume as they do in amino acid crystals. The folded protein interior is therefore more like a crystalline solid than an oil drop and so the best model for determining forces contributing to protein stability is the solid reference state.

The major forces contributing to the thermodynamics of protein folding are Van der Waals interactions, hydrogen bonds, electrostatic interactions, configurational entropy and the hydrophobic effect. Considering protein stability, the hydrophobic effect refers to the energetic consequences of removing apolar groups from the protein interior and exposing them to water. Comparing the energy of amino acid hydrolysis with protein unfolding in the solid reference state, the hydrophobic effect is the dominant force. Hydrogen bonds are established during the protein fold process and intramolecular bonds are formed at the expense of hydrogen bonds with water. Water molecules are "pushed out"of the packed, hydrophobic protein core. All of these forces combine and contribute to the overall stability of the folded protein where the degree to which ideal packing occurs determines the degree of relative stability of the protein. The result of maximum packing is to produce a center of residues or hydrophobic core that has maximum shielding from solvent.

Since it is likely that lipophilic drugs would reside in the hydrophobic core of a peptide, it would require energy to unfold the peptide before the drug can be released.

The unfolding process requires overcoming the hydrophobic effect by hydrating the amino acids or achieving the melting temperature of the protein. The heat of hydration is a destabilization of a protein. Typically, the folded state of a protein is favored by only 5-15 kcal/mole over the unfolded state. Nonetheless, protein unfolding at neutral pH and at room temperature requires chemical reagents. In fact, partial unfolding of a protein is often observed prior to the onset of irreversible chemical or conformation processes.

Moreover, protein conformation generally controls the rate and extent of deleterious chemical reactions.

Conformational protection of active agents by proteins depends on the stability of the protein's folded state and the thermodynamics associated with the agent's decomposition. Conditions necessary for the agent's decomposition should be different than for protein unfolding.

Selection of the amino acids will depend on the physical properties desired. For instance, if increase in bulk or lipophilicity is desired, then the carrier polypeptide will be enriched in the amino acids in the table provided below. Polar amino acids, on the other hand, can be selected to increase the hydrophilicity of the polypeptide.

Ionizing amino acids can be selected for pH controlled peptide unfolding.

Aspartic acid, glutamic acid and tyrosine carry a neutral charge in the stomach, but will ionize upon entry into the intestine. Conversely, basic amino acids, such as histidine, lysine and arginine, ionize in the stomach and are neutral in an alkaline environment.

Other factors such as n-jr interactions between aromatic residues, kinking of the peptide chain by addition of proline, disulfide crosslinking and hydrogen bonding can all be used to select the optimum amino acid sequence for a given application. Ordering of the linear sequence can influence how these interactions can be maximized and is important in directing the secondary and tertiary structures of the polypeptide.

Furthermore, amino acids with reactive side chains (e. g., glutamic acid, lysine, aspartic acid, serine, threonine and cysteine) can be incorporated for attaching multiple active agents or adjuvants to the same carrier peptide. This is particularly useful if a synergistic effect between two or more active agents is desired.

As stated above, variable molecular weights of the carrier compound can have profound effects'on the active agent release kinetics. As a result, low molecular weight

active agent delivery systems are preferred. An advantage of this invention is that chain length and molecular weight of the polypeptide can be optimized depending on the level of conformational protection desired. This property can be optimized in concert with the kinetics of the first order release mechanism. Thus, another advantage of this invention is that prolonged release time can be imparted by increasing the molecular weight of the carrier polypeptide. Another, significant advantage of the invention is that the kinetics of active agent release is primarily controlled by the enzymatic hydrolysis of the key bond between the carrier peptide and the active agent.

Dextran is the only polysaccharide known that has been explored as a macromolecular carrier for the covalent binding of drug for colon specific drug delivery.

Generally, it was only possible to load up to 1/10 of the total drug-dextran conjugate weight with drug. As stated earlier, polysaccharides are digested mainly in the colon and drug absorption is mainly limited to the colon. As compared to dextran, this invention has two major advantages. First, peptides are hydrolyzed by any one of several aminopeptidases found in the intestinal lumen or associated with the brush-border membrane and so active agent release and subsequent absorption can occur in the jejunum or the ileum. Second, the molecular weight of the carrier molecule can be controlled and, thus, active agent loading can also be controlled.

As a practical example, the following table lists the molecular weights of lipophilic amino acids (less one water molecule) and selected analgesics and vitamins.

TABLE Amino acid MW Active agent MW Glycine 57 Acetaminophen 151 Alanine 71 Vitamin B6 (Pyroxidine) 169 Valine 99 Vitamin C (Ascorbic acid) 176 Leucine 113 Aspirin 180 Isoleucine 113 Ibuprofen 206 Phenylalanine 147 Retinoic acid 300 Tyrosine 163 Vitamin B2 (Riboflavin) 376 Vitamin D2 397 Vitamin E (Tocopherol) 431 Lipophilic amino acids are preferred because conformational protection through the stomach is important for the selected active agents, which were selected based on ease of

covalent attachment to an oligopeptide. Eighteen was subtracted from the amino acid's molecular weight so that their condensation into a polypeptide is considered. For example, a decamer of glycine (MW=588) linked to aspirin would have a total molecular weight of 750 and aspirin would represent 24% of the total weight of the active agent delivery composition or over two times the maximum drug loading for dextran. This is only for an N-or C-terminus application, for those active agents attached to pendant groups of decaglutamic acid, for instance, a drug with a molecular weight of 180 could conceivably have a loading of 58%, although this may not be entirely practical.

The alcohol, amine or carboxylic acid group of an active agent may be covalently attached to the N-terminus, the C-terminus or the side chain of the oligopeptide or polypeptide. The location of attachment depends somewhat on the functional group selection. For instance, if the active drug is a carboxylic acid (e. g. , aspirin) then the N- terminus of the oligopeptide is the preferred point of attachment. If the active agent is an amine (e. g. , ampicillin), then the C-terminus is the preferred point of attachment in order to achieve a stable peptide linked active agent. In both, the C-and N-terminus examples, the peptide is, in essence, extended by one monomeric unit forming a new peptide bond.

If the active agent is an alcohol, then either the C-terminus or the N-terminus is the preferred point of attachment in order to achieve a stable composition. As in the example above where the alcohol, norethindrone, was covalently attached to poly (hydroxypropylglutamine), an alcohol can be converted into an alkylchloroformate with phosgene. This invention, then, pertains to the reaction of this key intermediate with the N-terminus of the peptide carrier. The active ingredient can be released from the peptide carrier by intestinal peptidases.

The alcohol can be selectively bound to the gamma carboxylate of glutamic acid and then this conjugate covalently attached to the C-terminus of the peptide carrier.

Because the glutamic acid-drug conjugate can be considered a dimer, this product adds two monomeric units to the C-terminus of the peptide carrier where the glutamic acid moiety serves as a spacer between the peptide and the drug as shown in Fig. 4. Intestinal enzymatic hydrolysis of the key peptide bond releases the glutamic acid-drug moiety from the peptide carrier. The newly formed free amine of the glutamic acid residue will then undergo an intramolecular transamination reaction, thereby, releasing the active

agent with coincident formation of pyroglutamic acid as shown in Fig. 5. Alternatively, the glutamic acid-drug dimer can be converted into the gamma ester of glutamic acid N- carboxyanhydride. This intermediate can then be polymerized, as described above, using any suitable initiator as shown in Fig. 4. The product of this polymerization is polyglutamic acid with active ingredients attached to multiple pendant groups. Hence, maximum drug loading of the carrier peptide can be achieved. In addition, other amino acid-NCA's can be copolymerized with the gamma ester glutamic acid NCA to impart specific properties to the drug delivery system.

The invention also provides a method of imparting the same mechanism of action for other polypeptides containing functional side chains. Examples include, but are not limited to, polylysine, polyasparagine, polyarginine, polyserine, polycysteine, polytyrosine, polythreonine and polyglutamine. The mechanism can translate to these polypeptides through a spacer or linker on the pendant group, which is terminated, preferably, by the glutamic acid-drug dimer. This carrier peptide-drug conjugate is distinguished from the prior art by virtue of the fact that the primary release of the druch moiety relies on petidases and not on testerases. Alternatively, the active agent can be attached directly to the pendant group where some other indigenous enzymes in the alimentary tract can affect release.

The active agent can be covalently attached to the N-terminus, the C-terminus. or the side chain of the polypeptide using known techniques. Examples of linking organic compounds to the N-terminus type of a peptide include, but are not limited to, the attachment of naphthylacetic acid to LH-RH, coumarinic acid to opioid peptides and 1,3- dialkyl-3-acyltriazenes to tetragastrin and pentagastrin. As another example, there are known techniques for forming peptide linked biotin and peptide linked acridine.

The polypeptide carrier can be prepared using conventional techniques. A preferred technique is copolymerization of mixtures of amino acid N-carboxyanhydrides.

Alternatively, if a specific sequence is desired, a solid state automated peptide synthesizer can be used.

The addition of stabilizers to the composition has the potential of stabilizing the polypeptide further. Stabilizers such as sugar, amino acids, polyethylene glycol (PEG) and salts have been shown to prevent protein unfolding. In another embodiment of the

invention, a pre-first order release of the active agent is imparted by microencapsulating the carrier polypeptide-active agent conjugate in a polysaccharide, amino acid complex, PEG or salts.

There is evidence that hydrophilic compounds are absorbed through the intestinal epithelia efficiently via specialized transporters. The entire membrane transport system is intrinsically asymmetric and responds asymmetrically to cofactors. Thus, one can expect that excitation of the membrane transport system will involve some sort of specialized adjuvant resulting in localized delivery of active agents. There are seven known intestinal transport systems classified according to the physical properties of the transported substrate. They include the amino acid, oligopeptide, glucose, monocarboxic acid, phosphate, bile acid and the P-glycoprotein transport systems and each has its own associated mechanism of transport. The mechanisms can depend on hydrogen ions, sodium ions, binding sites or other cofactors. The invention also allows targeting the mechanisms for intestinal epithelial transport systems to facilitate absorption of active agents.

In another embodiment of the invention, the composition includes one or more adjuvants to enhance the bioavailability of the active agent. Addition of an adjuvant is particularly preferred when using an otherwise poorly absorbed active agent. Suitable adjuvants, for example, include: papain, which is a potent enzyme for releasing the catalytic domain of aminopeptidase-N into the lumen; glycorecognizers, which activate enzymes in the BBM; and bile acids, which have been attached to peptides to enhance absorption of the peptides.

Compositions of the invention are, in essence, the formation of amides from acids and amines and can be prepared by the following examples.

Acid/N-terminus conjugation An acid bioactive agent can be dissolved in DMF under nitrogen and cooled to 0°C. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the amine peptide carrier. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, the product

precipitated out in ether and purified using gel permeation chromatography (GPC) or dialysis.

Amine/C-terminus conjugation The peptide carrier can be dissolved in DMF under nitrogen and cooled to 0°C.

The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the amine bioactive agent. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, and the product precipitated out in ether and purified using GPC or dialysis.

Alcohol/N-Terminus Conjugation In the following example the combination of the alcohol with triphosgene produces a chloroformate, which when reacted with the N-terminus of the peptide produces a carbamate. Pursuant to this, an alcohol bioactive agent can be treated with triphosgene in dry DMF under nitrogen. The suitably protected peptide carrier is then added slowly and the solution stirred at room temperature for several hours. The product is then precipitated out in ether. The crude product is suitably deprotected and purified using GPC.

Other solvents, activating agents, cocatalysts and bases can be used. Examples of other solvents include dimethylsulfoxide, ethers such as tetrahydrofuran or chlorinated solvents such as chloroform. Examples of other activating agents include dicyclohexylcarbodiimide or thionyl chloride. An example of another cocatalyst is N- hydroxysuccinimide. Examples of bases include pyrrolidinopyridine, dimethylaminopyridine, triethylamine or tributylamine.

Preparation of-Alkyl Glutamate There have been over 30 different y-alkyl glutamates prepared any one of which may be suitable for the drug alcohol of choice. For example, a suspension of glutamic acid, the alcohol and concentrated hydrochloric acid can be prepared and heated for

several hours. The-alkyl glutamate product can be precipitated out in acetone, filtered, dried and recrystallized from hot water. x Alkyl Glutamate/C-Terminus Conjugation The peptide carrier can be dissolved in DMF under nitrogen and cooled to 0°C.

The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the y-alkyl glutamate bioactive agent. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, and the product precipitated out in ether and purified using GPC or dialysis.

Preparation ofy-Alkyl Glutamate-NCA -Alkyl glutamate can be suspended in dry THF where triphosgene is added and the mixture refluxed under a nitrogen atmosphere until the mixture becomes homogenous. The solution can be poured into heptane to precipitate the NCA product, which is filtered, dried and recrystallized from a suitable solvent.

Preparation of Poly [y-Alkyl Glutamate] y-Alkyl glutamate-NCA can be dissolved in dry DMF where a catalytic amount of a primary amine can be added to the solution until it becomes viscous (typically overnight). The product can be isolated from the solution by pouring it into water and filtering. The product can be purified using GPC or dialysis.

Although illustrated and described above with reference to specific embodiments, the invention is nevertheless not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the spirit of the invention.

I The present invention provides several benefits for active agent delivery. First, the invention can stabilize leuprolide acetate and prevent its digestion in the stomach. In

Preparation of y-Alkyl Glutamate-NCA y-Alkyl glutamate can be suspended in dry THF where triphosgene is added and the mixture refluxed under a nitrogen atmosphere until the mixture becomes homogenous. The solution can be poured into heptane to precipitate the NCA product, which is filtered, dried and recrystallized from a suitable solvent.

Preparation of Poly [y-Alkyl Glutamate] y-Alkyl glutamate-NCA can be dissolved in dry DMF where a catalytic amount of a primary amine can be added to the solution until it becomes viscous (typically overnight). The product can be isolated from the solution by pouring it into water and filtering. The product can be purified using GPC or dialysis.

Although illustrated and described above with reference to specific embodiments, the invention is nevertheless not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the paragraphs and without departing from the spirit of the invention.

I The present invention provides several benefits for active agent delivery.

First, the invention can stabilize leuprolide acetate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of leuprolide acetate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Leuprolide acetate is the subject of U. S. Patent Numbers 5716640,5643607 and 5631021, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises leuprolide acetate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, leuprolide acetate is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-leuprolide acetate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and leuprolide acetate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein leuprolide acetate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein leuprolide acetate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing leuprolide acetate from said composition in a pH-dependent manner.

19. A method for protecting leuprolide acetate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of leuprolide acetate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching leuprolide acetate to said polypeptide.

21. A method for delivering leuprolide acetate to a patient comprising administering to said patient a composition comprising: a polypeptide; and leuprolide acetate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein leuprolide acetate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein leuprolide acetate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

II The present invention provides several benefits for active agent delivery.

First, the invention can stabilize levocarnitine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of levocarnitine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises levocarnitine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, levocarnitine is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-levocarnitine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and levocarnitine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein levocarnitine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein levocarnitine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing levocarnitine from said composition in a pH-dependent manner.

19. A method for protecting levocarnitine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of levocarnitine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching levocarnitine to said polypeptide.

21. A method for delivering levocarnitine to a patient comprising administering to said patient a composition comprising: a polypeptide; and levocarnitine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein levocarnitine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein levocarnitine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

III The present invention provides several benefits for active agent delivery.

First, the invention can stabilize levocetirizine and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of levocetirizine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Levocetirizine is the subject of EP 58146 B (1984), herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises levocetirizine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, levocetirizine is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-levocetirizine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and levocetirizine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein levocetirizine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein levocetirizine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing levocetirizine from said composition in a pH-dependent manner.

19. A method for protecting levocetirizine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of levocetirizine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching levocetirizine to said polypeptide.

21. A method for delivering levocetirizine to a patient comprising administering to said patient a composition comprising: a polypeptide; and levocetirizine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein levocetirizine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein levocetirizine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

IV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize levofloxacin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of levofloxacin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Levofloxacin is the subject of EP 206283 B (1993), herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises levofloxacin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, levofloxacin is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-levofloxacin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and levofloxacin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein levofloxacin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein levofloxacin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing levofloxacin from said composition in a pH-dependent manner.

19. A method for protecting levofloxacin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of levofloxacin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching levofloxacin to said polypeptide.

21. A method for delivering levofloxacin to a patient comprising administering to said patient a composition comprising: a polypeptide; and levofloxacin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein levofloxacin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein levofloxacin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

V The present invention provides several benefits for active agent delivery.

First, the invention can stabilize levothyroxine and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of

levothyroxine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises levothyroxine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, levothyroxine is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-levothyroxine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and levothyroxine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein levothyroxine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The-composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein levothyroxine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing levothyroxine from said composition in a pH-dependent manner.

19. A method for protecting levothyroxine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of levothyroxine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching levothyroxine to said polypeptide.

21. A method for delivering levothyroxine to a patient comprising administering to said patient a composition comprising: a polypeptide; and levothyroxine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein levothyroxine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein levothyroxine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

VI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize lintuzumab and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of lintuzumab.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Lintuzumab is the subject of U. S. Patent Number 5585089 (1996), herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises lintuzumab covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, lintuzumab is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-lintuzumab conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and lintuzumab covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein lintuzumab is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein lintuzumab is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing lintuzumab from said composition in a pH-dependent manner.

19. A method for protecting lintuzumab from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of lintuzumab from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching lintuzumab to said polypeptide.

21. A method for delivering lintuzumab to a patient comprising administering to said patient a composition comprising: a polypeptide; and lintuzumab covalently attached to said polypeptide.

22. The method of paragraph 21 wherein lintuzumab is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein lintuzumab is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

-VII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize lisinopril and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of lisinopril.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Lisinopril is the subject of EP 12401 B (1984), priority US 968249 (1978), herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises lisinopril covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, lisinopril is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-lisinopril conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and lisinopril covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein lisinopril is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein lisinopril is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing lisinopril from said composition in a pH-dependent manner.

19. A method for protecting lisinopril from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of lisinopril from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching lisinopril to said polypeptide.

21. A method for delivering lisinopril to a patient comprising administering to said patient a composition comprising: a polypeptide; and lisinopril covalently attached to said polypeptide.

22. The method of paragraph 21 wherein lisinopril is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein lisinopril is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

VIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize lisinopril and hydrochlorothiazide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by

delayed release of lisinopril and hydrochlorothiazide. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises lisinopril and hydrochlorothiazide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, lisinopril and hydrochlorothiazide are covalently attached to the polypeptide via the amine or carboxylic acid groups.

Preferably, the resultant peptide-lisinopril and hydrochlorothiazide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and lisinopril and hydrochlorothiazide covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein lisinopril and hydrochlorothiazide are covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein lisinopril and hydrochlorothiazide are conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing lisinopril and hydrochlorothiazide from said composition in a pH-dependent manner.

19. A method for protecting lisinopril and hydrochlorothiazide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of lisinopril and hydrochlorothiazide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching lisinopril and hydrochlorothiazide to said polypeptide.

21. A method for delivering lisinopril and hydrochlorothiazide to a patient comprising administering to said patient a composition comprising: a polypeptide; and

lisinopril and hydrochlorothiazide covalently attached to said polypeptide.

22. The method of paragraph 21 wherein lisinopril and hydrochlorothiazide are released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein lisinopril and hydrochlorothiazide are released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

IX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize carbapenem antibiotic and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of carbapenem antibiotic. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Carbapenem antibiotic is the subject of EP 599512 A (1994), herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises carbapenem antibiotic covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, carbapenem antibiotic is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-carbapenem antibiotic conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and

carbapenem antibiotic covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein carbapenem antibiotic is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein carbapenem antibiotic is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing carbapenem antibiotic from said composition in a pH-dependent manner.

19. A method for protecting carbapenem antibiotic from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of carbapenem antibiotic from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching carbapenem antibiotic to said polypeptide.

21. A method for delivering carbapenem antibiotic to a patient comprising administering to said patient a composition comprising: a polypeptide; and carbapenem antibiotic covalently attached to said polypeptide.

22. The method of paragraph 21 wherein carbapenem antibiotic is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein carbapenem antibiotic is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

X The present invention provides several benefits for active agent delivery.

First, the invention can stabilize loperamide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of loperamide.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Loperamide is the subject of GB 1319040 (1973), priority US 42530 (1970), EP 523847 B (1996), priority US 715949 (1991), herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises loperamide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, loperamide is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-loperamide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and loperamide covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein loperamide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.- 17. The composition of paragraph 1 wherein loperamide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing loperamide from said composition in a pH-dependent manner.

19. A method for protecting loperamide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of loperamide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching loperamide to said polypeptide.

21. A method for delivering loperamide to a patient comprising administering to said patient a composition comprising: a polypeptide; and loperamide covalently attached to said polypeptide.

22. The method of paragraph 21 wherein loperamide is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein loperamide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize loracarbef and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of loracarbef.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Loracarbef is the subject of EP 14476 B 1983, priority JP 14534 1979, EP 311366 B 1994, priority US 105776 1987, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises loracarbef covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, loracarbef is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-loracarbef conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and loracarbef covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein loracarbef is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein loracarbef is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing loracarbef from said composition in a pH-dependent manner.

19. A method for protecting loracarbef from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of loracarbef from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching loracarbef to said polypeptide.

21. A method for delivering loracarbef to a patient comprising administering to said patient a composition comprising: a polypeptide; and loracarbef covalently attached to said polypeptide.

22. The method of paragraph 21 wherein loracarbef is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein loracarbef is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize loratidine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of loratidine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Loratidine is the subject of U. S. Patent Number 4282233,4659716 and 4863931, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises loratidine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-loratidine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and loratidine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein loratidine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein loratidine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing loratidine from said composition in a pH-dependent manner.

19. A method for protecting loratidine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of loratidine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching loratidine to said polypeptide.

21. A method for delivering loratidine to a patient comprising administering to said patient a composition comprising: a polypeptide; and loratidine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein loratidine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein loratidine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize lorazepam and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of lorazepam.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises lorazepam covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, lorazepam is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-lorazepam conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and lorazepam covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein lorazepam is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

&lt; 10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein lorazepam is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing lorazepam from said composition in a pH-dependent manner.

19. A method for protecting lorazepam from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of lorazepam from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching lorazepam to said polypeptide.

21. A method for delivering lorazepam to a patient comprising administering to said patient a composition comprising: a polypeptide; and lorazepam covalently attached to said polypeptide.

22. The method of paragraph 21 wherein lorazepam is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein lorazepam is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize losartan and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of losartan.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Losartan is the subject of U. S. Patent Number 5138069 and 5153197, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises losartan covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more

naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, losartan is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-losartan conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and losartan covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein losartan is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein losartan is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing losartan from said composition in a pH-dependent manner.

19. A method for protecting losartan from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of losartan from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching losartan to said polypeptide.

21. A method for delivering losartan to a patient comprising administering to said patient a composition comprising: a polypeptide; and losartan covalently attached to said polypeptide.

22. The method of paragraph 21 wherein losartan is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein losartan is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize losartan and hydrochlorothiazide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of losartan and hydrochlorothiazide. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Losartan and hydrochlorothiazide are the subject of U. S. Patent Number 5138069 and 5153197, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises losartan and hydrochlorothiazide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, losartan and hydrochlorothiazide are covalently attached to the polypeptide via the hydroxyl and amino groups, respectively.

Preferably, the resultant peptide-losartan and hydrochlorothiazide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and losartan and hydrochlorothiazide covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein losartan and hydrochlorothiazide are covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein losartan and hydrochlorothiazide are conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing losartan and hydrochlorothiazide from said composition in a pH-dependent manner.

19. A method for protecting losartan and hydrochlorothiazide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of losartan and hydrochlorothiazide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching losartan and hydrochlorothiazide to said polypeptide.

21. A method for delivering losartan and hydrochlorothiazide to a patient comprising administering to said patient a composition comprising: a polypeptide; and losartan and hydrochlorothiazide covalently attached to said polypeptide.

22. The method of paragraph 21 wherein losartan and hydrochlorothiazide are released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein losartan and hydrochlorothiazide are released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize lovastatin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of lovastatin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Lovastatin is the subject of U. S. Patent Number 4231938, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises lovastatin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, lovastatin is covalently attached to the polypeptide via the hydroxyl.

Preferably, the resultant peptide-lovastatin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and lovastatin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein lovastatin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein lovastatin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing lovastatin from said composition in a pH-dependent manner.

19. A method for protecting lovastatin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of lovastatin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching lovastatin to said polypeptide.

21. A method for delivering lovastatin to a patient comprising administering to said patient a composition comprising: a polypeptide; and lovastatin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein lovastatin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein lovastatin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize marimastat and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of marimastat.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Marimastat is the subject of WO 94/2447 1994 and WO 96/25156 1996, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises marimastat covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, marimastat is covalently attached to the polypeptide via the hydroxyl.

Preferably, the resultant peptide-marimastat conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and marimastat covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein marimastat is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is . selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The* composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein marimastat is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing marimastat from said composition in a pH-dependent manner.

19. A method for protecting marimastat from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of marimastat from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching marimastat to said polypeptide.

21. A method for delivering marimastat to a patient comprising administering to said patient a composition comprising: a polypeptide; and marimastat covalently attached to said polypeptide.

22. The method of paragraph 21 wherein marimastat is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein marimastat is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XVIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize mecasermin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of mecasermin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Mecasermin is the subject of EP 476044 B 1997, priority US 361595 1989, and EP 219814 B 1991, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises mecasermin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, mecasermin is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-mecasermin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and mecasermin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mecasermin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein mecasermin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mecasermin from said composition in a pH-dependent manner.

19. A method for protecting mecasermin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mecasermin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mecasermin to said polypeptide.

21. A method for delivering mecasermin to a patient comprising administering to said patient a composition comprising: a polypeptide; and mecasermin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mecasermin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mecasermin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize medroxyprogesterone acetate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of medroxyprogesterone acetate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises medroxyprogesterone acetate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a

synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-medroxyprogesterone acetate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and medroxyprogesterone acetate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein medroxyprogesterone acetate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein medroxyprogesterone acetate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing medroxyprogesterone acetate from said composition in a pH-dependent manner.

19. A method for protecting medroxyprogesterone acetate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of medroxyprogesterone acetate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching medroxyprogesterone acetate to said polypeptide.

21. A method for delivering medroxyprogesterone acetate to a patient comprising administering to said patient a composition comprising: a polypeptide; and medroxyprogesterone acetate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein medroxyprogesterone acetate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein medroxyprogesterone acetate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize mefloquine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of mefloquine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Mefloquine is the subject of U. S. Patent Number 4579855, herein incorporated by reference, which-describes how to make that drug.

The composition of the invention comprises mefloquine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, mefloquine is covalently attached to the polypeptide via the hydroxyl.

Preferably, the resultant peptide-mefloquine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and mefloquine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a hompolymer of a syntheitic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mefloquine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein mefloquine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mefloquine from said composition in a pH-dependent manner.

19. A method for protecting mefloquine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mefloquine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mefloquine to said polypeptide.

21. A method for delivering mefloquine to a patient comprising administering to said patient a composition comprising: a polypeptide; and mefloquine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mefloquine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mefloquine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize megestrol acetate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of megestrol acetate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Megestrol acetate is the subject of U. S. Patent Number 5338732, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises megestrol acetate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-megestrol acetate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and megestrol acetate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein megestrol acetate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein megestrol acetate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing megestrol acetate from said composition in a pH-dependent manner.

19. A method for protecting megestrol acetate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of megestrol acetate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching megestrol acetate to said polypeptide.

21. A method for delivering megestrol acetate to a patient comprising administering to said patient a composition comprising: a polypeptide; and megestrol acetate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein megestrol acetate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein megestrol acetate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize an adenosine Al receptor antagonist and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of an adenosine Al receptor antagonist. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the

intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

An adenosine Al receptor antagonist is the subject of WO 95/11904 1995, priority US 144459 1993, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises an adenosine Al receptor antagonist covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, an adenosine Al receptor antagonist is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-an adenosine Al receptor antagonist conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and an adenosine Al receptor antagonist covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein an adenosine Al receptor antagonist is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein an adenosine Al receptor antagonist is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing an adenosine Al receptor antagonist from said composition in a pH-dependent manner.

19. A method for protecting an adenosine A1 receptor antagonist from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of an adenosine Al receptor antagonist from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching an adenosine Al receptor antagonist to said polypeptide.

21. A method for delivering an adenosine Al receptor antagonist to a patient comprising administering to said patient a composition comprising:

a polypeptide; and an adenosine A1 receptor antagonist covalently attached to said polypeptide.

22. The method of paragraph 21 wherein an adenosine Al receptor antagonist is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein an adenosine Al receptor antagonist is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize mercaptopurine and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of mercaptopurine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises mercaptopurine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, mercaptopurine is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-mercaptopurine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed. 1. A pharmaceutical composition comprising: a polypeptide; and mercaptopurine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mercaptopurine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein mercaptopurine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mercaptopurine from said composition in a pH-dependent manner.

19. A method for protecting mercaptopurine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mercaptopurine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mercaptopurine to said polypeptide.

21. A method for delivering mercaptopurine to a patient comprising administering to said patient a composition comprising: a polypeptide; and mercaptopurine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mercaptopurine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mercaptopurine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize meropenem and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of meropenem.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Meropenem is the subject of EP 126587 B 1995 and EP 256377 B 1992, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises meropenem covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more

naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, meropenem is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-meropenem conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and meropenem covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein meropenem is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein meropenem is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing meropenem from said composition in a pH-dependent manner.

19. A method for protecting meropenem from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of meropenem-from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching meropenem to said polypeptide.

21. A method for delivering meropenem to a patient comprising administering to said patient a composition comprising: a polypeptide; and meropenem covalently attached to said polypeptide.

22. The method of paragraph 21 wherein meropenem is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein meropenem is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize mesalamine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of mesalamine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Mesalamine is the subject of U. S. Patent Number 5541170 and 5541171, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises mesalamine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, mesalamine is covalently attached to the polypeptide via the carboxylic acid or amino group.

Preferably, the resultant peptide-mesalamine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and mesalamine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mesalamine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein mesalamine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mesalamine from said composition in a pH-dependent manner.

19. A method for protecting mesalamine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mesalamine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mesalamine to said polypeptide.

21. A method for delivering mesalamine to a patient comprising administering to said patient a composition comprising:

a polypeptide; and mesalamine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mesalamine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mesalamine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize mesna and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of mesna.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Mesna is the subject of U. S. Patent Number 4220660 and 5696172, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises mesna covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, mesna is covalently attached to the polypeptide via the thiol group.

Preferably, the resultant peptide-mesna conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and

mesna covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mesna is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein mesna is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mesna from said composition in a pH-dependent manner.

19. A method for protecting mesna from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mesna from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mesna to said polypeptide.

21. A method for delivering mesna to a patient comprising administering to said patient a composition comprising: a polypeptide; and mesna covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mesna is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mesna is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize metaxalone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of metaxalone.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises metaxalone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more

naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, metaxalone is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-metaxalone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and metaxalone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein metaxalone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein metaxalone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing metaxalone from said composition in a pH-dependent manner.

19. A method for protecting metaxalone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of metaxalone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching metaxalone to said polypeptide.

21. A method for delivering metaxalone to a patient comprising administering to said patient a composition comprising: a polypeptide; and metaxalone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein metaxalone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein metaxalone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXVIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize Metformin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of Metformin. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises Metformin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, Metformin is covalently attached to the polypeptide via the amine.

Preferably, the resultant peptide-Metformin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and Metformin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein Metformin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter 13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein Metformin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing Metformin from said composition in a pH-dependent manner.

19. A method for protecting Metformin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of Metformin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching Metformin to said polypeptide.

21. A method for delivering Metformin to a patient comprising administering to said patient a composition comprising: a polypeptide; and Metformin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein Metformin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein Metformin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize an oral nonsteroidal antiestrogen compound and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of an oral nonsteroidal antiestrogen compound. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

An oral nonsteroidal antiestrogen compound is the subject of WO 96/26201 1996, priority US 388207 1995, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises an oral nonsteroidal antiestrogen compound covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-an oral nonsteroidal antiestrogen compound conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and an oral nonsteroidal antiestrogen compound covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein an oral nonsteroidal antiestrogen compound is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein an oral nonsteroidal antiestrogen compound is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing an oral nonsteroidal antiestrogen compound from said composition in a pH- dependent manner.

19. A method for protecting an oral nonsteroidal antiestrogen compound from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of an oral nonsteroidal antiestrogen compound from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching an oral nonsteroidal antiestrogen compound to said polypeptide.

21. A method for delivering an oral nonsteroidal antiestrogen compound to a patient comprising administering to said patient a composition comprising: a polypeptide; and an oral nonsteroidal antiestrogen compound covalently attached to said polypeptide.

22. The method of paragraph 21 wherein an oral nonsteroidal antiestrogen compound is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein an oral nonsteroidal antiestrogen compound is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize methylphenidate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of methylphenidate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises methylphenidate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, methylphenidate is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-methylphenidate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and methylphenidate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein methylphenidate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein methylphenidate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing methylphenidate from said composition in a pH-dependent manner.

19. A method for protecting methylphenidate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of methylphenidate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching methylphenidate to said polypeptide.

21. A method for delivering methylphenidate to a patient comprising administering to said patient a composition comprising:

a polypeptide; and methylphenidate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein methylphenidate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein methylphenidate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize methylprednisone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of methylprednisone. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises methylprednisone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, methylprednisone is covalently attached to the polypeptide via the hydroxyl.

Preferably, the resultant peptide-methylprednisone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and methylprednisone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein methylprednisone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein methylprednisone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing methylprednisone from said composition in a pH-dependent manner.

19. A method for protecting methylprednisone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of methylprednisone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching methylprednisone to said polypeptide.

21. A method for delivering methylprednisone to a patient comprising administering to said patient a composition comprising: a polypeptide; and methylprednisone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein methylprednisone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein methylprednisone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize an antifungal agent and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of an antifungal agent. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

An antifungal agent is the subject of WO 96/11210 1996, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises an antifungal agent covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer

of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, an antifungal agent is covalently attached to the polypeptide via the hydroxyl.

Preferably, the resultant peptide-an antifungal agent conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and an antifungal agent covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein an antifungal agent is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein an antifungal agent is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing an antifungal agent from said composition in a pH-dependent manner.

19. A method for protecting an antifungal agent from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of an antifungal agent from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching an antifungal agent to said polypeptide.

21. A method for delivering an antifungal agent to a patient comprising administering to said patient a composition comprising: a polypeptide; and an antifungal agent covalently attached to said polypeptide.

22. The method of paragraph 21 wherein an antifungal agent is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein an antifungal agent is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize metolazone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of metolazone. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises metolazone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, metolazone is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-metolazone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and metolazone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein metolazone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein metolazone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing metolazone from said composition in a pH-dependent manner.

19. A method for protecting metolazone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of metolazone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching metolazone to said polypeptide.

21. A method for delivering metolazone to a patient comprising administering to said patient a composition comprising: a polypeptide; and metolazone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein metolazone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein metolazone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize metoprolol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of metoprolol. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises metoprolol covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, metoprolol is covalently attached to the polypeptide via the hydroxyl group Preferably, the resultant peptide-metoprolol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and metoprolol covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein metoprolol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein metoprolol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing metoprolol from said composition in a pH-dependent manner.

19. A method for protecting metoprolol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of metoprolol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching metoprolol to said polypeptide.

21. A method for delivering metoprolol to a patient comprising administering to said patient a composition comprising: a polypeptide; and metoprolol covalently attached to said polypeptide.

22. The method of paragraph 21 wherein metoprolol is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein metoprolol is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize a carbapenem antibiotic and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a carbapenem antibiotic. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

A carbapenem antibiotic is the subject of WO 93/15078 1993, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises a carbapenem antibiotic covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino

acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, a carbapenem antibiotic is covalently attached to the polypeptide via the carboxylic acid or alcohol group.

Preferably, the resultant peptide-a carbapenem antibiotic conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and a carbapenem antibiotic covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The oomposition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein a carbapenem antibiotic is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein a carbapenem antibiotic is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing a carbapenem antibiotic from said composition in a pH-dependent manner.

19. A method for protecting a carbapenem antibiotic from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a carbapenem antibiotic from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a carbapenem antibiotic to said polypeptide.

21. A method for delivering a carbapenem antibiotic to a patient comprising administering to said patient a composition comprising: a polypeptide; and a carbapenem antibiotic covalently attached to said polypeptide.

22. The method of paragraph 21 wherein a carbapenem antibiotic is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein a carbapenem antibiotic is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize metronidazole and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of metronidazole. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises metronidazole covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, metronidazole is covalently attached to the polypeptide via the hydroxyl.

Preferably, the resultant peptide-metronidazole conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and metronidazole covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein metronidazole is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

. 16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein metronidazole is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing metronidazole from said composition in a pH-dependent manner.

19. A method for protecting metronidazole from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of metronidazole from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching metronidazole to said polypeptide.

21. A method for delivering metronidazole to a patient comprising administering to said patient a composition comprising: a polypeptide; and metronidazole covalently attached to said polypeptide.

22. The method of paragraph 21 wherein metronidazole is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein metronidazole is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXVII The present invention provides several benefits for active agent delivery. First, the invention can stabilize milrinone lactate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of milrinone lactate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Milrinone lactate is the subject of U. S. Patent Number 4313951, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises milrinone lactate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-milrinone lactate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and

milrinone lactate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein milrinone lactate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein milrinone lactate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing milrinone lactate from said composition in a pH-dependent manner.

19. A method for protecting milrinone lactate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of milrinone lactate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching milrinone lactate to said polypeptide.

21. A method for delivering milrinone lactate to a patient comprising administering to 6aid patient a composition comprising: a polypeptide; and milrinone lactate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein milrinone lactate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein milrinone lactate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXVIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize minocycline and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of minocycline. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Minocycline is the subject of GB 1003474, priority US 147137 1961, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises minocycline covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, minocycline is covalently attached to the polypeptide via the hydroxyl.

Preferably, the resultant peptide-minocycline conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and minocycline covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein minocycline is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein minocycline is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing minocycline from said composition in a pH-dependent manner.

19. A method for protecting minocycline from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of minocycline from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching minocycline to said polypeptide.

21. A method for delivering minocycline to a patient comprising administering to said patient a composition comprising: a polypeptide; and minocycline covalently attached to said polypeptide.

22. The method of paragraph 21 wherein minocycline is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein minocycline is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXIX The present invention provides several benefits for active agent delivery. First, the invention can stabilize mirtazapine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of mirtazapine. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Mirtazapine is the subject of GB 1543171 1979, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises mirtazapine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-mirtazapine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and mirtazapine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mirtazapine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein mirtazapine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mirtazapine from said composition in a pH-dependent manner.

19. A method for protecting mirtazapine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mirtazapine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mirtazapine to said polypeptide.

21. A method for delivering mirtazapine to a patient comprising administering to said patient a composition comprising: a polypeptide; and mirtazapine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mirtazapine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mirtazapine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XL The present invention provides several benefits for active agent delivery.

First, the invention can stabilize misoprostol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of misoprostol.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Misoprostol is the subject of GB 1492426 1974, priority US 454913 1974, US 5252602 1993, US 4301146, and EP 527887 B 1995, priority US 518353 1990, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises misoprostol covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, misoprostol is covalently attached to the polypeptide via the alcohol group.

Preferably, the resultant peptide-misoprostol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and misoprostol covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein misoprostol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein misoprostol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing misoprostol from said composition in a pH-dependent manner.

19. A method for protecting misoprostol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of misoprostol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching misoprostol to said polypeptide.

21. A method for delivering misoprostol to a patient comprising administering to said patient a composition comprising: a polypeptide ; and misoprostol covalently attached to said polypeptide.

22. The method of paragraph 21 wherein misoprostol is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein misoprostol is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize mitiglinide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of mitiglinide.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Mitiglinide is the subject of EP 507534 B 1992, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises mitiglinide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, mitiglinide is covalently attached to the polypeptide via the carboxylic acid.

Preferably, the resultant peptide-mitiglinide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and mitiglinide covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mitiglinide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

. 17. The composition of paragraph 1 wherein mitiglinide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mitiglinide from said composition in a pH-dependent manner.

19. A method for protecting mitiglinide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mitiglinide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mitiglinide to said polypeptide.

21. A method for delivering mitiglinide to a patient comprising administering to said patient a composition comprising: a polypeptide; and mitiglinide covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mitiglinide is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mitiglinide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize mitoxantrone and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of mitoxantrone. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Mitoxantrone is the subject of U. S. Patent Number 4278689 and 4820738, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises mitoxantrone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, mitoxantrone is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-mitoxantrone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and mitoxantrone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mitoxantrone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein mitoxantrone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mitoxantrone from said composition in a pH-dependent manner.

19. A method for protecting mitoxantrone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mitoxantrone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mitoxantrone to said polypeptide.

21. A method for delivering mitoxantrone to a patient comprising administering to said patient a composition comprising : a polypeptide; and mitoxantrone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mitoxantrone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mitoxantrone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize mivacurium and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of mivacurium.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Mivacurium is the subject of U. S. Patent Number 4761418, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises mivacurium covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a

heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-mivacurium conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and mivacurium covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mivacurium is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein mivacurium is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mivacurium from said composition in a pH-dependent manner.

19. A method for protecting mivacurium from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mivacurium from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mivacurium to said polypeptide.

21. A method for delivering mivacurium to a patient comprising administering to said patient a composition comprising: a polypeptide; and mivacurium covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mivacurium is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mivacurium is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize modafinil and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of modafinil.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Modafinil is the subject of U. S. Patent Number 49278555618845, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises modafinil covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, modafinil is covalently attached to the polypeptide via the amido group.

Preferably, the resultant peptide-modafinil conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and modafinil covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein modafinil is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein modafinil is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing modafinil from said composition in a pH-dependent manner.

19. A method for protecting modafinil from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of modafinil from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching modafinil to said polypeptide.

21. A method for delivering modafinil to a patient comprising administering to said patient a composition comprising: a polypeptide; and modafinil covalently attached to said polypeptide.

22. The method of paragraph 21 wherein modafinil is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein modafinil is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize moexipril and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of moexipril.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Moexipril is the subject of U. S. Patent Number 4344949 and 4743450, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises moexipril covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, moexipril is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-moexipril conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and moexipril covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is'a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein moexipril is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein moexipril is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing moexipril from said composition in a pH-dependent manner.

19. A method for protecting moexipril from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of moexipril from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching moexipril to said polypeptide.

21. A method for delivering moexipril to a patient comprising administering to said patient a composition comprising: a polypeptide; and moexipril covalently attached to said polypeptide.

22. The method of paragraph 21 wherein moexipril is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein moexipril is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize montelukast and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of montelukast.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Montelukast is the subject of U. S. Patent Number 5565473, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises montelukast covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, montelukast is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-montelukast conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and montelukast covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein montelukast is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein montelukast is conformationally protected by folding of said polypeptide about said active agent.

. 18. The composition of paragraph 1 wherein said polypeptide is capable of releasing montelukast from said composition in a pH-dependent manner.

19. A method for protecting montelukast from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of montelukast from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching montelukast to said polypeptide.

21. A method for delivering montelukast to a patient comprising administering to said patient a composition comprising: a polypeptide; and montelukast covalently attached to said polypeptide.

22. The method of paragraph 21 wherein montelukast is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein montelukast is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize morphine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of morphine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises morphine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, morphine is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-morphine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and morphine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein morphine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein morphine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing morphine from said composition in a pH-dependent manner.

19. A method for protecting morphine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of morphine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching morphine to said polypeptide.

21. A method for delivering morphine to a patient comprising administering to said patient a composition comprising: a polypeptide; and morphine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein morphine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein morphine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLVIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize mycophenylate mofetil and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of mycophenylate mofetil. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Mycophenylate mofetil is the subject of EP 281713 B 1991, priority US 8717 1987, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises mycophenylate mofetil covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, mycophenylate mofetil is covalently attached to the polypeptide via the hydroxyl.

Preferably, the resultant peptide-mycophenylate mofetil conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and mycophenylate mofetil covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein mycophenylate mofetil is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein mycophenylate mofetil is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing mycophenylate mofetil from said composition in a pH-dependent manner.

19. A method for protecting mycophenylate mofetil from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of mycophenylate mofetil from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching mycophenylate mofetil to said polypeptide.

21. A method for delivering mycophenylate mofetil to a patient comprising administering to said patient a composition comprising: a polypeptide; and mycophenylate mofetil covalently attached to said polypeptide.

22. The method of paragraph 21 wherein mycophenylate mofetil is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein mycophenylate mofetil is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nabumetone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nabumetone.

Furthermore, active agents can be combined to produce synergistic effects. Also,

absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nabumetone is the subject of U. S. Patent Number 4420639, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nabumetone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates..

Preferably, the resultant peptide-nabumetone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nabumetone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nabumetone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nabumetone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nabumetone from said composition in a pH-dependent manner.

19. A method for protecting nabumetone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nabumetone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nabumetone to said polypeptide.

21. A method for delivering nabumetone to a patient comprising administering to said patient a composition comprising: a polypeptide; and nabumetone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nabumetone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nabumetone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

L The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nadolol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nadolol.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises nadolol covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nadolol is covalently attached to the polypeptide via a hydroxyl group.

Preferably, the resultant peptide-nadolol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nadolol covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nadolol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nadolol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nadolol from said composition in a pH-dependent manner.

19. A method for protecting nadolol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nadolol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nadolol to said polypeptide.

21. A method for delivering nadolol to a patient comprising administering to said patient a composition comprising: a polypeptide; and nadolol covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nadolol is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nadolol is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize naproxen and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of naproxen.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises naproxen covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, naproxen is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-naproxen conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and naproxen covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein naproxen is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein naproxen is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing naproxen from said composition in a pH-dependent manner.

19. A method for protecting naproxen from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of naproxen from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching naproxen to said polypeptide.

21. A method for delivering naproxen to a patient comprising administering to- said patient a composition comprising: a polypeptide; and naproxen covalently attached to said polypeptide.

22. The method of paragraph 21 wherein naproxen is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein naproxen is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize naratriptan and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of naratriptan.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Naratriptan is the subject of U. S. Patent Number 4997841, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises naratriptan covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, naratriptan is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-naratriptan conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and naratriptan covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein naratriptan is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein naratriptan is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing naratriptan from said composition in a pH-dependent manner.

19. A method for protecting naratriptan from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of naratriptan from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching naratriptan to said polypeptide.

21. A method for delivering naratriptan to a patient comprising administering to said patient a composition comprising: a polypeptide; and naratriptan covalently attached to said polypeptide.

22. The method of paragraph 21 wherein naratriptan is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein naratriptan is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nefazodone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nefazodone.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nefazodone is the subject of U. S. Patent Number 4338317 and 5256664, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nefazodone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-nefazodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nefazodone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nefazodone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nefazodone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nefazodone from said composition in a pH-dependent manner.

19. A method for protecting nefazodone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nefazodone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nefazodone to said polypeptide.

21. A method for delivering nefazodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and nefazodone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nefazodone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nefazodone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nelarabine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nelarabine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nelarabine is the subject of EP 294114 B 1996, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nelarabine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more

naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nelarabine is covalently attached to the polypeptide via the hydroxyl or amino group.

Preferably, the resultant peptide-nelarabine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nelarabine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nelarabine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nelarabine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nelarabine from said composition in a pH-dependent manner.

19. A method for protecting nelarabine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nelarabine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nelarabine to said polypeptide.

21. A method for delivering nelarabine to a patient comprising administering to said patient a composition comprising: a polypeptide; and nelarabine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nelarabine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nelarabine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nelfinavir mesylate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nelfinavir mesylate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nelfinavir mesylate is the subject of U. S. Patent Number 5484926 and 5952343, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nelfinavir mesylate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nelfinavir mesylate is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-nelfinavir mesylate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nelfinavir mesylate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nelfinavir mesylate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nelfinavir mesylate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nelfinavir mesylate from said composition in a pH-dependent manner.

19. A method for protecting nelfinavir mesylate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nelfinavir mesylate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nelfinavir mesylate to said polypeptide.

21. A method for delivering nelfinavir mesylate to a patient comprising administering to said patient a composition comprising:

a, polypeptide; and nelfinavir mesylate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nelfinavir mesylate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nelfinavir mesylate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nesiritide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nesiritide.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nesiritide is the subject of EP 418308 B 1995, priority US 200383 1988, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nesiritide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nesiritide is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-nesiritide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and

nesiritide covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nesiritide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 1 lez wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nesiritide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nesiritide from said composition in a pH-dependent manner.

19. A method for protecting nesiritide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nesiritide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nesiritide to said polypeptide.

21. A method for delivering nesiritide to a patient comprising administering to said patient a composition comprising: a polypeptide; and nesiritide covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nesiritide is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nesiritide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nevirapine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nevirapine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nevirapine is the subject of U. S. Patent Number 5366972, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nevirapine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii)'a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nevirapine is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-nevirapine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and nevirapine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nevirapine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nevirapine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nevirapine from said composition in a pH-dependent manner.

19. A method for protecting nevirapine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nevirapine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nevirapine to said polypeptide.

21. A method for delivering nevirapine to a patient comprising administering to said patient a composition comprising: a polypeptide; and nevirapine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nevirapine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nevirapine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LVIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nifedipine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nifedipine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nifedipine is the subject of U. S. Patent Numbers 4327725,4612008, 4765989, 4783337 and 5Z64446, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nifedipine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nifedipine is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-nifedipine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nifedipine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4'. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nifedipine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nifedipine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nifedipine from said composition in a pH-dependent manner.

19. A method for protecting nifedipine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nifedipine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nifedipine to said polypeptide.

21. A method for delivering nifedipine to a patient comprising administering to said patient a composition comprising: a polypeptide; and nifedipine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nifedipine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nifedipine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nimodipine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nimodipine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nimodipine is the subject of U. S. Patent Number 4406906, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nimodipine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nimodipine is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-nimodipine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed. polypeptide; and nimodipine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one. or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nimodipine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nimodipine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nimodipine from said composition in a pH-dependent manner.

19. A method for protecting nimodipine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nimodipine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nimodipine to said polypeptide.

21. A method for delivering nimodipine to a patient comprising administering to said patient a composition comprising: a polypeptide; and nimodipine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nimodipine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nimodipine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nisoldipine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nisoldipine.

Furthermore, active agents can be combined to produce synergistic effects. Also,

absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nisoldipine is the subject of U. S. Patent Number 4892741, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nisoldipine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nisoldipine is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-nisoldipine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nisoldipine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nisoldipine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The. composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nisoldipine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nisoldipine from said composition in a pH-dependent manner.

19. A method for protecting nisoldipine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nisoldipine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nisoldipine to said polypeptide.

21. A method for delivering nisoldipine to a patient comprising administering to said patient a composition comprising: a polypeptide; and nisoldipine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nisoldipine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nisoldipine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nitrofurantoin and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of nitrofurantoin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises nitrofurantoin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nitrofurantoin is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-nitrofurantoin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nitrofurantoin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nitrofurantoin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nitrofurantoin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nitrofurantoin from said composition in a pH-dependent manner.

19. A method for protecting nitrofurantoin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nitrofurantoin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nitrofurantoin to said polypeptide.

21. A method for delivering nitrofurantoin to a patient comprising administering to said patient a composition comprising: a polypeptide; and nitrofurantoin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nitrofurantoin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nitrofurantoin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

. LXII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nitroglycerin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nitroglycerin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises nitroglycerin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nitroglycerin is covalently attached to the polypeptide via the nitro group or, alternatively through an artificial linker.

Preferably, the resultant peptide-nitroglycerin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nitroglycerin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nitroglycerin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nitroglycerin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nitroglycerin from said composition in a pH-dependent manner.

19. A method for protecting nitroglycerin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nitroglycerin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nitroglycerin to said polypeptide.

21. A method for delivering nitroglycerin to a patient comprising administering to said patient a composition comprising: a polypeptide; and nitroglycerin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nitroglycerin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nitroglycerin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nizatidine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nizatidine.

Furthermore, active agents can be combined to produce synergistic effects. Also,

absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Nizatidine is the subject of U. S. Patent Number 4375547, 4382090 and 4760775, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises nizatidine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of'two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nizatidine is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-nizatidine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and nizatidine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nizatidine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nizatidine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nizatidine from said composition in a pH-dependent manner.

19. A method for protecting nizatidine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nizatidine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nizatidine to said polypeptide.

21. A method for delivering nizatidine to a patient comprising administering to said patient a composition comprising: a polypeptide; and nizatidine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nizatidine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nizatidine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize norastemizole and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of norastemizole. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Norastemizole is the subject of EP 5318 B 1982, priority US 892534 1978, WO 94/7495 1994, priority US 940054 1992, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises norastemizole covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, norastemizole is covalently attached to the polypeptide via the amino groups.

Preferably, the resultant peptide-norastemizole conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and norastemizole covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein norastemizole is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein norastemizole is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing norastemizole from said composition in a pH-dependent manner.

19. A method for protecting norastemizole from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of norastemizole from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching norastemizole to said polypeptide.

21. A method for delivering norastemizole to a patient comprising administering to said patient a composition comprising: a polypeptide; and norastemizole covalently attached to said polypeptide.

22. The method of paragraph 21 wherein norastemizole is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein norastemizole is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize norethindrone and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of norethindrone. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises norethindrone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a

heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, norethindrone is covalently attached to the polypeptide via the amine groups.

Preferably, the resultant peptide-norethindrone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and norethindrone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein norethindrone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein norethindrone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing norethindrone from said composition in a pH-dependent manner.

19. A method for protecting norethindrone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of norethindrone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching norethindrone to said polypeptide.

21. A method for delivering norethindrone to a patient comprising administering to said patient a composition comprising : a polypeptide; and norethindrone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein norethindrone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein norethindrone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize norfloxacin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of norfloxacin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Norfloxacin is the subject of U. S. Patent Numbers 4146719 and 4639458, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises norfloxacin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, norfloxacin is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-norfloxacin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and norfloxacin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein norfloxacin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein norfloxacin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing norfloxacin from said composition in a pH-dependent manner.

19. A method for protecting norfloxacin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of norfloxacin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching norfloxacin to said polypeptide.

21. A method for delivering norfloxacin to a patient comprising administering to said patient a composition comprising:

a polypeptide; and norfloxacin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein norfloxacin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein norfloxacin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize nortriptyline and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of nortriptyline.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises nortriptyline covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, nortriptyline is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-nortriptyline conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and nortriptyline covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein nortriptyline is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein nortriptyline is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing nortriptyline from said composition in a pH-dependent manner.

19. A method for protecting nortriptyline from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of nortriptyline from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching nortriptyline to said polypeptide.

21. A method for delivering nortriptyline to a patient comprising administering to said patient a composition comprising: a polypeptide; and nortriptyline covalently attached to said polypeptide.

22. The method of paragraph 21 wherein nortriptyline is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein nortriptyline is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXVIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize octreotide acetate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of octreotide acetate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Octreotide acetate is the subject of U. S. Patent Numbers 4395403, 5538739, 5639480,5688530, 5922338 and 5922682, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises octreotide acetate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of

one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, octreotide acetate is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-octreotide acetate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and octreotide acetate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein octreotide acetate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein octreotide acetate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing octreotide acetate from said composition in a pH-dependent manner.

19. A method for protecting octreotide acetate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of octreotide acetate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching octreotide acetate to said polypeptide.

21. A method for delivering octreotide acetate to a patient comprising administering to said patient a composition comprising: a polypeptide; and octreotide acetate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein octreotide acetate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein octreotide acetate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize oxycodone and acetaminophen and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of oxycodone and acetaminophen. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises oxycodone and acetaminophen covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, oxycodone and acetaminophen are covalently attached to the polypeptide via the amino group and hydroxyl group, respectively.

Preferably, the resultant peptide-oxycodone and acetaminophen conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and oxycodone and acetaminophen covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein oxycodone and acetaminophen are covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein oxycodone and acetaminophen are conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing oxycodone and acetaminophen from said composition in a pH-dependent manner.

19. A method for protecting oxycodone and acetaminophen from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of oxycodone and acetaminophen from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching oxycodone and acetaminophen to said polypeptide.

21. A method for delivering oxycodone and acetaminophen to a patient comprising administering to said patient a composition comprising: a polypeptide; and oxycodone and acetaminophen covalently attached to said polypeptide.

22. The method of paragraph 21 wherein oxycodone and acetaminophen are released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein oxycodone and acetaminophen are released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize ofloxacin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ofloxacin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Ofloxacin is the subject of U. S. Patent Number 4382892, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises ofloxacin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, ofloxacin is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-ofloxacin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ofloxacin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein ofloxacin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein ofloxacin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing ofloxacin from said composition in a pH-dependent manner.

19. A method for protecting ofloxacin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ofloxacin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ofloxacin to said polypeptide.

21. A method for delivering ofloxacin to a patient comprising administering to said patient a composition comprising: a polypeptide; and ofloxacin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein ofloxacin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein ofloxacin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize olanzapine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of olanzapine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Olanzapine is the subject of U. S. Patent Numbers 5229382,5605897, 5736541, and 5919485, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises olanzapine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, olanzapine is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-olanzapine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and olanzapine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein olanzapine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein olanzapine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing olanzapine from said composition in a pH-dependent manner.

19. A method for protecting olanzapine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of olanzapine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching olanzapine to said polypeptide.

21. A method for delivering olanzapine to a patient comprising administering to said patient a composition comprising: a polypeptide; and olanzapine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein olanzapine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein olanzapine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize omeprezole and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of omeprezole.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Omeprezole is the subject of U. S. Patent Numbers 4255431,4636499, 4786505 and 4853230, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises omeprezole covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, omeprezole is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-omeprezole conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and omeprezole covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein omeprezole is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein omeprezole is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing omeprezole from said composition in a pH-dependent manner.

19. A method for protecting omeprezole from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of omeprezole from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching omeprezole to said polypeptide.

21. A method for delivering omeprezole to a patient comprising administering to said patient a composition comprising: a polypeptide; and omeprezole covalently attached to said polypeptide.

22. The method of paragraph 21 wherein omeprezole is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein omeprezole is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize ondansetron and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ondansetron. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Ondansetron is the subject of U. S. Patent Numbers 4695578, 4753789, 5344658, and 5578628, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises ondansetron covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more

naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-ondansetron conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ondansetron covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein ondansetron is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein ondansetron is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing ondansetron from said composition in a pH-dependent manner.

19. A method for protecting ondansetron from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ondansetron from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ondansetron to said polypeptide.

21. A method for delivering ondansetron to a patient comprising administering to said patient a composition comprising: a polypeptide; and ondansetron covalently attached to said polypeptide.

22. The method of paragraph 21 wherein ondansetron is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein ondansetron is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXIVThe present invention provides several benefits for active agent delivery.

First, the invention can stabilize oprelvekin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of oprelvekin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Oprelvekin is the subject of EP 504177 A 1992, priority US 441100 1989, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises oprelvekin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, oprelvekin is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-oprelvekin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and oprelvekin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein oprelvekin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein oprelvekin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing oprelvekin from said composition in a pH-dependent manner.

19. A method for protecting oprelvekin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of oprelvekin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching oprelvekin to said polypeptide.

21. A method for delivering oprelvekin to a patient comprising administering to said patient a composition comprising: a polypeptide; and oprelvekin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein oprelvekin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein oprelvekin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize orlistat and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of orlistat.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Orlistat is the subject of U. S. Patent Numbers 4598089 and 6004996, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises orlistat covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, orlistat is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-orlistat conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and orlistat covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein orlistat is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein orlistat is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing orlistat from said composition in a pH-dependent manner.

19. A method for protecting orlistat from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of orlistat from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching orlistat to said polypeptide.

21. A method for delivering orlistat to a patient comprising administering to said patient a composition comprising: a polypeptide ; and orlistat covalently attached to said polypeptide.

22. The method of paragraph 21 wherein orlistat is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein orlistat is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize orphenadrine citrate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of orphenadrine citrate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises orphenadrine citrate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-orphenadrine citrate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and orphenadrine citrate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein orphenadrine citrate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein orphenadrine citrate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing orphenadrine citrate from said composition in a pH-dependent manner.

19. A method for protecting orphenadrine citrate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of orphenadrine citrate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching orphenadrine citrate to said polypeptide.

21. A method for delivering orphenadrine citrate to a patient comprising administering to said patient a composition comprising: a polypeptide; and orphenadrine citrate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein orphenadrine citrate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein orphenadrine citrate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXVII The present invention provides several benefits for active agent delivery. First, the invention can stabilize oxaprozin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of oxaprozin. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Oxaprozin is the subject of GB 1206403 1970, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises oxaprozin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, oxaprozin is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-oxaprozin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and oxaprozin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein oxaprozin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

. 13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein oxaprozin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing oxaprozin from said composition in a pH-dependent manner.

19. A method for protecting oxaprozin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of oxaprozin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching oxaprozin to said polypeptide.

21. A method for delivering oxaprozin to a patient comprising administering to said patient a composition comprising: a polypeptide; and oxaprozin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein oxaprozin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein oxaprozin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXVIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize oxazepam and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of oxazepam. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises oxazepam covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, oxazepam is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-oxazepam conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and oxazepam covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein oxazepam is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein oxazepam is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing oxazepam from said composition in a pH-dependent manner.

19. A method for protecting oxazepam from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of oxazepam from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching oxazepam to said polypeptide.

21. A method for delivering oxazepam to a patient comprising administering to said patient a composition comprising: a polypeptide; and oxazepam covalently attached to said polypeptide.

22. The method of paragraph 21 wherein oxazepam is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein oxazepam is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXIX The present invention provides several benefits for active agent delivery. First, the invention can stabilize Oxybutynin chloride and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of Oxybutynin chloride. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be

enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Oxybutynin chloride is the subject of U. S. Patent Numbers 4519801, 4612008, 4783337,5082668, 5674895, 5840754, and 5912268, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises Oxybutynin chloride covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, Oxybutynin chloride is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-Oxybutynin chloride conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and Oxybutynin chloride covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein Oxybutynin chloride is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein Oxybutynin chloride is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing Oxybutynin chloride from said composition in a pH-dependent manner.

19. A method for protecting Oxybutynin chloride from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of Oxybutynin chloride from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching Oxybutynin chloride to said polypeptide.

21. A method for delivering Oxybutynin chloride to a patient comprising administering to said patient a composition comprising: a polypeptide; and Oxybutynin chloride covalently attached to said polypeptide.

22. The method of paragraph 21 wherein Oxybutynin chloride is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein Oxybutynin chloride is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize oxycodone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of oxycodone.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises oxycodone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, oxycodone is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-oxycodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide ;. and oxycodone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein oxycodone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein oxycodone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing oxycodone from said composition in a pH-dependent manner.

19. A method for protecting oxycodone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of oxycodone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching oxycodone to said polypeptide.

21. A method for delivering oxycodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and oxycodone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein oxycodone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein oxycodone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXI The present invention provides several benefits for active agent delivery. First, the invention can stabilize a gastroprokinetic compound and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a gastroprokinetic compound. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

A gastroprokinetic compound is the subject of EP 643068 A 1995, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises a gastroprokinetic compound covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, a gastroprokinetic compound is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-a gastroprokinetic compound conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and a gastroprokinetic compound covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein a gastroprokinetic compound is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein a gastroprokinetic compound is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing a gastroprokinetic compound from said composition in a pH-dependent manner.

19. A method for protecting a gastroprokinetic compound from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a gastroprokinetic compound from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a gastroprokinetic compound to said polypeptide.

21. A method for delivering a gastroprokinetic compound to a patient comprising administering to said patient a composition comprising: a polypeptide; and a gastroprokinetic compound covalently attached to said polypeptide.

22. The method of paragraph 21 wherein a gastroprokinetic compound is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein a gastroprokinetic compound is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXII The present invention provides several benefits for active agent delivery. First, the invention can stabilize a macrophage colony stimulating factor and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a macrophage colony stimulating factor. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises a macrophage colony stimulating factor covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, a macrophage colony stimulating factor is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-a macrophage colony stimulating factor conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and a macrophage colony stimulating factor covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein a macrophage colony stimulating factor is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein a macrophage colony stimulating factor is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing a macrophage colony stimulating factor from said composition in a pH- dependent manner.

19. A method for protecting a macrophage colony stimulating factor from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a macrophage colony stimulating factor from a composition wherein said composition comprises a polypeptide, said method

comprising covalently attaching a macrophage colony stimulating factor to said polypeptide.

21. A method for delivering a macrophage colony stimulating factor to a patient comprising administering to said patient a composition comprising: a polypeptide; and a macrophage colony stimulating factor covalently attached to said polypeptide.

22. The method of paragraph 21 wherein a macrophage colony stimulating factor is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein a macrophage colony stimulating factor is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize pagoclone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pagoclone. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pagoclone is the subject of EP 274930 B 1991, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pagoclone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more

functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-pagoclone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and pagoclone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pagoclone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pagoclone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pagoclone from said composition in a pH-dependent manner.

19. A method for protecting pagoclone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pagoclone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pagoclone to said polypeptide.

21. A method for delivering pagoclone to a patient comprising administering to said patient a composition comprising: a polypeptide; and pagoclone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pagoclone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pagoclone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize palivizumab and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of

palivizumab. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises palivizumab covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, palivizumab is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-palivizumab conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and palivizumab covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein palivizumab is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein palivizumab is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing palivizumab from said composition in a pH-dependent manner.

19. A method for protecting palivizumab from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of palivizumab from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching palivizumab to said polypeptide.

21. A method for delivering palivizumab to a patient comprising administering to said patient a composition comprising: a polypeptide; and palivizumab covalently attached to said polypeptide.

22. The method of paragraph 21 wherein palivizumab is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein palivizumab is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXV The present invention provides several benefits for active agent delivery. First, the invention can stabilize pamidronate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pamidronate. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pamidronate is the subject of U. S. Patent Number 4711880, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pamidronate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, pamidronate is covalently attached to the polypeptide via the amino or hydroxyl group.

Preferably, the resultant peptide-pamidronate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pamidronate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pamidronate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pamidronate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pamidronate from said composition in a pH-dependent manner.

19. A method for protecting pamidronate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pamidronate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pamidronate to said polypeptide.

21. A method for delivering pamidronate to a patient comprising administering to said patient a composition comprising: a polypeptide; and pamidronate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pamidronate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pamidronate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize paricalcitrol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of paricalcitrol. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Paricalcitrol is the subject of U. S. Patent Number 5246925 and 5587497, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises paricalcitrol covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, paricalcitrol is covalently attached to the polypeptide via the hydroxyl groups.

Preferably, the resultant peptide-paricalcitrol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and paricalcitrol covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein paricalcitrol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein paricalcitrol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing paricalcitrol from said composition in a pH-dependent manner.

19. A method for protecting paricalcitrol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of paricalcitrol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching paricalcitrol to said polypeptide.

21. A method for delivering paricalcitrol to a patient comprising administering to said patient a composition comprising: a polypeptide; and paricalcitrol covalently attached to said polypeptide.

22. The method of paragraph 21 wherein paricalcitrol is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein paricalcitrol is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXVII The present invention provides several benefits for active agent delivery. First, the invention can stabilize paroxetine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of

paroxetine. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Paroxetine is the subject of U. S. Patent Numbers 4721723,4839177, 5422123, 5789449, 5872132, 5900423,6063927 and 6080759, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises paroxetine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, paroxetine is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-paroxetine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and paroxetine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein paroxetine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

- The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein paroxetine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing paroxetine from said composition in a pH-dependent manner.

19. A method for protecting paroxetine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of paroxetine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching paroxetine to said polypeptide.

21. A method for delivering paroxetine to a patient comprising administering to said patient a composition comprising: a polypeptide; and paroxetine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein paroxetine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein paroxetine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXVIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize pemetrexed and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pemetrexed. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pemetrexed is the subject of EP 432677 B (1996), priority US 448742 (1989), herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pemetrexed covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, pemetrexed is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-pemetrexed conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pemetrexed covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pemetrexed is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pemetrexed is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pemetrexed from said composition in a pH-dependent manner.

19. A method for protecting pemetrexed from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pemetrexed from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pemetrexed to said polypeptide.

21. A method for delivering pemetrexed to a patient comprising administering to said patient a composition comprising: a polypeptide; and pemetrexed covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pemetrexed is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pemetrexed is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXIX The present invention provides several benefits for active agent delivery. First, the invention can stabilize pemoline and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pemoline. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises pemoline covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a

heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, pemoline is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-pemoline conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pemoline covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pemoline is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pemoline is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pemoline from said composition in a pH-dependent manner.

19. A method for protecting pemoline from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pemoline from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pemoline to said polypeptide.

21. A method for delivering pemoline to a patient comprising administering to said patient a composition comprising: a polypeptide; and pemoline covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pemoline is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pemoline is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XC The present invention provides several benefits for active agent delivery.

First, the invention can stabilize penicillin V and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of penicillin V.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises penicillin V covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, penicillin V is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-penicillin V conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and penicillin V covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein penicillin V is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEQ), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet : 15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein penicillin V is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing penicillin V from said composition in a pH-dependent manner.

19. A method for protecting penicillin V from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of penicillin V from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching penicillin V to said polypeptide.

21. A method for delivering penicillin V to a patient comprising administering to said patient a composition comprising: a polypeptide; and penicillin V covalently attached to said polypeptide.

22. The method of paragraph 21 wherein penicillin V is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein penicillin V is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize pentosan polysulfate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pentosan polysulfate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pentosan polysulfate is the subject of U. S. Patent Number 5180715, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pentosan polysulfate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, pentosan polysulfate is covalently attached to the polypeptide via the sulfate or hydroxyl group.

Preferably, the resultant peptide-pentosan polysulfate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pentosan polysulfate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pentosan polysulfate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pentosan polysulfate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pentosan polysulfate from said composition in a pH-dependent manner.

19. A method for protecting pentosan polysulfate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pentosan polysulfate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pentosan polysulfate to said polypeptide.

21. A method for delivering pentosan polysulfate to a patient comprising administering to said patient a composition comprising: a polypeptide; and pentosan polysulfate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pentosan polysulfate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pentosan polysulfate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize pentoxifylline and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of pentoxifylline. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises pentoxifylline covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a

heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-pentoxifylline conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pentoxifylline covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pentoxifylline is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pentoxifylline is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pentoxifylline from said composition in a pH-dependent manner.

19. A method for protecting pentoxifylline from degradation comprising covalently attaching said active agent to a polypeptide.

-20. A method for controlling release of pentoxifylline from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pentoxifylline to said polypeptide.

21. A method for delivering pentoxifylline to a patient comprising administering to said patient a composition comprising: a polypeptide; and pentoxifylline covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pentoxifylline is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pentoxifylline is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize pergolide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pergolide.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pergolide is the subject of U. S. Patent Number 4166182, 4797405 and 5114948, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pergolide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-pergolide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pergolide covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is. a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pergolide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pergolide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pergolide from said composition in a pH-dependent manner.

19. A method for protecting pergolide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pergolide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pergolide to said polypeptide.

21. A method for delivering pergolide to a patient comprising administering to said patient a composition comprising : a polypeptide; and pergolide covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pergolide is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pergolide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize an orally active carbohydrate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of an orally active carbohydrate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises an orally active carbohydrate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a

heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, an orally active carbohydrate is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-an orally active carbohydrate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and an orally active carbohydrate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein an orally active carbohydrate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein an orally active carbohydrate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing an orally active carbohydrate from said composition in a pH-dependent manner.

19. A method for protecting an orally active carbohydrate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of an orally active carbohydrate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching an orally active carbohydrate to said polypeptide.

21. A method for delivering an orally active carbohydrate to a patient comprising administering to said patient a composition comprising: a polypeptide; and an orally active carbohydrate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein an orally active carbohydrate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein an orally active carbohydrate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize phenobarbital and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of phenobarbital. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises phenobarbital covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, phenobarbital is covalently attached to the polypeptide via the amine groups.

Preferably, the resultant peptide-phenobarbital conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and phenobarbital covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein phenobarbital is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet..

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein phenobarbital is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing phenobarbital from said composition in a pH-dependent manner.

19. A method for protecting phenobarbital from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of phenobarbital from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching phenobarbital to said polypeptide.

21. A method for delivering phenobarbital to a patient comprising administering to said patient a composition comprising: a polypeptide; and phenobarbital covalently attached to said polypeptide.

22. The method of paragraph 21 wherein phenobarbital is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein phenobarbital is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize phenytoin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of phenytoin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises phenytoin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, phenytoin is covalently attached to the polypeptide via the amine groups.

Preferably, the resultant peptide-phenytoin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and phenytoin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein phenytoin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein phenytoin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing phenytoin from said composition in a pH-dependent manner.

19. A method for protecting phenytoin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of phenytoin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching phenytoin to said polypeptide.

21. A method for delivering phenytoin to a patient comprising administering to said patient a composition comprising: a polypeptide; and phenytoin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein phenytoin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein phenytoin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize pioglitazone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pioglitazone.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pioglitazone is the subject of U. S. Patent Number 4687777, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pioglitazone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one

of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, pioglitazone is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-pioglitazone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pioglitazone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pioglitazone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pioglitazone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pioglitazone from said composition in a pH-dependent manner.

19. A method for protecting pioglitazone from degradation comprising covalently attaching said active agent to a polypeptide.

. 20. A method for controlling release of pioglitazone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pioglitazone to said polypeptide.

21. A method for delivering pioglitazone to a patient comprising administering to said patient a composition comprising: a polypeptide; and pioglitazone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pioglitazone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pioglitazone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCVIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize piperacillin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of piperacillin. Furthermore, active agents can be combined to produce synergistic effects.

Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises piperacillin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, piperacillin is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-piperacillin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and piperacillin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein piperacillin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein piperacillin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing piperacillin from said composition in a pH-dependent manner.

19. A method for protecting piperacillin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of piperacillin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching piperacillin to said polypeptide.

21. A method for delivering piperacillin to a patient comprising administering to said patient a composition comprising: a polypeptide; and piperacillin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein piperacillin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein piperacillin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize pleconaril and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pleconaril.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pleconaril is the subject of EP 566199 A 1993, priority US 869287 1992, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pleconaril covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more

functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-pleconaril conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pleconaril covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pleconaril is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pleconaril is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pleconaril from said composition in a pH-dependent manner.

19. A method for protecting pleconaril from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pleconaril from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pleconaril to said polypeptide.

21. A method for delivering pleconaril to a patient comprising administering to said patient a composition comprising: a polypeptide; and pleconaril covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pleconaril is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pleconaril is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

C The present invention provides several benefits for active agent delivery.

First, the invention can stabilize poloxamer 188 and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of poloxamer 188. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Poloxamer 188 is the subject of U. S. Patent Number 5523492, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises poloxamer 188 covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, poloxamer 188 is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-poloxamer 188 conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and poloxamer 188 covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein poloxamer 188 is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet : 15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein poloxamer 188 is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing poloxamer 188 from said composition in a pH-dependent manner.

19. A method for protecting poloxamer 188 from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of poloxamer 188 from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching poloxamer 188 to said polypeptide.

21. A method for delivering poloxamer 188 to a patient comprising administering to said patient a composition comprising: a polypeptide ; and poloxamer 188 covalently attached to said polypeptide.

22. The method of paragraph 21 wherein poloxamer 188 is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein poloxamer 188 is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize posaconazole and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of posaconazole. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Posaconazole is the subject of WO 95/17407 1995, priority US 171083 1993, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises posaconazole covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, posaconazole is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-posaconazole conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and

posaconazole covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is'a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein posaconazole is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein posaconazole is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing posaconazole from said composition in a pH-dependent manner.

19. A method for protecting posaconazole from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of posaconazole from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching posaconazole to said polypeptide.

21. A method for delivering posaconazole to a patient comprising administering to said patient a composition comprising: a polypeptide; and posaconazole covalently attached to said polypeptide.

22. The method of paragraph 21 wherein posaconazole is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein posaconazole is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize an insulin analogue and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of an insulin analogue. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises an insulin analogue covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a

homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, an insulin analogue is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-an insulin analogue conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and an insulin analogue covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein an insulin analogue is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein an insulin analogue is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing an insulin analogue from said composition in a pH-dependent manner.

19. A method for protecting an insulin analogue from degradation comprising covalently attaching said active agent to a polypeptide.

. 20. A method for controlling release of an insulin analogue from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching an insulin analogue to said polypeptide.

21. A method for delivering an insulin analogue to a patient comprising administering to said patient a composition comprising: a polypeptide; and an insulin analogue covalently attached to said polypeptide.

22. The method of paragraph 21 wherein an insulin analogue is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein an insulin analogue is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize pramipexole and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pramipexole.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pramipexole is the subject of U. S. Patent Number 4843086 and 4886812, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pramipexole covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, pramipexole is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-pramipexole conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide ; and pramipexole covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pramipexole is covalently attached to, a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pramipexole is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pramipexole from said composition in a pH-dependent manner.

19. A method for protecting pramipexole from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pramipexole from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pramipexole to said polypeptide.

21. A method for delivering pramipexole to a patient comprising administering to said patient a composition comprising: a polypeptide; and pramipexole covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pramipexole is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pramipexole is released from said composition by apH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize pravastatin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pravastatin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pravastatin is the subject of U. S. Patent Number 4346227,5030447, and 5180589, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pravastatin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, pravastatin is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-pravastatin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pravastatin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph I wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pravastatin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises prednisone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, prednisone is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-prednisone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide ; and prednisone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein prednisone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein prednisone is conformationally protected by folding of said polypeptide about said active agent.

. 18. The composition of paragraph 1 wherein said polypeptide is capable of releasing prednisone from said composition in a pH-dependent manner.

19. A method for protecting prednisone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of prednisone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching prednisone to said polypeptide.

21. A method for delivering prednisone to a patient comprising administering to said patient a composition comprising: a polypeptide; and prednisone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein prednisone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein prednisone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize pregabalin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pregabalin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Pregabalin is the subject of WO 93/23383 1993, priority US 886080 1992, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises pregabalin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, pregabalin is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-pregabalin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pregabalin covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein pregabalin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein pregabalin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing pregabalin from said composition in a pH-dependent manner.

19. A method for protecting pregabalin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pregabalin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pregabalin to said polypeptide.

21. A method for delivering pregabalin to a patient comprising administering to said patient a composition comprising: a polypeptide ; and pregabalin covalently attached to said polypeptide.

22. The method of paragraph 21 wherein pregabalin is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein pregabalin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize primidone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of primidone.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises primidone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, primidone is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-primidone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and primidone covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein primidone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein primidone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing primidone from said composition in a pH-dependent manner.

19. A method for protecting primidone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of primidone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching primidone to said polypeptide.

21. A method for delivering primidone to a patient comprising administering to said patient a composition comprising: a polypeptide; and primidone covalently attached to said polypeptide.

22. The method of paragraph 21 wherein primidone is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein primidone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CVIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize prinomastat and prevent its digestion in the stomach. In

addition, the pharmacologic effect can be prolonged by delayed release of prinomastat.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Prinomastat is the subject of U. S. Patent Number 5753653, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises prinomastat covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, prinomastat is covalently attached to the polypeptide via the hydroxyl.

Preferably, the resultant peptide-prinomastat conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and prinomastat covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein prinomastat is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein prinomastat is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing prinomastat from said composition in a pH-dependent manner.

19. A method for protecting prinomastat from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of prinomastat from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching prinomastat to said polypeptide.

21. A method for delivering prinomastat to a patient comprising administering to said patient a composition comprising: a polypeptide; and prinomastat covalently attached to said polypeptide.

22. The method of paragraph 21 wherein prinomastat is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein prinomastat is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize prochlorperazine maleate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of prochlorperazine maleate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises prochlorperazine maleate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-prochlorperazine maleate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and

prochlorperazine maleate covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is-a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein prochlorperazine maleate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein prochlorperazine maleate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing prochlorperazine maleate from said composition in a pH-dependent manner.

19. A method for protecting prochlorperazine maleate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of prochlorperazine maleate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching prochlorperazine maleate to said polypeptide.

21. A method for delivering prochlorperazine maleate to a patient comprising administering to said patient a composition comprising: a polypeptide; and prochlorperazine maleate covalently attached to said polypeptide.

22. The method of paragraph 21 wherein prochlorperazine maleate is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein prochlorperazine maleate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize promethazine and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of promethazine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises promethazine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of

one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Proteins, oligopeptides and polypeptides are polymers of amino acids that have primary, secondary and tertiary structures. The secondary structure of the protein is the local conformation of the polypeptide chain and consists of helices, pleated sheets and turns. The protein's amino acid sequence and the structural constraints on the conformations of the chain determine the spatial arrangement of the molecule. The folding of the secondary structure and the spatial arrangement of the side chains constitute the tertiary structure.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-promethazine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and promethazine covalently attached to said polypeptide.

2. The composition of paragraph 1 wherein said polypeptide is an oligopeptide.

3. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of paragraph 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of paragraph 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of paragraph 1 wherein promethazine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of paragraph 1 further comprising a microencapsulating agent.

10. The composition of paragraph 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of paragraph 1 further comprising an adjuvant.

12. The composition of paragraph 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of paragraph 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of paragraph 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of paragraph 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of paragraph 1 wherein said composition is in the form of an oral suspension.

17. The composition of paragraph 1 wherein promethazine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of paragraph 1 wherein said polypeptide is capable of releasing promethazine from said composition in a pH-dependent manner.

19. A method for protecting promethazine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of promethazine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching promethazine to said polypeptide.

21. A method for delivering promethazine to a patient comprising administering to said patient a composition comprising: a polypeptide; and promethazine covalently attached to said polypeptide.

22. The method of paragraph 21 wherein promethazine is released from said composition by an enzyme-catalyzed release.

23. The method of paragraph 21 wherein promethazine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of paragraph 21 wherein said active agent is released from said composition in a sustained release.

25. The method of paragraph 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

UNITED STATES PATENT AND TRADEMARK OFFICE DOCUMENT CLASSIFICATION BARCODE SHEET <BR> <BR> New International<BR> Application<BR> Other Scanable Documents D ss t i q f 1 5 ; F i 13 sE , 3 fR i . 3 f Version 1. 0 Index 1. 1. 13 Rev 12/06/01 I The present invention provides several benefits for active agent delivery. First, the invention can stabilize a cholecystokinin antagonist and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of a cholecystokinin antagonist. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The cholecystokinin antagonist is the subject of WO 93/897 1993, priority US 729271 1991, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises a cholecystokinin antagonist covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the components of the cholecystokinin antagonist are covalently attached to the polypeptide via the carboxylic acid and hydroxyl groups, respectively.

Preferably, the resultant peptide-a cholecystokinin antagonist conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and a cholecystokinin antagonist covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein a cholecystokinin antagonist is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein a cholecystokinin antagonist is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing a cholecystokinin antagonist from said composition in a pH-dependent manner.

19. A method for protecting a cholecystokinin antagonist from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a cholecystokinin antagonist from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a cholecystokinin antagonist to said polypeptide.

21. A method for delivering a cholecystokinin antagonist to a patient comprising administering to said patient a composition comprising: a polypeptide; and a cholecystokinin antagonist covalently attached to said polypeptide.

22. The method of claim 21 wherein a cholecystokinin antagonist is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein a cholecystokinin antagonist is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

II The present invention provides several benefits for active agent delivery. First, the invention can stabilize propoxyphene and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of propoxyphene. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises propoxyphene covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-propoxyphene conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and propoxyphene covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein propoxyphene is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein propoxyphene is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing propoxyphene from said composition in a pH-dependent manner.

19. A method for protecting propoxyphene from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of propoxyphene from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching propoxyphene to said polypeptide.

21. A method for delivering propoxyphene to a patient comprising administering to said patient a composition comprising: a polypeptide; and propoxyphene covalently attached to said polypeptide.

22. The method of claim 21 wherein propoxyphene is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein propoxyphene is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

HI The present invention provides several benefits for active agent delivery. First, the invention can stabilize propranolol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of propranolol. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises propranolol covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, propranolol is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-propranolol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.' 1. A pharmaceutical composition comprising: a polypeptide; and propranolol covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein propranolol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein propranolol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing propranolol from said composition in a pH-dependent manner.

19. A method for protecting propranolol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of propranolol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching propranolol to said polypeptide.

21. A method for delivering propranolol to a patient comprising administering to said patient a composition comprising: a polypeptide; and propranolol covalently attached to said polypeptide.

22. The method of claim 21 wherein propranolol is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein propranolol is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

IV The present invention provides several benefits for active agent delivery. First, the invention can stabilize prourokinase and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of prourokinase. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Prourokinase is the subject of U. S. Patent Number 5741682, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises prourokinase covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, prourokinase is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-prourokinase conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and prourokinase covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein prourokinase is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein prourokinase is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing prourokinase from said composition in a pH-dependent manner.

19. A method for protecting prourokinase from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of prourokinase from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching prourokinase to said polypeptide.

21. A method for delivering prourokinase to a patient comprising administering to said patient a composition comprising: a polypeptide; and prourokinase covalently attached to said polypeptide.

22. The method of claim 21 wherein prourokinase is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein prourokinase is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

The present invention provides several benefits for active agent delivery. First, the invention can stabilize quetiapine fumarate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of quetiapine fumarate.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Quetiapine fumarate is the subject of EP 240228 B 1990 and 4879288, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises quetiapine fumarate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, quetiapine fumarate is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-quetiapine fumarate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and quetiapine fumarate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein quetiapine fumarate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein quetiapine fumarate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing quetiapine fumarate from said composition in a pH-dependent manner.

19. A method for protecting quetiapine fumarate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of quetiapine fumarate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching quetiapine fumarate to said polypeptide.

21. A method for delivering quetiapine fumarate to a patient comprising administering to said patient a composition comprising: a polypeptide; and quetiapine fumarate covalently attached to said polypeptide.

22. The method of claim 21 wherein quetiapine fumarate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein quetiapine fumarate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

VI The present invention provides several benefits for active agent delivery. First, the invention can stabilize quinapril and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of quinapril. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Quinapril is the subject of U. S. Patent Number 4344949,4743450, 5684016 and 5747504, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises quinapril covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, quinapril is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-quinapril conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and quinapril covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein quinapril is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein quinapril is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing quinapril from said composition in a pH-dependent manner.

19. A method for protecting quinapril from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of quinapril from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching quinapril to said polypeptide.

21. A method for delivering quinapril to a patient comprising administering to said patient a composition comprising : a polypeptide; and quinapril covalently attached to said polypeptide.

22. The method of claim 21 wherein quinapril is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein quinapril is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

VII The present invention provides several benefits for active agent delivery. First, the invention can stabilize rabeprazole and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of rabeprazole. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Rabeprazole is the subject of EP 268956 B 1994, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises rabeprazole covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, rabeprazole is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-rabeprazole conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and rabeprazole covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein rabeprazole is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein rabeprazole is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing rabeprazole from said composition in a pH-dependent manner.

19. A method for protecting rabeprazole from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of rabeprazole from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching rabeprazole to said polypeptide.

21. A method for delivering rabeprazole to a patient comprising administering to said patient a composition comprising: a polypeptide; and rabeprazole covalently attached to said polypeptide.

22. The method of claim 21 wherein rabeprazole is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein rabeprazole is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said, composition is controlled by said polypeptide.

VIM The present invention provides several benefits for active agent delivery. First, the invention can stabilize raloxifene and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of raloxifene. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Raloxifene is the subject of U. S. Patent Numbers 4418068,5393763, 5457117,5466810, 5478847,5514826, 5569772,5629425, 5641790,5659087, 5710285,5731327, 5731342, 5747510, 5808061, 5811120, 5843984, and 5972383, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises raloxifene covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, raloxifene is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-raloxifene conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and raloxifene covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein raloxifene is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein raloxifene is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing raloxifene from said composition in a pH-dependent manner.

19. A method for protecting raloxifene from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of raloxifene from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching raloxifene to said polypeptide.

21. A method for delivering raloxifene to a patient comprising administering to said patient a composition comprising: a polypeptide; and raloxifene covalently attached to said polypeptide.

22. The method of claim 21 wherein raloxifene is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein raloxifene is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

IX The present invention provides several benefits for active agent delivery. First, the invention can stabilize ramipril and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ramipril. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Ramipril is the subject of U. S. Patent Number 4587258 and 5061722, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises ramipril covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, ramipril is covalently attached to the polypeptide via the carboxylic acid groups.

Preferably, the resultant peptide-ramipril conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ramipril covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein ramipril is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein ramipril is conformationally protected by folding of said polypeptide about said active agent.

18.. The composition of claim 1 wherein said polypeptide is capable of releasing ramipril from said composition in a pH-dependent manner.

19. A method for protecting ramipril from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ramipril from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ramipril to said polypeptide.

21. A method for delivering ramipril to a patient comprising administering to said patient a composition comprising: a polypeptide; and ramipril covalently attached to said polypeptide.

22. The method of claim 21 wherein ramipril is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein ramipril is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

X The present invention provides several benefits for active agent delivery. First, the invention can stabilize ranitidine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ranitidine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Ranitidine is. the subject of U. S. Patent Number GB 2220937 B 1991, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises ranitidine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, ranitidine is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-ranitidine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ranitidine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein ranitidine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant-activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein ranitidine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing ranitidine from said composition in a pH-dependent manner.

19. A method for protecting ranitidine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ranitidine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ranitidine to said polypeptide.

21. A method for delivering ranitidine to a patient comprising administering to said patient a composition comprising: a polypeptide; and ranitidine covalently attached to said polypeptide.

22. The method of claim 21 wherein ranitidine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein ranitidine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XI The present invention provides several benefits for active agent delivery. First, the invention can stabilize ranolazine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ranolazine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Ranolazine is the subject of EP 126449 B 1987, priority US 495904 1983, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises ranolazine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, ranolazine is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-ranolazine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ranolazine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein ranolazine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein ranolazine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing ranolazine from said composition in a pH-dependent manner.

19. A method for protecting ranolazine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ranolazine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ranolazine to said polypeptide.

21. A method for delivering ranolazine to a patient comprising administering to said patient a composition comprising: a polypeptide; and ranolazine covalently attached to said polypeptide.

22. The method of claim 21 wherein ranolazine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein ranolazine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XII The present invention provides several benefits for active agent delivery. First, the invention can stabilize relaxin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of relaxin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Relaxin is the subject of EP 112149 B 1991, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises relaxin covalently attached to a polypeptide.

Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, relaxin is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-relaxin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and relaxin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein relaxin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein relaxin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing relaxin from said composition in a pH-dependent manner.

19. A method for protecting relaxin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of relaxin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching relaxin to said polypeptide.

21. A method for delivering relaxin to a patient comprising administering to said patient a composition comprising: a polypeptide; and relaxin covalently attached to said polypeptide.

22. The method of claim 21 wherein relaxin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein relaxin is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize remacemide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of remacemide. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Remacemide is the subject of EP 279937 B 1991, priority US 11982 1987, and WO 93/21910 1993, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises remacemide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, remacemide is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-remacemide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and remacemide covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein remacemide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein remacemide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing remacemide from said composition in a pH-dependent manner.

19. A method for protecting remacemide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of remacemide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching remacemide to said polypeptide.

21. A method for delivering remacemide to a patient comprising administering to said patient a composition comprising: a polypeptide; and remacemide covalently attached to said polypeptide.

22. The method of claim 21 wherein remacemide is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein remacemide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize repaglinide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of repaglinide. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Repaglinide is the subject of EP 589874 B 1999, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises repaglinide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, repaglinide is covalently attached to the polypeptide via the carboxylic acid.

Preferably, the resultant peptide-repaglinide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and repaglinide covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein repaglinide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein repaglinide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing repaglinide from said composition in a pH-dependent manner.

19. A method for protecting repaglinide from degradation comprising covalently attaching said active agent to a polypeptide.

20.. A method for controlling release of repaglinide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching repaglinide to said polypeptide.

21. A method for delivering repaglinide to a patient comprising administering to said patient a composition comprising: a polypeptide; and repaglinide covalently attached to said polypeptide.

22. The method of claim 21 wherein repaglinide is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein repaglinide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XV The present invention provides several benefits for active agent delivery. First, the invention can stabilize repinotan and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of repinotan. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Repinotan is the subject of U. S. Patent Number 5137901, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises repinotan covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, repinotan is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-repinotan conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide ; and repinotan covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein repinotan is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein repinotan is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing repinotan from said composition in a pH-dependent manner.

19. A method for protecting repinotan from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of repinotan from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching repinotan to said polypeptide.

21. A method for delivering repinotan to a patient comprising administering to said patient a composition comprising : a polypeptide; and repinotan covalently attached to said polypeptide.

22. The method of claim 21 wherein repinotan is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein repinotan is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize ribavirin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ribavirin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises ribavirin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, ribavirin is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-ribavirin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and ribavirin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein ribavirin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein ribavirin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing ribavirin from said composition in a pH-dependent manner.

19. A method for protecting ribavirin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ribavirin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ribavirin to said polypeptide.

21. A method for delivering ribavirin to a patient comprising administering to said patient a composition comprising : a polypeptide; and ribavirin covalently attached to said polypeptide.

22. The method of claim 21 wherein ribavirin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein ribavirin is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XVII The present invention provides several benefits for active agent delivery. First, the invention can stabilize riluzole and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of riluzole. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Riluzole is the subject of EP 50551 B 1984, EP 282971 A 1988 (priority US 26428 1987), and EP 305277 A 1989, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises riluzole covalently attached to a polypeptide.

Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, riluzole is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-riluzole conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and riluzole covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein riluzole is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein riluzole is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing riluzole from said composition in a pH-dependent manner.

19. A method for protecting riluzole from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of riluzole from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching riluzole to said polypeptide.

21. A method for delivering riluzole to a patient comprising administering to said patient a composition comprising: a polypeptide; and riluzole covalently attached to said polypeptide.

22. The method of claim 21 wherein riluzole is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein riluzole is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XVIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize rimantadine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of rimantadine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Rimantadine is the subject of GB 1069563 1967, priority US 297233 1963, EP 162444 B 1990, priority US 613374 1984, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises rimantadine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, rimantadine is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-rimantadine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed. 1. A pharmaceutical composition comprising : a polypeptide; and rimantadine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein rimantadine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein rimantadine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing rimantadine from said composition in a pH-dependent manner.

19. A method for protecting rimantadine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of rimantadine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching rimantadine to said polypeptide.

21. A method for delivering rimantadine to a patient comprising administering to said patient a composition comprising: a polypeptide; and rimantadine covalently attached to said polypeptide.

22. The method of claim 21 wherein rimantadine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein rimantadine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XIX The present invention provides several benefits for active agent delivery. First, the invention can stabilize risperidone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of risperidone. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Risperidone is the subject of U. S. Patent Number 4804663 and 5158952, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises risperidone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-risperidone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and risperidone covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein risperidone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein risperidone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing risperidone from said composition in a pH-dependent manner.

19. A method for protecting risperidone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of risperidone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching risperidone to said polypeptide.

21. A method for delivering risperidone to a patient comprising administering to said patient a composition comprising: a polypeptide; and risperidone covalently attached to said polypeptide.

22. The method of claim 21 wherein risperidone is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein risperidone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XX The present invention provides several benefits for active agent delivery. First, the invention can stabilize ritonavir and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ritonavir. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Ritonavir is the subject of U. S. Patent Number 5484801, 5541206,5635523, 5648497, 5674882, 5846987, 5886036, and 6037157, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises ritonavir covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, ritonavir is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-ritonavir conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ritonavir covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition'of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein ritonavir is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein ritonavir is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing ritonavir from said composition in a pH-dependent manner.

19. A method for protecting ritonavir from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ritonavir from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ritonavir to said polypeptide.

21. A method for delivering ritonavir to a patient comprising administering to said patient a composition comprising : a polypeptide; and ritonavir covalently attached to said polypeptide.

22. The method of claim 21 wherein ritonavir is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein ritonavir is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXI The present invention provides several benefits for active agent delivery. First, the invention can stabilize rizatriptan benzoate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of rizatriptan benzoate.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Rizatriptan benzoate is the subject of U. S. Patent Number 4371516, 5298520, 5457895, and 5602162, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises rizatriptan benzoate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, rizatriptan benzoate is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-rizatriptan benzoate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and rizatriptan benzoate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein rizatriptan benzoate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein rizatriptan benzoate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing rizatriptan benzoate from said composition in a pH-dependent manner.

19. A method for protecting rizatriptan benzoate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of rizatriptan benzoate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching rizatriptan benzoate to said polypeptide.

21. A method for delivering rizatriptan benzoate to a patient comprising administering to said patient a composition comprising: a polypeptide; and rizatriptan benzoate covalently attached to said polypeptide.

22. The method of claim 21 wherein rizatriptan benzoate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein rizatriptan benzoate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXII The present invention provides several benefits for active agent delivery. First, the invention can stabilize rocuronium and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of rocuronium. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Rocuronium is the subject of U. S. Patent Number 4894369, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises rocuronium covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, rocuronium is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-rocuronium conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and rocuronium covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein rocuronium is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein rocuronium is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing rocuronium from said composition in a pH-dependent manner.

19. A method for protecting rocuronium from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of rocuronium from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching rocuronium to said polypeptide.

21. A method for delivering rocuronium to a patient comprising administering to said patient a composition comprising: a polypeptide; and rocuronium covalently attached to said polypeptide.

22. The method of claim 21 wherein rocuronium is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein rocuronium is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXBI The present invention provides several benefits for active agent delivery. First, the invention can stabilize rofecoxib and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of rofecoxib. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Rofecoxib is the subject of U. S. Patent Number 5474995, 5691374, and 6063811, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises rofecoxib covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-rofecoxib conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and rofecoxib covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein rofecoxib is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein rofecoxib is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing rofecoxib from said composition in a pH-dependent manner.

19. A method for protecting rofecoxib from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of rofecoxib from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching rofecoxib to said polypeptide.

21. A method for delivering rofecoxib to a patient comprising administering to said patient a composition comprising: a polypeptide; and rofecoxib covalently attached to said polypeptide.

22. The method of claim 21 wherein rofecoxib is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein rofecoxib is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize ropinirole and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ropinirole. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Ropinirole is the subject of U. S. Patent Number 4452808 and 4824860, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises ropinirole covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, ropinirole is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-ropinirole conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ropinirole covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein ropinirole is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein ropinirole is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing ropinirole from said composition in a pH-dependent manner.

19. A method for protecting ropinirole from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ropinirole from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ropinirole to said polypeptide.

21. A method for delivering ropinirole to a patient comprising administering to said patient a composition comprising: a polypeptide; and ropinirole covalently attached to said polypeptide.

22. The method of claim 21 wherein ropinirole is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein ropinirole is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXV The present invention provides several benefits for active agent delivery. First, the invention can stabilize rosiglitazone maleate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of rosiglitazone maleate.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Rosiglitazone maleate is the subject of U. S. Patent Number 5002953 and 5741803, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises rosiglitazone maleate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, rosiglitazone maleate is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-rosiglitazone maleate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and rosiglitazone maleate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein rosiglitazone maleate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein rosiglitazone maleate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing rosiglitazone maleate from said composition in a pH-dependent manner.

19. A method for protecting rosiglitazone maleate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of rosiglitazone maleate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching rosiglitazone maleate to said polypeptide.

21. A method for delivering rosiglitazone maleate to a patient comprising administering to said patient a composition comprising: a polypeptide; and rosiglitazone maleate covalently attached to said polypeptide.

22. The method of claim 21 wherein rosiglitazone maleate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein rosiglitazone maleate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize goserelin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of goserelin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Goserelin is the subject of GB 1524747 1978, herein incorporated by reference, which describes how to make that drug : The composition of the invention comprises goserelin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, goserelin is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-goserelin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and goserelin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein goserelin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein goserelin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing goserelin from said composition in a pH-dependent manner.

19. A method for protecting goserelin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of goserelin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching goserelin to said polypeptide.

21. A method for delivering goserelin to a patient comprising administering to said patient a composition comprising: a polypeptide; and goserelin covalently attached to said polypeptide.

22. The method of claim 21 wherein goserelin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein goserelin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize rubitecan and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of rubitecan. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Rubitecan is the subject of JP 91/12069 1991, US 5922877 1999 and WO 99/30684 1999 (priority US 989281 1997), herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises rubitecan covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, rubitecan is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-rubitecan conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and rubitecan covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein rubitecan is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein rubitecan is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing rubitecan from said composition in a pH-dependent manner.

19. A method for protecting rubitecan from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of rubitecan from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching rubitecan to said polypeptide.

21. A method for delivering rubitecan to a patient comprising administering to said patient a composition comprising: a polypeptide; and rubitecan covalently attached to said polypeptide.

22. The method of claim 21 wherein rubitecan is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein rubitecan is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXVin The present invention provides several benefits for active agent delivery.

First, the invention can stabilize sagramostim and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sagramostim.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sagramostim is the subject of EP 183350 B 1992, priority US 666041 1984, and EP 212914 B 1992, priority US 763130 1985, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sagramostim covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sagramostim is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-sagramostim conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sagramostim covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally. occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sagramostim is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sagramostim is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sagramostim from said composition in a pH-dependent manner.

19. A method for protecting sagramostim from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sagramostim from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sagramostim to said polypeptide.

21. A method for delivering sagramostim to a patient comprising administering to said patient a composition comprising: a polypeptide; and sagramostim covalently attached to said polypeptide.

22. The method of claim 21 wherein sagramostim is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sagramostim is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXIX The present invention provides several benefits for active agent delivery. First, the invention can stabilize saquinavir and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of saquinavir. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Saquinavir is the subject of U. S. Patent Number 5196438, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises saquinavir covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, saquinavir is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-saquinavir conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and saquinavir covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein saquinavir is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein saquinavir is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing saquinavir from said composition in a pH-dependent manner.

19. A method for protecting saquinavir from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of saquinavir from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching saquinavir to said polypeptide.

21. A method for delivering saquinavir to a patient comprising administering to said patient a composition comprising: a polypeptide; and saquinavir covalently attached to said polypeptide.

22. The method of claim 21 wherein saquinavir is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein saquinavir is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXX The present invention provides several benefits for active agent delivery. First, the invention can stabilize docetaxel and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of docetaxel. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Docetaxel is the subject of EP 253738 B 1990 and EP 593656 B 1997, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises docetaxel covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, docetaxel is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-docetaxel conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and docetaxel covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein docetaxel is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein docetaxel is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing docetaxel from said composition in a pH-dependent manner.

19. A method for protecting docetaxel from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of docetaxel from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching docetaxel to said polypeptide.

21. A method for delivering docetaxel to a patient comprising administering to said patient a composition comprising: a polypeptide; and docetaxel covalently attached'to said polypeptide.

22. The method of claim 21 wherein docetaxel is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein docetaxel is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXI The present invention provides several benefits for active agent delivery. First, the invention can stabilize satraplatin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of satraplatin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Satraplatin is the subject of EP 328274 B 1994, priority US 151674 1988, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises satraplatin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, satraplatin is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-satraplatin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and satraplatin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein satraplatin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein satraplatin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing satraplatin from said composition in a pH-dependent manner.

19. A method for protecting satraplatin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of satraplatin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching satraplatin to said polypeptide.

21. A method for delivering satraplatin to a patient comprising administering to said patient a composition comprising: a polypeptide ; and satraplatin covalently attached to said polypeptide.

22. The method of claim 21 wherein satraplatin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein satraplatin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize selegiline and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of selegiline. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises selegiline covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-selegiline conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and selegiline covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein selegiline is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein selegiline is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing selegiline from said composition in a pH-dependent manner.

19. A method for protecting selegiline from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of selegiline from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching selegiline to said polypeptide.

21. A method for delivering selegiline to a patient comprising administering to said patient a composition comprising: a polypeptide; and selegiline covalently attached to said polypeptide.

22. The method of claim 21 wherein selegiline is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein selegiline is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize sertraline and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sertraline. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sertraline is the subject of U. S. Patent Number 4536518,4962128, and 5248699, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sertraline covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sertraline is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-sertraline conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sertraline covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sertraline is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sertraline is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sertraline from said composition in a pH-dependent manner.

19. A method for protecting sertraline from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sertraline from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sertraline to said polypeptide.

21. A method for delivering sertraline to a patient comprising administering to said patient a composition comprising: a polypeptide ; and sertraline covalently attached to said polypeptide.

22. The method of claim 21 wherein sertraline is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sertraline is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXTV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize sevelamer and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sevelamer. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sevelamer is the subject of U. S. Patent Number 5496545 and 5667775, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sevelamer covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sevelamer is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-sevelamer conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sevelamer covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sevelamer is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sevelamer is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sevelamer from said composition in a pH-dependent manner.

19. A method for protecting sevelamer from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sevelamer from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sevelamer to said polypeptide.

21. A method for delivering sevelamer to a patient comprising administering to said patient a composition comprising: a polypeptide; and sevelamer covalently attached to said polypeptide.

22. The method of claim 21 wherein sevelamer is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sevelamer is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize sevirumab and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sevirumab. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sevirumab is the subject of U. S. Patent Number 5750106, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sevirumab covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sevirumab is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-sevirumab conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sevirumab covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sevirumab is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sevirumab is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sevirumab from said composition in a pH-dependent manner.

19. A method for protecting sevirumab from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sevirumab from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sevirumab to said polypeptide.

21. A method for delivering sevirumab to a patient comprising administering to said patient a composition comprising: a polypeptide; and sevirumab covalently attached to said polypeptide.

22. The method of claim 21 wherein sevirumab is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sevirumab is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize sibutramine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sibutramine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sibutramine is the subject of U. S. Patent Number 4746680 and 4929629, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sibutramine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-sibutramine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sibutramine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sibutramine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sibutramine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sibutramine from said composition in a pH-dependent manner.

19. A method for protecting sibutramine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sibutramine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sibutramine to said polypeptide.

21. A method for delivering sibutramine to a patient comprising administering to said patient a composition comprising: a polypeptide; and sibutramine covalently attached to said polypeptide.

22. The method of claim 21 wherein sibutramine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sibutramine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize sildenafil citrate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sildenafil citrate.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sildenafil citrate is the subject of U. S. Patent Number 5250534, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sildenafil citrate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sildenafil citrate is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-sildenafil citrate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sildenafil citrate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sildenafil citrate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sildenafil citrate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sildenafil citrate from said composition in a pH-dependent manner.

19. A method for protecting sildenafil citrate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sildenafil citrate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sildenafil citrate to said polypeptide.

21. A method for delivering sildenafil citrate to a patient comprising administering to said patient a composition comprising: a polypeptide; and sildenafil citrate covalently attached to said polypeptide.

22. The method of claim 21 wherein sildenafil citrate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sildenafil citrate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXVIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize simvastatin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of simvastatin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Simvastatin is the subject of U. S. Patent Number 4444784, RE36481 and RE36520, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises simvastatin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, simvastatin is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-simvastatin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and simvastatin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein simvastatin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein simvastatin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing simvastatin from said composition in a pH-dependent manner.

19. A method for protecting simvastatin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of simvastatin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching simvastatin to said polypeptide.

21. A method for delivering simvastatin to a patient comprising administering to said patient a composition comprising: a polypeptide; and simvastatin covalently attached to said polypeptide.

22. The method of claim 21 wherein simvastatin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein simvastatin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XXXIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize sinapultide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sinapultide. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sinapultide is the subject of WO 92/22315 1992, priority US 715397 1991, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sinapultide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sinapultide is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-sinapultide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and sinapultide covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sinapultide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sinapultide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sinapultide from said composition in a pH-dependent manner.

19. A method for protecting sinapultide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sinapultide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sinapultide to said polypeptide.

21. A method for delivering sinapultide to a patient comprising administering to said patient a composition comprising: a polypeptide; and sinapultide covalently attached to said polypeptide.

22. The method of claim 21 wherein sinapultide is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sinapultide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XL The present invention provides several benefits for active agent delivery. First, the invention can stabilize sitafloxacin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sitafloxacin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sitafloxacin is the subject of EP 341493 A 1989, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sitafloxacin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sitafloxacin is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-sitafloxacin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sitafloxacin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer. of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sitafloxacin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sitafloxacin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sitafloxacin from said composition in a pH-dependent manner.

19. A method for protecting sitafloxacin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sitafloxacin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sitafloxacin to said polypeptide.

21. A method for delivering sitafloxacin to a patient comprising administering to said patient a composition comprising: a polypeptide; and sitafloxacin covalently attached to said polypeptide.

22. The method of claim 21 wherein sitafloxacin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sitafloxacin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained'release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLI The present invention provides several benefits for active agent delivery. First, the invention can stabilize polystyrene sulfonate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of polystyrene sulfonate.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises polystyrene sulfonate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Preferably, the resultant peptide-polystyrene sulfonate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and polystyrene sulfonate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein polystyrene sulfonate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein polystyrene sulfonate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing polystyrene sulfonate from said composition in a pH-dependent manner.

19. A method for protecting polystyrene sulfonate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of polystyrene sulfonate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching polystyrene sulfonate to said polypeptide.

21. A method for delivering polystyrene sulfonate to a patient comprising administering to said patient a composition comprising: a polypeptide; and polystyrene sulfonate covalently attached to said polypeptide.

22. The method of claim 21 wherein polystyrene sulfonate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein polystyrene sulfonate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLB The present invention provides several benefits for active agent delivery. First, the invention can stabilize sotalol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sotalol. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sotalol is the subject of GB 993584 1965, priority US 168498 1962, and EP 127435 B 1991, priority US 497368 1983, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sotalol covalently attached to a polypeptide.

Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sotalol is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-sotalol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide ; and sotalol covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sotalol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sotalol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sotalol from said composition in a pH-dependent manner.

19. A method for protecting sotalol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sotalol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sotalol to said polypeptide.

21. A method for delivering sotalol to a patient comprising administering to said patient a composition comprising: a polypeptide; and sotalol covalently attached to said polypeptide.

22. The method of claim 21 wherein sotalol is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sotalol is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize sparfosic acid and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sparfosic acid. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises sparfosic acid covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sparfosic acid is covalently attached to the polypeptide via the hydroxyl or carboxylic acid group.

Preferably, the resultant peptide-sparfosic acid conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sparfosic acid covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sparfosic acid is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sparfosic acid is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sparfosic acid from said composition in a pH-dependent manner.

19. A method for protecting sparfosic acid from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sparfosic acid from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sparfosic acid to said polypeptide.

21. A method for delivering sparfosic acid to a patient comprising administering to said patient a composition comprising: a polypeptide; and sparfosic acid covalently attached to said polypeptide.

22. The method of claim 21 wherein sparfosic acid is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sparfosic acid is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize spironolactone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of spironolactone. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises spironolactone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-spironolactone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and spironolactone covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein spironolactone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein spironolactone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing spironolactone from said composition in a pH-dependent manner.

19. A method for protecting spironolactone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of spironolactone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching spironolactone to said polypeptide.

21. A method for delivering spironolactone to a patient comprising administering to said patient a composition comprising: a polypeptide; and spironolactone covalently attached to said polypeptide.

22. The method of claim 21 wherein spironolactone is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein spironolactone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLV The present invention provides several benefits for active agent delivery. First, the invention can stabilize stavudine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of stavudine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Stavudine is the subject of U. S. Patent Number 4978655, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises stavudine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, stavudine is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-stavudine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and stavudine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein stavudine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein stavudine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing stavudine from said composition in a pH-dependent manner.

19. A method for protecting stavudine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of stavudine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching stavudine to said polypeptide.

21. A method for delivering stavudine to a patient comprising administering to said patient a composition comprising: a polypeptide; and stavudine covalently attached to said polypeptide.

22. The method of claim 21 wherein stavudine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein stavudine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize sucralfate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sucralfate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sucralfate is the subject of U. S. Patent Number 4816470 and 5037845, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sucralfate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sucralfate is covalently attached to the polypeptide via the zzzzzzz.

Preferably, the resultant peptide-sucralfate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sucralfate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide-is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sucralfate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sucralfate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sucralfate from said composition in a pH-dependent manner.

19. A method for protecting sucralfate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sucralfate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sucralfate to said polypeptide.

21. A method for delivering sucralfate to a patient comprising administering to said patient a composition comprising : a polypeptide; and sucralfate covalently attached to said polypeptide.

22. The method of claim 21 wherein sucralfate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sucralfate is released from said composition by'a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize sumatriptan and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of sumatriptan.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Sumatriptan is the subject of U. S. Patent Number 4816470 and 5037845, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises sumatriptan covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, sumatriptan is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-sumatriptan conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and sumatriptan covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein sumatriptan is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein sumatriptan is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing sumatriptan from said composition in a pH-dependent manner.

19. A method for protecting sumatriptan from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of sumatriptan from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching sumatriptan to said polypeptide.

21. A method for delivering sumatriptan to a patient comprising administering to said patient a composition comprising: a polypeptide; and sumatriptan covalently attached to said polypeptide.

22. The method of claim 21 wherein sumatriptan is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein sumatriptan is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLVIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize tabimorelin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tabimorelin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tabimorelin is the subject of WO 97/23508 1997, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tabimorelin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tabimorelin is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-tabimorelin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tabimorelin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tabimorelin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tabimorelin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tabimorelin from said composition in a pH-dependent manner.

19. A method for protecting tabimorelin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tabimorelin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tabimorelin to said polypeptide.

21. A method for delivering tabimorelin to a patient comprising administering to said patient a composition comprising: a polypeptide; and tabimorelin covalently attached to said polypeptide.

22. The method of claim 21 wherein tabimorelin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tabimorelin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XLIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize Tamoxifen and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of Tamoxifen. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tamoxifen is the subject of U. S. Patent Number 4536516, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises Tamoxifen covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-Tamoxifen conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and Tamoxifen covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein Tamoxifen is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein Tamoxifen is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing Tamoxifen from said composition in a pH-dependent manner.

19. A method for protecting Tamoxifen from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of Tamoxifen from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching Tamoxifen to said polypeptide.

21. A method for delivering Tamoxifen to a patient comprising administering to said patient a composition comprising: a polypeptide ; and Tamoxifen covalently attached to said polypeptide.

22. The method of claim 21 wherein Tamoxifen is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein Tamoxifen is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

L The present invention provides several benefits for active agent delivery. First, the invention can stabilize tamsulosin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tamsulosin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tamsulosin is the subject of U. S. Patent Number 4731478,4703063, 4772475, and 4868216, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tamsulosin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tamsulosin is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-tamsulosin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tamsulosin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tamsulosin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12.. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tamsulosin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tamsulosin from said composition in a pH-dependent manner.

19. A method for protecting tamsulosin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tamsulosin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tamsulosin to said polypeptide.

21. A method for delivering tamsulosin to a patient comprising administering to said patient a composition comprising: a polypeptide; and tamsulosin covalently attached to said polypeptide.

22. The method of claim 21 wherein tamsulosin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tamsulosin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LI The present invention provides several benefits for active agent delivery. First, the invention can stabilize temazepam and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of temazepam. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises temazepam covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, temazepam is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-temazepam conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and temazepam covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide-is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein temazepam is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein temazepam is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing temazepam from said composition in a pH-dependent manner.

19. A method for protecting temazepam from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of temazepam from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching temazepam to said polypeptide.

21. A method for delivering temazepam to a patient comprising administering to said patient a composition comprising: a polypeptide; and temazepam covalently attached to said polypeptide.

22. The method of claim 21 wherein temazepam is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein temazepam is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LII The present invention provides several benefits for active agent delivery. First, the invention can stabilize tenofovir disoproxil and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tenofovir disoproxil.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tenofovir disoproxil is the subject of WO 94/3467 1994, priority US 925610 1992, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tenofovir disoproxil covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tenofovir disoproxil is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-tenofovir disoproxil conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tenofovir disoproxil covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tenofovir disoproxil is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tenofovir disoproxil is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tenofovir disoproxil from said composition in a pH-dependent manner.

19. A method for protecting tenofovir disoproxil from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tenofovir disoproxil from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tenofovir disoproxil to said polypeptide.

21. A method for delivering tenofovir disoproxil to a patient comprising administering to said patient a composition comprising: a polypeptide; and tenofovir disoproxil covalently attached to said polypeptide.

22. The method of claim 21 wherein tenofovir disoproxil is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tenofovir disoproxil is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LE The present invention provides several benefits for active agent delivery. First, the invention can stabilize tepoxalin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tepoxalin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tepoxalin is the subject of EP 248594 B 1987, priority US 867996 1986, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tepoxalin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tepoxalin is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-tepoxalin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tepoxalin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8 : The composition of claim 1 wherein tepoxalin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tepoxalin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tepoxalin from said composition in a pH-dependent manner.

19. A method for protecting tepoxalin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tepoxalin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tepoxalin to said polypeptide.

21. A method for delivering tepoxalin to a patient comprising administering to said patient a composition comprising: a polypeptide; and tepoxalin covalently attached to said polypeptide.

22. The method of claim 21 wherein tepoxalin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tepoxalin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize terazosin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of terazosin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Terazosin is the subject of GB 1517403 1978, priority US 621980 1975, GB 1591490 1981, priority US 821675 1977, WO 92/73 1992, priority US 546349 1990, and US 5294615 1994, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises terazosin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, terazosin is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-terazosin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and terazosin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein terazosin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein terazosin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing terazosin from said composition in a pH-dependent manner.

19. A method for protecting terazosin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of terazosin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching terazosin to said polypeptide.

21. A method for delivering terazosin to a patient comprising administering to said patient a composition comprising: a polypeptide; and terazosin covalently attached to said polypeptide.

22. The method of claim 21 wherein terazosin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein terazosin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LV The present invention provides several benefits for active agent delivery. First, the invention can stabilize terbinafine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of terbinafine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Terbinafine is the subject of U. S. Patent Number 4680291 and 4755534, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises terbinafine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-terbinafine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and terbinafine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein terbinafine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13.. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein terbinafine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing terbinafine from said composition in a pH-dependent manner.

19. A method for protecting terbinafine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of terbinafine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching terbinafine to said polypeptide.

21. A method for delivering terbinafine to a patient comprising administering to said patient a composition comprising: a polypeptide; and terbinafine covalently attached to said polypeptide.

22. The method of claim 21 wherein terbinafine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein terbinafine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize terbutaline sulfate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of terbutaline sulfate.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises terbutaline sulfate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, terbutaline sulfate is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-terbutaline sulfate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and terbutaline sulfate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein terbutaline sulfate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein terbutaline sulfate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing terbutaline sulfate from said composition in a pH-dependent manner.

19. A method for protecting terbutaline sulfate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of terbutaline sulfate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching terbutaline sulfate to said polypeptide.

21. A method for delivering terbutaline sulfate to a patient comprising administering to said patient a composition comprising: a polypeptide; and terbutaline sulfate covalently attached to said polypeptide.

22. The method of claim 21 wherein terbutaline sulfate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein terbutaline sulfate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LVII The present invention provides several benefits for active agent delivery. First, the invention can stabilize teriparatide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of teriparatide. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises teriparatide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, teriparatide is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-teriparatide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and teriparatide covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein teriparatide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein teriparatide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing teriparatide from said composition in a pH-dependent manner.

19. A method for protecting teriparatide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of teriparatide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching teriparatide to said polypeptide.

21. A method for delivering teriparatide to a patient comprising administering to said patient a composition comprising: a polypeptide; and teriparatide covalently attached to said polypeptide.

22. The method of claim 21 wherein teriparatide is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein teriparatide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LVE The present invention provides several benefits for active agent delivery. First, the invention can stabilize tetracycline and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tetracycline. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises tetracycline covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tetracycline is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-tetracycline conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tetracycline covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tetracycline is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tetracycline is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tetracycline from said composition in a pH-dependent manner.

19. A method for protecting tetracycline from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tetracycline from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tetracycline to said polypeptide.

21. A method for delivering tetracycline to a patient comprising administering to said patient a composition comprising : a polypeptide; and tetracycline covalently attached to said polypeptide.

22. The method of claim 21 wherein tetracycline is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tetracycline is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LlS The present invention provides several benefits for active agent delivery. First, the invention can stabilize thalidomide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of thalidomide. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Thalidomide is the subject of U. S. Patent Number 5463063, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises thalidomide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, thalidomide is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-thalidomide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and thalidomide covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein thalidomide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein thalidomide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing thalidomide from said composition in a pH-dependent manner.

19. A method for protecting thalidomide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of thalidomide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching thalidomide to said polypeptide.

21. A method for delivering thalidomide to a patient comprising administering to said patient a composition comprising: a polypeptide; and thalidomide covalently attached to said polypeptide.

22. The method of claim 21 wherein thalidomide is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein thalidomide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LX The present invention provides several benefits for active agent delivery. First, the invention can stabilize theophylline and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of theophylline. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises theophylline covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, theophylline is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-theophylline conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and theophylline covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein theophylline is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein theophylline is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing theophylline from said composition in a pH-dependent manner.

19. A method for protecting theophylline from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of theophylline from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching theophylline to said polypeptide.

21. A method for delivering theophylline to a patient comprising administering to said patient a composition comprising : a polypeptide; and theophylline covalently attached to said polypeptide.

22. The method of claim 21 wherein theophylline is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein theophylline is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXI The present invention provides several benefits for active agent delivery. First, the invention can stabilize thiotepa and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of thiotepa. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises thiotepa covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-thiotepa conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and thiotepa covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein thiotepa is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein thiotepa is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing thiotepa from said composition in a pH-dependent manner.

19. A method for protecting thiotepa from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of thiotepa from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching thiotepa to said polypeptide.

21. A method for delivering thiotepa to a patient comprising administering to said patient a composition comprising: a polypeptide; and thiotepa covalently attached to said polypeptide.

22. The method of claim 21 wherein thiotepa is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein thiotepa is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXII The present invention provides several benefits for active agent delivery. First, the invention can stabilize thrombopoetin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of thrombopoetin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises thrombopoetin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, thrombopoetin is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-thrombopoetin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide ; and thrombopoetin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein thrombopoetin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein thrombopoetin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing thrombopoetin from said composition in a pH-dependent manner.

19. A method for protecting thrombopoetin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of thrombopoetin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching thrombopoetin to said polypeptide.

21. A method for delivering thrombopoetin to a patient comprising administering to said patient a composition comprising: a polypeptide; and thrombopoetin covalently attached to said polypeptide.

22. The method of claim 21 wherein thrombopoetin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein thrombopoetin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide. am The present invention provides several benefits for active agent delivery. First, the invention can stabilize tiagabine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tiagabine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tiagabine is the subject of U. S. Patent Number 5010090 and 5354760, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tiagabine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tiagabine is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-tiagabine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and tiagabine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tiagabine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tiagabine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tiagabine from said composition in a pH-dependent manner.

19. A method for protecting tiagabine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tiagabine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tiagabine to said polypeptide.

21. A method for delivering tiagabine to a patient comprising administering to said patient a composition comprising: a polypeptide; and tiagabine covalently attached to said polypeptide.

22. The method of claim 21 wherein tiagabine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tiagabine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize ticlopidine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ticlopidine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Ticlopidine is the subject of U. S. Patent Number 5529791, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises ticlopidine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, titi) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-ticlopidine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ticlopidine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein ticlopidine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein ticlopidine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing ticlopidine from said composition in a pH-dependent manner.

19. A method for protecting ticlopidine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ticlopidine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ticlopidine to said polypeptide.

21. A method for delivering ticlopidine to a patient comprising administering to said patient a composition comprising: a polypeptide; and ticlopidine covalently attached to said polypeptide.

22. The method of claim 21 wherein ticlopidine is released from said composition by an. enzyme-catalyzed release.

23. The method of claim 21 wherein ticlopidine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXV The present invention provides several benefits for active agent delivery. First, the invention can stabilize tifacogin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tifacogin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tifacogin is the subject of Canadian application 2196296, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tifacogin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tifacogin is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-tifacogin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tifacogin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tifacogin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet. f5. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tifacogin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tifacogin from said composition in a pH-dependent manner.

19. A method for protecting tifacogin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tifacogin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tifacogin to said polypeptide.

21. A method for delivering tifacogin to a patient comprising administering to said patient a composition comprising: a polypeptide; and tifacogin covalently attached to said polypeptide.

22. The method of claim 21 wherein tifacogin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tifacogin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize tirapazamine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tirapazamine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tirapazamine is the subject of WO 91/4028 1991, priority PCT/US/4112 1989, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tirapazamine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tirapazamine is covalently attached to the polypeptide via the hydroxyl or amine group.

Preferably, the resultant peptide-tirapazamine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tirapazamine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tirapazamine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tirapazamine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tirapazamine from said composition in a pH-dependent manner.

19. A method for protecting tirapazamine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tirapazamine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tirapazamine to said polypeptide.

21. A method for delivering tirapazamine to a patient comprising administering to said patient a composition comprising: a polypeptide; and tirapazamine covalently attached to said polypeptide.

22. The method of claim 21 wherein tirapazamine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tirapazamine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

I LXVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize tirofiban and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tirofiban. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tirofiban is the subject of U. S. Patent Numbers 5292756,5658929, 5733919, 5880136, 5965581, 5972967 and 5978698, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tirofiban covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tirofiban is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-tirofiban conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tirofiban covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tirofiban is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tirofiban is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tirofiban from said composition in a pH-dependent manner.

19. A method for protecting tirofiban from degradation comprising covalently attaching- said active agent to a polypeptide.

20. A method for controlling release of tirofiban from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tirofiban to said polypeptide.

21. A method for delivering tirofiban to a patient comprising administering to said patient a composition comprising: a polypeptide; and tirofiban covalently attached to said polypeptide.

22. The method of claim 21 wherein tirofiban is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tirofiban is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXVIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize tizanidine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tizanidine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tizanidine is the subject of GB 1429926 1976 and GB 1559811 1980, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tizanidine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tizanidine is covalently attached to the polypeptide via the amine groups.

Preferably, the resultant peptide-tizanidine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tizanidine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tizanidine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tizanidine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tizanidine from said composition in a pH-dependent manner.

19. A method for protecting tizanidine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tizanidine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tizanidine to said polypeptide.

21. A method for delivering tizanidine to a patient comprising administering to said patient a composition comprising : a polypeptide ; and tizanidine covalently attached to said polypeptide.

22. The method of claim 21 wherein tizanidine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tizanidine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXIX The present invention provides several benefits for active agent delivery. First, the invention can stabilize tobramycin sulfate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tobramycin sulfate.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises tobramycin sulfate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) -a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tobramycin sulfate is covalently attached to the polypeptide via the hydroxyl or amino groups.

Preferably, the resultant peptide-tobramycin sulfate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tobramycin sulfate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tobramycin sulfate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tobramycin sulfate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tobramycin sulfate from said composition in a pH-dependent manner.

19. A method for protecting tobramycin sulfate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tobramycin sulfate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tobramycin sulfate to said polypeptide.

21. A method for delivering tobramycin sulfate to a patient comprising administering to said patient a composition comprising: a polypeptide; and tobramycin sulfate covalently attached to said polypeptide.

22. The method of claim 21 wherein tobramycin sulfate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tobramycin sulfate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXX The present invention provides several benefits for active agent delivery. First, the invention can stabilize tolterodine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tolterodine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tolterodine is the subject of U. S. Patent Numbers 5382600 and 5559269, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tolterodine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tolterodine is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-tolterodine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tolterodine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tolterodine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tolterodine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tolterodine from said composition in a pH-dependent manner.

19. A method for protecting tolterodine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tolterodine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tolterodine to said polypeptide.

21. A method for delivering tolterodine to a patient comprising administering to said patient a composition comprising: a polypeptide; and tolterodine covalently attached to said polypeptide.

22. The method of claim 21 wherein tolterodine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tolterodine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXI The present invention provides several benefits for active agent delivery. First, the invention can stabilize tomoxetine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tomoxetine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Tomoxetine is the subject of US 4314081 1980, and EP 52492 B 1984, priority US 206498 198, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises tomoxetine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tomoxetine is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-tomoxetine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tomoxetine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer. of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tomoxetine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tomoxetine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tomoxetine from said composition in a pH-dependent manner.- 19. A method for protecting tomoxetine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tomoxetine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tomoxetine to said polypeptide.

21. A method for delivering tomoxetine to a patient comprising administering to said patient a composition comprising: a polypeptide; and tomoxetine covalently attached to said polypeptide.

22. The method of claim 21 wherein tomoxetine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tomoxetine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize topiramate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of topiramate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Topiramate is the subject of U. S. Patent Number 4513006, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises topiramate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, topiramate is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-topiramate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and topiramate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein topiramate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein topiramate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing topiramate from said composition in a pH-dependent manner.

19. A method for protecting topiramate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of topiramate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching topiramate to said polypeptide.

21. A method for delivering topiramate to a patient comprising administering to said patient a composition comprising : a polypeptide; and topiramate covalently attached to said polypeptide.

22. The method of claim 21 wherein topiramate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein topiramate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

IXXIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize topotecan and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of topotecan. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Topotecan is the subject of EP 321122 A 1989, priority US 127148 1987, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises topotecan covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, topotecan is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-topotecan conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and topotecan covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein topotecan is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein topotecan is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing topotecan from said composition in a pH-dependent manner.

19. A method for protecting topotecan from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of topotecan from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching topotecan to said polypeptide.

21. A method for delivering topotecan to a patient comprising administering to said patient a composition comprising: a polypeptide; and topotecan covalently attached to said polypeptide.

22. The method of claim 21 wherein topotecan is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein topotecan is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize toresemide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of toresemide. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Toresemide is the subject of U. S. Patent Number 4861786 and RE34672, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises toresemide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii). a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, toresemide is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-toresemide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and toresemide covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein toresemide is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein toresemide is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing toresemide from said composition in a pH-dependent manner.

19. A method for protecting toresemide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of toresemide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching toresemide to said polypeptide.

21. A method for delivering toresemide to a patient comprising administering to said patient a composition comprising: a polypeptide; and toresemide covalently attached to said polypeptide.

22. The method of claim 21 wherein toresemide is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein toresemide is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize TPA ANALOGUE and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of TPA ANALOGUE.

Furthermore, active'agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises TPA ANALOGUE covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, TPA ANALOGUE is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-TPA ANALOGUE conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and TPA ANALOGUE covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein TPA ANALOGUE is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein TPA ANALOGUE is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing TPA ANALOGUE from said composition in a pH-dependent manner.

19. A method for protecting TPA ANALOGUE from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of TPA ANALOGUE from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching TPA ANALOGUE to said polypeptide.

21. A method for delivering TPA ANALOGUE to a patient comprising administering to said patient a composition comprising: a polypeptide; and TPA ANALOGUE covalently attached to said polypeptide.

22. The method of claim 21 wherein TPA ANALOGUE is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein TPA ANALOGUE is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize tramadol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of tramadol. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises tramadol covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, tramadol is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-tramadol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and tramadol covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein tramadol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein tramadol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing tramadol from said composition in a pH-dependent manner.

19. A method for protecting tramadol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of tramadol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching tramadol to said polypeptide.

21. A method for delivering tramadol to a patient comprising administering to said patient a composition comprising: a polypeptide; and tramadol covalently attached to said polypeptide.

22. The method of claim 21 wherein tramadol is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein tramadol is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize trandolapril and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of trandblapril.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Trandolapril is the subject of U. S. Patent Number 4233361 and 5744496, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises trandolapril covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, trandolapril is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-trandolapril conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and trandolapril covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein trandolapril is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene'glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein trandolapril is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing trandolapril from said composition in a pH-dependent manner.

19. A method for protecting trandolapril from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of trandolapril from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching trandolapril to said polypeptide.

21. A method for delivering trandolapril to a patient comprising administering to said patient a composition comprising: a polypeptide; and trandolapril covalently attached to said polypeptide.

22. The method of claim 21 wherein trandolapril is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein trandolapril is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXVIO The present invention provides several benefits for active agent delivery.

First, the invention can stabilize trastuzumab and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of trastuzumab.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises trastuzumab covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, trastuzumab is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-trastuzumab conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and trastuzumab covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein trastuzumab is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein trastuzumab is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing trastuzumab from said composition in a pH-dependent manner.

19. A method for protecting trastuzumab from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of trastuzumab from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching trastuzumab to said polypeptide.

21. A method for delivering trastuzumab to a patient comprising administering to said patient a composition comprising: a polypeptide; and trastuzumab covalently attached to said polypeptide.

22. The method of claim 21 wherein trastuzumab is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein trastuzumab is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize trazadone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of trazadone. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises trazadone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Proteins, oligopeptides and polypeptides are-polymers of amino acids that have primary, secondary and tertiary structures. The secondary structure of the protein is the local conformation of the polypeptide chain and consists of helices, pleated sheets and turns. The protein's amino acid sequence and the structural constraints on the conformations of the chain determine the spatial arrangement of the molecule. The folding of the secondary structure and . the spatial arrangement of the side chains constitute the tertiary structure.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-trazadone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and trazadone covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein trazadone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the. form of an oral suspension.

17. The composition of claim 1 wherein trazadone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing trazadone from said composition in a pH-dependent manner.

19. A method for protecting trazadone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of trazadone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching trazadone to said polypeptide.

21. A method for delivering trazadone to a patient comprising administering to said patient a composition comprising: a polypeptide; and trazadone covalently attached to said polypeptide.

22. The method of claim 21 wherein trazadone is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein trazadone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize triamterene and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of triamterene.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises triamterene covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, triamterene is covalently attached to the polypeptide via an amino group.

Preferably, the resultant peptide-triamterene conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and triamterene covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein triamterene is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein triamterene is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing triamterene from said composition in a pH-dependent manner.

19. A method for protecting triamterene from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of triamterene from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching triamterene to said polypeptide.

21. A method for delivering triamterene to a patient comprising administering to said patient a composition comprising: a polypeptide; and triamterene covalently attached to said polypeptide.

22. The method of claim 21 wherein triamterene is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein triamterene is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize troglitazone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of troglitazone.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Troglitazone is the subject of EP 139421 B 1988, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises troglitazone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, troglitazone is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-troglitazone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and troglitazone covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein troglitazone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12.-The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein troglitazone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing troglitazone from said composition in a pH-dependent manner.

19. A method for protecting troglitazone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of troglitazone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching troglitazone to said polypeptide.

21. A method for delivering troglitazone to a patient comprising administering to said patient a composition comprising: a polypeptide; and troglitazone covalently attached to said polypeptide.

22. The method of claim 21 wherein troglitazone is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein troglitazone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize trovafloxacin mesylate and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of trovafloxacin mesylate. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Trovafloxacin mesylate is the subject of U. S. Patent Number 5164402,5763454, and 6080756, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises trovafloxacin mesylate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, trovafloxacin mesylate is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-trovafloxacin mesylate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and trovafloxacin mesylate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein trovafloxacin mesylate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein trovafloxacin mesylate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing trovafloxacin mesylate from said composition in a pH-dependent manner.

19. A method for protecting trovafloxacin mesylate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of trovafloxacin mesylate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching trovafloxacin mesylate to said polypeptide.

21. A method for delivering trovafloxacin mesylate to a patient comprising administering to said patient a composition comprising: a polypeptide; and trovafloxacin mesylate covalently attached to said polypeptide.

22. The method of claim 21 wherein trovafloxacin mesylate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein trovafloxacin mesylate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXm The present invention provides several benefits for active agent delivery.

First, the invention can stabilize urokinase and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of urokinase. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises urokinase covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, urokinase is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-urokinase conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and urokinase covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein urokinase is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein urokinase is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing urokinase from said composition in a pH-dependent manner.

19. A method for protecting urokinase from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of urokinase from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching urokinase to said polypeptide.

21. A method for delivering urokinase to a patient comprising administering to said patient a composition comprising: a polypeptide; and urokinase covalently attached to said polypeptide.

22. The method of claim 21 wherein urokinase is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein urokinase is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXTV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize ursodiol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ursodiol. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises ursodiol covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, ursodiol is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-ursodiol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ursodiol covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally . occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein ursodiol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein ursodiol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing ursodiol from said composition in a pH-dependent manner.

19. A method for protecting ursodiol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ursodiol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ursodiol to said polypeptide.

21. A method for delivering ursodiol to a patient comprising administering to said patient a composition comprising : a polypeptide; and ursodiol covalently attached to said polypeptide.

22. The method of claim 21 wherein ursodiol is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein ursodiol is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize valacyclovir and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of valacyclovir.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Valacyclovir is the subject of U. S. Patent Number 4957924, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises valacyclovir covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, valacyclovir is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-valacyclovir conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and valacyclovir covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein valacyclovir is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein valacyclovir is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing valacyclovir from said composition in a pH-dependent manner.

19. A method for protecting valacyclovir from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of valacyclovir from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching valacyclovir to said polypeptide.

21. A method for delivering valacyclovir to a patient comprising administering to said patient a composition comprising : a polypeptide; and valacyclovir covalently attached to said polypeptide.

22. The method of claim 21 wherein valacyclovir is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein valacyclovir is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize valdecoxib and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of valdecoxib. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Valdecoxib is the subject of WO 96/25405 1996, priority US 387680 1995, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises valdecoxib covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, valdecoxib is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-valdecoxib conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and valdecoxib covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein valdecoxib is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16.. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein valdecoxib is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing valdecoxib from said composition in a pH-dependent manner.

19. A method for protecting valdecoxib from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for. controlling release of valdecoxib from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching valdecoxib to said polypeptide.

21. A method for delivering valdecoxib to a patient comprising administering to said patient a composition comprising: a polypeptide; and valdecoxib covalently attached to said polypeptide.

22. The method of claim 21 wherein valdecoxib is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein valdecoxib is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide. iXXXVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize valproic acid and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of valproic acid.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises valproic acid covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, valproic acid is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-valproic acid conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and valproic acid covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein valproic acid is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein valproic acid is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing valproic acid from said composition in a pH-dependent manner.

19. A method for protecting valproic acid from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of valproic acid from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching valproic acid to said polypeptide.

21. A method for delivering valproic acid to a patient comprising administering to said patient a composition comprising: a polypeptide ; and valproic acid covalently attached to said polypeptide.

22. The method of claim 21 wherein valproic acid is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein valproic acid is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

IXXXVIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize valsartan and hydrochlorothiazide and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of valsartan and hydrochlorothiazide. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced.

The invention also allows targeted delivery of active agents to specifics sites of action.

Valsartan and hydrochlorothiazide are the subject of U. S. Patent Number 5399578, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises valsartan and hydrochlorothiazide covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, valsartan and hydrochlorothiazide are covalently attached to the polypeptide via the carboxyloic acid and amino groups, respectively.

Preferably, the resultant peptide-valsartan and hydrochlorothiazide conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and valsartan and hydrochlorothiazide covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein valsartan and hydrochlorothiazide are covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein valsartan and hydrochlorothiazide are conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing valsartan and hydrochlorothiazide from said composition in a pH-dependent manner.

19. A method for protecting valsartan and hydrochlorothiazide from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of valsartan and hydrochlorothiazide from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching valsartan and hydrochlorothiazide to said polypeptide.

21. A method for delivering valsartan and hydrochlorothiazide to a patient comprising administering to said patient a composition comprising: a polypeptide; and valsartan and hydrochlorothiazide covalently attached to said polypeptide.

22. The method of claim 21 wherein valsartan and hydrochlorothiazide are released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein valsartan and hydrochlorothiazide are released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

LXXXIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize valspodar and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of valspodar. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Valspodar is the subject of EP 296122 B 1993, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises valspodar covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, valspodar is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-valspodar conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and valspodar covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein valspodar is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein valspodar is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing valspodar from said composition in a pH-dependent manner.

19. A method for protecting valspodar from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of valspodar from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching valspodar to said polypeptide.

21. A method for delivering valspodar to a patient comprising administering to said patient a composition comprising: a polypeptide ; and valspodar covalently attached to said polypeptide.

22. The method of claim 21 wherein valspodar is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein valspodar is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XC The present invention provides several benefits for active agent delivery. First, the invention can stabilize vancomycin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of vancomycin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises vancomycin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, vancomycin is covalently attached to the polypeptide via the carboxylic acid group.

Preferably, the resultant peptide-vancomycin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and vancomycin covalently attached to said polypeptide.

2. The composition of claim wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein vancomycin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein vancomycin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing vancomycin from said composition in a pH-dependent manner.

19. A method for protecting vancomycin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of vancomycin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching vancomycin to said polypeptide.

21. A method for delivering vancomycin to a patient comprising administering to said patient a composition comprising : a polypeptide; and vancomycin covalently attached to said polypeptide.

22. The method of claim 21 wherein vancomycin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein vancomycin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCI The present invention provides several benefits for active agent delivery. First, the invention can stabilize vecuronium and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of vecuronium. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises vecuronium covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-vecuronium conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and vecuronium covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein vecuronium is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein vecuronium is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing vecuronium from said composition in a pH-dependent manner.

19. A method for protecting vecuronium from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of vecuronium from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching vecuronium to said polypeptide.

21. A method for delivering vecuronium to a patient comprising administering to said patient a composition comprising: a polypeptide; and vecuronium covalently attached to said polypeptide.

22. The method of claim 21 wherein vecuronium is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein vecuronium is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCII The present invention provides several benefits for active agent delivery. First, the invention can stabilize venlafaxine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of venlafaxine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Venlafaxine is the subject of U. S. Patent Number 4535186, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises venlafaxine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, venlafaxine is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-venlafaxine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and venlafaxine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein venlafaxine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein venlafaxine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing venlafaxine from said composition in a pH-dependent manner.

19. A method for protecting venlafaxine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of venlafaxine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching venlafaxine to said polypeptide.

21. A method for delivering venlafaxine to a patient comprising administering to said patient a composition comprising : a polypeptide; and venlafaxine covalently attached to said polypeptide.

22. The method of claim 21 wherein venlafaxine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein venlafaxine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

I XCIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize verapamil and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of verapamil. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises verapamil covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-verapamil conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and verapamil covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein verapamil is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein verapamil is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing verapamil from said composition in a pH-dependent manner.

19. A method for protecting verapamil from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of verapamil from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching verapamil to said polypeptide.

21. A method for delivering verapamil to a patient comprising administering to said patient a composition comprising: a polypeptide; and verapamil covalently attached to said polypeptide.

22. The method of claim 21 wherein verapamil is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein verapamil is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize vinorelbine tartrate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of vinorelbine tartrate.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Vinorelbine tartrate is the subject of U. S. Patent Number 4307100, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises vinorelbine tartrate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, vinorelbine tartrate is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-vinorelbine tartrate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and vinorelbine tartrate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic. amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein vinorelbine tartrate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein vinorelbine tartrate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing vinorelbine tartrate from said composition in a pH-dependent manner.

19. A method for protecting vinorelbine tartrate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of vinorelbine tartrate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching vinorelbine tartrate to said polypeptide.

21. A method for delivering vinorelbine tartrate to a patient comprising administering to said patient a composition comprising: a polypeptide; and vinorelbine tartrate covalently attached to said polypeptide.

22. The method of claim 21 wherein vinorelbine tartrate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein vinorelbine tartrate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCV The present invention provides several benefits for active agent delivery. First, the invention can stabilize vitamin B 12 and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of vitamin B12. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Vitamin B12 is the subject of U. S. Patent Number yyyyy, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises vitamin B 12 covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-vitamin B12 conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and vitamin B12 covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein vitamin B12 is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein vitamin B 12 is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim I wherein said polypeptide is capable of releasing vitamin B12 from said composition in a pH-dependent manner.

19. A method for protecting vitamin B12 from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of vitamin B 12 from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching vitamin B12 to said polypeptide.

21. A method for delivering vitamin B12 to a patient comprising administering to said patient a composition comprising: a polypeptide; and vitamin B12 covalently attached to said polypeptide.

22. The method of claim 21 wherein vitamin B12 is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein vitamin B 12 is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize vitamin C and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of vitamin C. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises vitamin C covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, vitamin C is covalently attached to the polypeptide via a hydroxyl group.

Preferably, the resultant peptide-vitamin C conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and vitamin C covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein vitamin C is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein vitamin C is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing vitamin C from said composition in a pH-dependent manner.

19. A method for protecting vitamin C from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of vitamin C from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching vitamin C to said polypeptide.

21. A method for delivering vitamin C to a patient comprising administering to said patient a composition comprising : a polypeptide; and vitamin C covalently attached to said polypeptide.

22. The method of claim 21 wherein vitamin C is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein vitamin C is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize voriconazole and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of voriconazole.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Voriconazole is the subject of EP 440372 B 1993, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises voriconazole covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, voriconazole is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-voriconazole conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and voriconazole covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein voriconazole is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein voriconazole is'conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing voriconazole from said composition in a pH-dependent manner.

19. A method for protecting voriconazole from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of voriconazole from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching voriconazole to said polypeptide.

21. A method for delivering voriconazole to a patient comprising administering to said patient a composition comprising: a polypeptide; and voriconazole covalently attached to said polypeptide.

22. The method of claim 21 wherein voriconazole is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein voriconazole is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XGYIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize warfarin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of warfarin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises warfarin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, warfarin is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-warfarin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and warfarin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein warfarin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein warfarin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing warfarin from said composition in a pH-dependent manner.

19. A method for protecting warfarin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of warfarin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching warfarin to said polypeptide.

21. A method for delivering warfarin to a patient comprising administering to said patient a composition comprising: a polypeptide ; and warfarin covalently attached to said polypeptide.

22. The method of claim 21 wherein warfarin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein warfarin is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

XCIX The present invention provides several benefits for active agent delivery. First, the invention can stabilize xaliproden and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of xaliproden. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Xaliproden is the subject of EP 101381 B 1985, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises xaliproden covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-xaliproden conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and xaliproden covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein xaliproden is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein xaliproden is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing xaliproden from said composition in a pH-dependent manner.

19. A method for protecting xaliproden from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of xaliproden from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching xaliproden to said polypeptide.

21. A method for delivering xaliproden to a patient comprising administering to said patient a composition comprising : a polypeptide; and xaliproden covalently attached to said polypeptide.

22. The method of claim 21 wherein xaliproden is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein xaliproden is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

C The present invention provides several benefits for active agent delivery. First, the invention can stabilize zafirlukast and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of zafirlukast. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Zafirlukast is the subject of EP 199543 B 1991, EP 490648 B 1995, EP 490649 A 1992and U. S. Patent Numbers 4859692, 5294636, 5319097, 5482963,5583152, and 5612367, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises zafirlukast covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, zafirlukast is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-zafirlukast conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and zafirlukast covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein zafirlukast is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein zafirlukast is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing zafirlukast from said composition in a pH-dependent manner.

19. A method for protecting zafirlukast from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of zafirlukast from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching zafirlukast to said polypeptide.

21. A method for delivering zafirlukast to a patient comprising administering to said patient a composition comprising: a polypeptide; and zafirlukast covalently attached to said polypeptide.

22. The method of claim 21 wherein zafirlukast is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein zafirlukast is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CI The present invention provides several benefits for active agent delivery. First, the invention can stabilize zaleplon and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of zaleplon. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Zaleplon is the subject of U. S. Patent Number 4626538, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises zaleplon covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-zaleplon conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and zaleplon covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein zaleplon is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein zaleplon is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing zaleplon from said composition in a pH-dependent manner.

19. A method for protecting zaleplon from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of zaleplon from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching zaleplon to said polypeptide.

21. A method for delivering zaleplon to a patient comprising administering to said patient a composition comprising: a polypeptide; and zaleplon covalently attached to said polypeptide.

22. The method of claim 21 wherein zaleplon is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein zaleplon is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CII The present invention provides several benefits for active agent delivery. First, the invention can stabilize zenarestat and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of zenarestat. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to. specifics sites of action.

Zenarestat is the subject of EP 218999 B 1991, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises zenarestat covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, zenarestat is covalently attached to the polypeptide via the carboxylic acid.

Preferably, the resultant peptide-zenarestat conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and zenarestat covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein zenarestat is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein zenarestat is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing zenarestat from said composition in a pH-dependent manner.

19. A method for protecting zenarestat from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of zenarestat from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching zenarestat to said polypeptide.

21. A method for delivering zenarestat to a patient comprising administering to said patient a composition comprising: a polypeptide; and zenarestat covalently attached to said polypeptide.

22. The method of claim 21 wherein zenarestat is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein zenarestat is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CM The present invention provides several benefits for active agent delivery. First, the invention can stabilize zidovudine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of zidovudine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Zidovudine is the subject of U. S. Patent Number 4724232, 4818538, 4828838, and 4833130, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises zidovudine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, zidovudine is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-zidovudine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and zidovudine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein zidovudine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein zidovudine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing zidovudine from said composition in a pH-dependent manner.

19. A method for protecting zidovudine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of zidovudine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching zidovudine to said polypeptide.

21. A method for delivering zidovudine to a patient comprising administering to said patient a composition comprising: a polypeptide; and zidovudine covalently attached to said polypeptide.

22. The method of claim 21 wherein zidovudine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein zidovudine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize zolmitriptan and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of zolmitriptan. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Zolmitriptan is the subject of U. S. Patent Number 5466699 and 5863935, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises zolmitriptan covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, zolmitriptan is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-zolmitriptan conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and zolmitriptan covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein zolmitriptan is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein zolmitriptan is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing zolmitriptan from said composition in a pH-dependent manner.

19. A method for protecting zolmitriptan from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of zolmitriptan from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching zolmitriptan to said polypeptide.

21. A method for delivering zolmitriptan to a patient comprising administering to said patient a composition comprising: a polypeptide ; and zolmitriptan covalently attached to said polypeptide.

22. The method of claim 21 wherein zolmitriptan is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein zolmitriptan is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of'claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CV The present invention provides several benefits for active agent delivery. First, the invention can stabilize zolpidem and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of zolpidem. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Zolpidem is the subject of U. S. Patent Number 4382938, EP 50563 B 1984, and EP 251859 B 1990, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises zolpidem covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-zolpidem conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and zolpidem covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein zolpidem is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein zolpidem is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing zolpidem from said composition in a pH-dependent manner.

19. A method for protecting zolpidem from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of zolpidem from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching zolpidem to said polypeptide.

21. A method for delivering zolpidem to a patient comprising administering to said patient a composition comprising: a polypeptide; and zolpidem covalently attached to said polypeptide.

22. The method of claim 21 wherein zolpidem is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein zolpidem is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize bleomycin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of bleomycin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises bleomycin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, bleomycin is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-bleomycin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and bleomycin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein bleomycin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein bleomycin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing bleomycin from said composition in a pH-dependent manner.

19. A method for protecting bleomycin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of bleomycin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching bleomycin to said polypeptide.

21. A method for delivering bleomycin to a patient comprising administering to said patient a composition comprising: a polypeptide; and bleomycin covalently attached to said polypeptide.

22. The method of claim 21 wherein bleomycin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein bleomycin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CVII The present invention provides several benefits for active agent delivery. First, the invention can stabilize phytoseterol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of phytoseterol. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises phytoseterol covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-phytoseterol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and phytoseterol covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein phytoseterol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein phytoseterol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing phytoseterol from said composition in a pH-dependent manner.

19. A method for protecting phytoseterol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of phytoseterol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching phytoseterol to said polypeptide.

21. A method for delivering phytoseterol to a patient comprising administering to said patient a composition comprising: a polypeptide; and phytoseterol covalently attached to said polypeptide.

22. The method of claim 21 wherein phytoseterol is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein phytoseterol is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CVin The present invention provides several benefits for active agent delivery. First, the invention can stabilize paclitaxel and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of paclitaxel. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Paclitaxel is the subject of EP 584001 B 1997 (priority US 923628 1992), EP 645145 B 1997 (priority US 128026 1993), and EP 717041 A 1996 (priority US 355125 1994), herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises paclitaxel covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, paclitaxel is covalently attached to the polypeptide via the hydroxel group.

Preferably, the resultant peptide-paclitaxel conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and paclitaxel covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein paclitaxel is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein paclitaxel is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing paclitaxel from said composition in a pH-dependent manner.

19. A method for protecting paclitaxel from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of paclitaxel from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching paclitaxel to said polypeptide.

21. A method for delivering paclitaxel to a patient comprising administering to said patient a composition comprising: a polypeptide; and paclitaxel covalently attached to said polypeptide.

22. The method of claim 21 wherein paclitaxel is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein paclitaxel is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CIX The present invention provides several benefits for active agent delivery. First, the invention can stabilize fluticasone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of fluticasone. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics-sites of action.

Fluticasone is the subject of GB 2088877 B 1984, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises fluticasone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, fluticasone is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-fluticasone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and fluticasone covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein fluticasone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein fluticasone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing fluticasone from said composition in a pH-dependent manner.

19. A method for protecting fluticasone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of fluticasone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching fluticasone to said polypeptide.

21. A method for delivering fluticasone to a patient comprising administering to said patient a composition comprising: a polypeptide; and fluticasone covalently attached to said polypeptide.

22. The method of claim 21 wherein fluticasone is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein fluticasone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CX The present invention provides several benefits for active agent delivery. First, the invention can stabilize flurouracil and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of flurouracil. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises flurouracil covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, flurouracil is covalently attached to the polypeptide via the amine group.

Preferably, the resultant peptide-flurouracil conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and flurouracil covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein flurouracil is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein flurouracil is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing flurouracil from said composition in a pH-dependent manner.

19. A method for protecting flurouracil from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of flurouracil from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching flurouracil to said polypeptide.

21. A method for delivering flurouracil to a patient comprising administering to said patient a composition comprising: a polypeptide; and flurouracil covalently attached to said polypeptide.

22. The method of claim 21 wherein flurouracil is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein flurouracil is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXI The present invention provides several benefits for active agent delivery. First, the invention can stabilize pseudoephedrine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of pseudoephedrine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises pseudoephedrine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, pseudoephedrine is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-pseudoephedrine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and pseudoephedrine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein pseudoephedrine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17.-The composition of claim 1 wherein pseudoephedrine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing pseudoephedrine from said composition in a pH-dependent manner.

19. A method for protecting pseudoephedrine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of pseudoephedrine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching pseudoephedrine to said polypeptide.

21. A method for delivering pseudoephedrine to a patient comprising administering to said patient a composition comprising: a polypeptide; and pseudoephedrine covalently attached to said polypeptide.

22. The method of claim 21 wherein pseudoephedrine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein pseudoephedrine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXII The present invention provides several benefits for active agent delivery. First, the invention can stabilize a lipoxygenase inhibitor and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a lipoxygenase inhibitor. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises a lipoxygenase inhibitor covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-a lipoxygenase inhibitor conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and a lipoxygenase inhibitor covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein a lipoxygenase inhibitor is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein a lipoxygenase inhibitor is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing a lipoxygenase inhibitor from said composition in a pH-dependent manner.

19. A method for protecting a lipoxygenase inhibitor from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a lipoxygenase inhibitor from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a lipoxygenase inhibitor to said polypeptide.

21. A method for delivering a lipoxygenase inhibitor to a patient comprising administering to said patient a composition comprising : a polypeptide; and a lipoxygenase inhibitor covalently attached to said polypeptide.

22. The method of claim 21 wherein a lipoxygenase inhibitor is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein a lipoxygenase inhibitor is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXIII The present invention provides several benefits for active agent delivery. First, the invention can stabilize a composite vascular protectant and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a composite vascular protectant. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced.

The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises a composite vascular protectant covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Preferably, the resultant peptide-a composite vascular protectant conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and a composite vascular protectant covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein a composite vascular protectant is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein a composite vascular protectant is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing a composite vascular protectant from said composition in a pH-dependent manner.

19. A method for protecting a composite vascular protectant from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a composite vascular protectant from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a composite vascular protectant to said polypeptide.

21. A method for delivering a composite vascular protectant to a patient comprising administering to said patient a composition comprising: a polypeptide; and a composite vascular protectant covalently attached to said polypeptide.

22. The method of claim 21 wherein a composite vascular protectant is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein a composite vascular protectant is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXIV The present invention provides several benefits for active agent delivery. First, the invention can stabilize an oral neuraminidase inhibitor and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of an oral neuraminidase inhibitor. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises an oral neuraminidase inhibitor covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Preferably, the resultant peptide-an oral neuraminidase inhibitor conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and an oral neuraminidase inhibitor covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring. amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein an oral neuraminidase inhibitor is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein an oral neuraminidase inhibitor is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing an oral neuraminidase inhibitor from said composition in a pH-dependent manner.

19. A method for protecting an oral neuraminidase inhibitor from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of an oral neuraminidase inhibitor from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching an oral neuraminidase inhibitor to said polypeptide.

21. A method for delivering an oral neuraminidase inhibitor to a patient comprising administering to said patient a composition comprising: a polypeptide; and an oral neuraminidase inhibitor covalently attached to said polypeptide.

22. The method of claim 21 wherein an oral neuraminidase inhibitor is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein an oral neuraminidase inhibitor is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXV The present invention provides several benefits for active agent delivery. First, the invention can stabilize the soluble chimeric protein CTLA4Ig and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of the soluble chimeric protein CTLA4Ig. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced.

The invention also allows targeted delivery of active agents to specifics sites of action.

The soluble chimeric protein CTLA4Ig is the subject of EP 606217 B 1998, priority US 723617 1991, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises the soluble chimeric protein CTLA4Ig covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the soluble chimeric protein CTLA4Ig is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-the soluble chimeric protein CTLA4Ig conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and the soluble chimeric protein CTLA4Ig covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein the soluble chimeric protein CTLA4Ig is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein the soluble chimeric protein CTLA4Ig is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing the soluble chimeric protein CTLA4Ig from said composition in a pH-dependent manner.

19. A method for protecting the soluble chimeric protein CTLA4Ig from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of the soluble chimeric protein CTLA4Ig from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching the soluble chimeric protein CTLA4Ig to said polypeptide.

21. A method for delivering the soluble chimeric protein CTLA4Ig to a patient comprising administering to said patient a composition comprising: a polypeptide; and the soluble chimeric protein CTLA4Ig covalently attached to said polypeptide.

22. The method of claim 21 wherein the soluble chimeric protein CTLA4Ig is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein the soluble chimeric protein CTLA4Ig is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXVI The present invention provides several benefits for active agent delivery. First, the invention can stabilize a selective endothelin A receptor antagonist and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a selective endothelin A receptor antagonist. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises a selective endothelin A receptor antagonist covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Preferably, the resultant peptide-a selective endothelin A receptor antagonist conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and a selective endothelin A receptor antagonist covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein a selective endothelin A receptor antagonist is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein a selective endothelin A receptor antagonist is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing a selective endothelin A receptor antagonist from said composition in a pH-dependent manner.

19. A method for protecting a selective endothelin A receptor antagonist from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a selective endothelin A receptor antagonist from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a selective endothelin A receptor antagonist to said polypeptide.

21. A method for delivering a selective endothelin A receptor antagonist to a patient comprising administering to said patient a composition comprising: a polypeptide; and a selective endothelin A receptor antagonist covalently attached to said polypeptide.

22. The method of claim 21 wherein a selective endothelin A receptor antagonist is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein a selective endothelin A receptor antagonist is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXVII The present invention provides several benefits for active agent delivery. First, the invention can stabilize a potassium channel modulator and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a potassium channel modulator. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced.

The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises a potassium channel modulator covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Preferably, the resultant peptide-a potassium channel modulator conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and a potassium channel modulator covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer. of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein a potassium channel modulator is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein a potassium channel modulator is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing a potassium channel modulator from said composition in a pH-dependent manner.

19. A method for protecting a potassium channel modulator from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a potassium channel modulator from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a potassium channel modulator to said polypeptide.

21. A method for delivering a potassium channel modulator to a patient comprising administering to said patient a composition comprising: a polypeptide; and a potassium channel modulator covalently attached to said polypeptide.

22. The method of claim 21 wherein a potassium channel modulator is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein a potassium channel modulator is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXVIQ The present invention provides several benefits for active agent delivery.

First, the invention can stabilize a bactericidal/permeability increasing protein derivative and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a bactericidal/permeability increasing protein derivative. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises a bactericidal/permeability increasing protein derivative covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, a bactericidal/permeability increasing protein derivative is covalently attached to the polypeptide via the a peptide bond.

Preferably, the resultant peptide-a bactericidal/permeability increasing protein derivative conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and a bactericidal/permeability increasing protein derivative covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein a bactericidal/permeability increasing protein derivative is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein a bactericidal/permeability increasing protein derivative is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing a bactericidal/permeability increasing protein derivative from said composition in a pH-dependent manner.

19. A method for protecting a bactericidal/permeability increasing protein derivative from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a bactericidal/permeability increasing protein derivative from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a bactericidal/permeability increasing protein derivative to said polypeptide.

21. A method for delivering a bactericidal/permeability increasing protein derivative to a patient comprising administering to said patient a composition comprising: a polypeptide; and a bactericidal/permeability increasing protein derivative covalently attached to said polypeptide.

22. The method of claim 21 wherein a bactericidal/permeability increasing protein derivative is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein a bactericidal/permeability increasing protein derivative is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXIX The present invention provides several benefits for active agent delivery. First, the invention can stabilize humanized monoclonal antibody, hu 1124, directed against CD1 la and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of humanized monoclonal antibody, hu 1124, directed against CD la.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Humanized monoclonal antibody, hu 1124, directed against CD1 la is the subject of U. S.

Patent Number 5622700, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises humanized monoclonal antibody, hu 1124, directed against CD 1 la covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, humanized monoclonal antibody, hu 1124, directed against CD1 la is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-humanized monoclonal antibody, hu 1124, directed against CD la conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and humanized monoclonal antibody, hu 1124, directed against CD1 la covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein humanized monoclonal antibody, hu 1124, directed against CD1 la is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein humanized monoclonal antibody, hu 1124, directed against CD1 la is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing humanized monoclonal antibody, hu 1124, directed against CD1 la from said composition in a pH-dependent manner.

19. A method for protecting humanized monoclonal antibody, hu 1124, directed against CD1 la from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of humanized monoclonal antibody, hu 1124, directed against CD1 la from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching humanized monoclonal antibody, hu 1124, directed against CD1 la to said polypeptide.

21. A method for delivering humanized monoclonal antibody, hu 1124, directed against CD1 la to a patient comprising administering to said patient a composition comprising: a polypeptide; and humanized monoclonal antibody, hu 1124, directed against CD1 la covalently attached to said polypeptide.

22. The method of claim 21 wherein humanized monoclonal antibody, hu 1124, directed against CD1 la is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein humanized monoclonal antibody, hu 1124, directed against CD1 la is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

The present invention provides several benefits for active agent delivery. First, the invention can stabilize a lipid lowering agent and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a lipid lowering agent.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises a lipid lowering agent covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Preferably, the resultant peptide-a lipid lowering agent conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and a lipid lowering agent covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein a lipid lowering agent is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein a lipid lowering agent is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing a lipid lowering agent from said composition in a pH-dependent manner.

19. A method for protecting a lipid lowering agent from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a lipid lowering agent from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a lipid lowering agent to said polypeptide.

21. A method for delivering a lipid lowering agent to a patient comprising administering to said patient a composition comprising : a polypeptide; and a lipid lowering agent covalently attached to said polypeptide.

22. The method of claim 21 wherein a lipid lowering agent is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein a lipid lowering agent is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXI The present invention provides several benefits for active agent delivery. First, the invention can stabilize propofol and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of propofol. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises propofol covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, propofol is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-propofol conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and propofol covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein propofol is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein propofol is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing propofol from said composition in a pH-dependent manner.

19. A method for protecting propofol from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of propofol from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching propofol to said polypeptide.

21. A method for delivering propofol to a patient comprising administering to said patient a composition comprising: a polypeptide; and propofol covalently attached to said polypeptide.

22. The method of claim 21 wherein propofol is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein propofol is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXII The present invention provides several benefits for active agent delivery. First, the invention can stabilize a Cholesterol/Triglyceride Reducer and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a Cholesterol/Triglyceride Reducer. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced.

The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises a Cholesterol/Triglyceride Reducer covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-a Cholesterol/Triglyceride Reducer conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and a Cholesterol/Triglyceride Reducer covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein a Cholesterol/Triglyceride Reducer is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein a Cholesterol/Triglyceride Reducer is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing a Cholesterol/Triglyceride Reducer from said composition in a pH-dependent manner.

19. A method for protecting a Cholesterol/Triglyceride Reducer from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a Cholesterol/Triglyceride Reducer from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a Cholesterol/Triglyceride Reducer to said polypeptide.

1 21. A method for delivering a Cholesterol/Triglyceride Reducer to a patient comprising administering to said patient a composition comprising: a polypeptide; and a Cholesterol/Triglyceride Retlucer covalently attached to said polypeptide.

22. The method of claim 21 wherein a Cholesterol/Triglyceride Reducer is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein a Cholesterol/Triglyceride Reducer is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXIII The present invention provides serveral benefits for active agent delivery.

First, the invention can stabilize a recombinant hepatitis B vaccine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of a recombinant hepatitis B vaccine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced.

The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises a recombinant hepatitis B vaccine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, a recombinant hepatitis B vaccine is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-a recombinant hepatitis B vaccine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and a recombinant hepatitis B vaccine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein a recombinant hepatitis B vaccine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt..

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein a recombinant hepatitis B vaccine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim i wherein said polypeptide is capable of releasing a recombinant hepatitis B vaccine from said composition in a pH-dependent manner.

19. A method for protecting a recombinant hepatitis B vaccine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of a recombinant hepatitis B vaccine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching a recombinant hepatitis B vaccine to said polypeptide.

21. A method for delivering a recombinant hepatitis B vaccine to a patient comprising administering to said patient a composition comprising: a polypeptide; and a recombinant hepatitis B vaccine covalently attached to said polypeptide.

22. The method of claim 21 wherein a recombinant hepatitis B vaccine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein a recombinant hepatitis B vaccine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize an angiotensin II antagonist and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of an angiotensin II antagonist. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises an angiotensin II antagonist covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, the active agent is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.

Preferably, the resultant peptide-an angiotensin II antagonist conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and an angiotensin II antagonist covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein an angiotensin II antagonist is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein an angiotensin II antagonist is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing an angiotensin II antagonist from said composition in a pH-dependent manner.

19. A method for protecting an angiotensin II antagonist from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of an angiotensin II antagonist from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching an angiotensin II antagonist to said polypeptide.

21. A method for delivering an angiotensin II antagonist to a patient comprising administering to said patient a composition comprising: a polypeptide; and an angiotensin II antagonist covalently attached to said polypeptide.

22. The method of claim 21 wherein an angiotensin II antagonist is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein an angiotensin II antagonist is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize an immunosuppressant protein and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of an immunosuppressant protein. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

An immunosuppressant protein is the subject of U. S. Patent Number 5547853, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises an immunosuppressant protein covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, an immunosuppressant protein is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-an immunosuppressant protein conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and an immunosuppressant protein covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein an immunosuppressant protein is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein an immunosuppressant protein is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing an immunosuppressant protein from said composition in a pH-dependent manner.

19. A method for protecting an immunosuppressant protein from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of an immunosuppressant protein from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching an immunosuppressant protein to said polypeptide.

21. A method for delivering an immunosuppressant protein to a patient comprising administering to said patient a composition comprising: a polypeptide; and an immunosuppressant protein covalently attached to said polypeptide.

22. The method of claim 21 wherein an immunosuppressant protein is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein an immunosuppressant protein is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize daily multivitamin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of daily multivitamin.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises daily multivitamin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Preferably, the resultant peptide-daily multivitamin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and daily multivitamin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein daily multivitamin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein daily multivitamin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing daily multivitamin from said composition in a pH-dependent manner.

19. A method for protecting daily multivitamin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of daily multivitamin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching daily multivitamin to said polypeptide.

21. A method for delivering daily multivitamin to a patient comprising administering to said patient a composition comprising: a polypeptide; and daily multivitamin covalently attached to said polypeptide.

22. The method of claim 21 wherein daily multivitamin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein daily multivitamin is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXVB The present invention provides several benefits for active agent delivery.

First, the invention can stabilize erythromycin and sulfx and prevent its digestion in the stomach.

In addition, the pharmacologic effect can be prolonged by delayed release of erythromycin and sulfx. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises erythromycin and sulfx covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

Preferably, the resultant peptide-erythromycin and sulfx conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and erythromycin and sulfx covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein erythromycin and sulfx is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein erythromycin and sulfx is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing erythromycin and sulfx from said composition in a pH-dependent manner.

19. A method for protecting erythromycin and sulfx from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of erythromycin and sulfx from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching erythromycin and sulfx to said polypeptide.

21. A method for delivering erythromycin and sulfx to a patient comprising administering to said patient a composition comprising: a polypeptide; and erythromycin and sulfx covalently attached to said polypeptide.

22. The method of claim 21 wherein erythromycin and sulfx is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein erythromycin and sulfx is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXVIII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize ethinyl estradiol and dogestrel and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ethinyl estradiol and dogestrel. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises ethinyl estradiol and dogestrel covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, ethinyl estradiol and dogestrel is covalently attached to the polypeptide via the alcohol groups.

Preferably, the resultant peptide-ethinyl estradiol and dogestrel conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and ethinyl estradiol and dogestrel covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein ethinyl estradiol and dogestrel is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein ethinyl estradiol and dogestrel is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing ethinyl estradiol and dogestrel from said composition in a pH-dependent manner.

19. A method for protecting ethinyl estradiol and dogestrel from degradation. comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of ethinyl estradiol and dogestrel from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ethinyl estradiol and dogestrel to said polypeptide.

21. A method for delivering ethinyl estradiol and dogestrel to a patient comprising administering to said patient a composition comprising: a polypeptide; and ethinyl estradiol and dogestrel covalently attached to said polypeptide.

22. The method of claim 21 wherein ethinyl estradiol and dogestrel is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein ethinyl estradiol and dogestrel is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize lithium carbonate and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of lithium carbonate.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises lithium carbonate covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, lithium carbonate is covalently attached to the polypeptide via the carbonate group.

Preferably, the resultant peptide-lithium carbonate conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and lithium carbonate covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein lithium carbonate is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15.. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein lithium carbonate is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing lithium carbonate from said composition in a pH-dependent manner.

19. A method for protecting lithium carbonate from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of lithium carbonate from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching lithium carbonate to said polypeptide.

21. A method for delivering lithium carbonate to a patient comprising administering to said patient a composition comprising: a polypeptide; and lithium carbonate covalently attached to said polypeptide.

22. The method of claim 21 wherein lithium carbonate is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein lithium carbonate is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize LYM 1 and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of LYM 1. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises LYM 1 covalently attached to a polypeptide.

Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, LYM 1 is covalently attached to the polypeptide via the amino or carboxyl group.

Preferably, the resultant peptide-LYM 1 conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and LYM 1 covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein LYM 1 is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein LYM 1 is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing LYM 1 from said composition in a pH-dependent manner.

19. A method for protecting LYM 1 from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of LYM 1 from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching LYM 1 to said polypeptide.

21. A method for delivering LYM 1 to a patient comprising administering to said patient a composition comprising: a polypeptide; and LYM 1 covalently attached to said polypeptide.

22. The method of claim 21 wherein LYM 1 is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein LYM 1 is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXXI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize methylprednisolone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of methylprednisolone.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises methylprednisolone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, methylprednisolone is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-methylprednisolone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and methylprednisolone covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein methylprednisolone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein methylprednisolone is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing methylprednisolone from said composition in a pH-dependent manner.

19. A method for protecting methylprednisolone from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of methylprednisolone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching methylprednisolone to said polypeptide.

21. A method for delivering methylprednisolone to a patient comprising administering to said patient a composition comprising: a polypeptide; and methylprednisolone covalently attached to said polypeptide.

22. The method of claim 21 wherein methylprednisolone is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein methylprednisolone is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXXII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize rotavirus vaccine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of rotavirus vaccine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises rotavirus vaccine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, rotavirus vaccine is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-rotavirus vaccine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and rotavirus vaccine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein rotavirus vaccine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein rotavirus vaccine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing rotavirus vaccine from said composition in a pH-dependent manner.

19. A method for protecting rotavirus vaccine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of rotavirus vaccine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching rotavirus vaccine to said polypeptide.

21. A method for delivering rotavirus vaccine to a patient comprising administering to said patient a composition comprising: a polypeptide; and rotavirus vaccine covalently attached to said polypeptide.

22. The method of claim 21 wherein rotavirus vaccine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein rotavirus vaccine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXXIM The present invention provides several benefits for active agent delivery.

First, the invention can stabilize saquinavir and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of saquinavir. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises saquinavir covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, saquinavir is covalently attached to the polypeptide via the amido or hydroxy group.

Preferably, the resultant peptide-saquinavir conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and saquinavir covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein saquinavir is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein saquinavir is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing saquinavir from said composition in a pH-dependent manner.

19. A method for protecting saquinavir from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of saquinavir from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching saquinavir to said polypeptide.

21. A method for delivering saquinavir to a patient comprising administering to said patient a composition comprising: a polypeptide; and saquinavir covalently attached to said polypeptide.

22. The method of claim 21 wherein saquinavir is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein saquinavir is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXXIV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize arginine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of arginine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises arginine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, arginine is covalently attached to the polypeptide via the amino group.

Preferably, the resultant peptide-arginine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and arginine covaleritly attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heterpolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein arginine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein arginine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing arginine from said composition in a pH-dependent manner.

19. A method for protecting arginine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of arginine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching arginine to said polypeptide.

21. A method for delivering arginine to a patient comprising administering to said patient a composition comprising: a polypeptide; and arginine covalently attached to said polypeptide.

22. The method of claim 21 wherein arginine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein arginine is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXXV The present invention provides several benefits for active agent delivery.

First, the invention can stabilize heparin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of heparin. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises heparin covalently attached to a polypeptide.

Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, heparin is covalently attached to the polypeptide via the hydroxyl group.

Preferably, the resultant peptide-heparin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and heparin covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein heparin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein heparin is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing heparin from said composition in a pH-dependent manner.

19. A method for protecting heparin from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of heparin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching heparin to said polypeptide.

21. A method for delivering heparin to a patient comprising administering to said patient a composition comprising: a polypeptide; and heparin covalently attached to said polypeptide.

22. The method of claim 21 wherein heparin is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein heparin is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXXVI The present invention provides several benefits for active agent delivery.

First, the invention can stabilize thymosin alpha and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of thymosin alpha.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

Thymosin alpha is the subject of U. S. Patent Number 4,079, 127, herein incorporated by reference, which describes how to make that drug.

The composition of the invention comprises thymosin alpha covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, thymosin alpha is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-thymosin alpha conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising : a polypeptide; and thymosin alpha covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein thymosin alpha is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein thymosin alpha is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing thymosin alpha from said composition in a pH-dependent manner.

19. A method for protecting thymosin alpha from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of thymosin alpha from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching thymosin alpha to said polypeptide.

21. A method for delivering thymosin alpha to a patient comprising administering to said patient a composition comprising: a polypeptide; and thymosin alpha covalently attached to said polypeptide.

22. The method of claim 21 wherein thymosin alpha is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein thymosin alpha is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXEVII The present invention provides several benefits for active agent delivery.

First, the invention can stabilize montelukast and fexofenadine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of montelukast and fexofenadine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced.

The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises montelukast and fexofenadine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, montelukast and fexofenadine is covalently attached to the polypeptide via their respective carboxyl groups.

Preferably, the resultant peptide-montelukast and fexofenadine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and montelukast and fexofenadine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein montelukast and fexofenadine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein montelukast and fexofenadine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing montelukast and fexofenadine from said composition in a pH-dependent manner.

19. A method for protecting montelukast and fexofenadine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of montelukast and fexofenadine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching montelukast and fexofenadine to said polypeptide.

21. A method for delivering montelukast and fexofenadine to a patient comprising administering to said patient a composition comprising: a polypeptide; and montelukast and fexofenadine covalently attached to said polypeptide.

22. The method of claim 21 wherein montelukast and fexofenadine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein montelukast and fexofenadine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXXVIM The present invention provides several benefits for active agent delivery.

First, the invention can stabilize iodothyronine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of iodothyronine.

Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises iodothyronine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, iodothyronine is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-iodothyronine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and iodothyronine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein iodothyronine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein iodothyronine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing iodothyronine from said composition in a pH-dependent manner.

19. A method for protecting iodothyronine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of iodothyronine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching iodothyronine to said polypeptide.

21. A method for delivering iodothyronine to a patient comprising administering to said patient a composition comprising: a polypeptide; and iodothyronine covalently attached to said polypeptide.

22. The method of claim 21 wherein iodothyronine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein iodothyronine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXXXIX The present invention provides several benefits for active agent delivery.

First, the invention can stabilize iodothyronine and thyroxine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of iodothyronine and thyroxine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises iodothyronine and thyroxine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, iodothyronine and thyroxine is covalently attached to the polypeptide via a peptide bond.

Preferably, the resultant peptide-iodothyronine and thyroxine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and iodothyronine and thyroxine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein iodothyronine and thyroxine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein iodothyronine and thyroxine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing iodothyronine and thyroxine from said composition in a pH-dependent manner.

19. A method for protecting iodothyronine and thyroxine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of iodothyronine and thyroxine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching iodothyronine and thyroxine to said polypeptide.

21. A method for delivering iodothyronine and thyroxine to a patient comprising administering to said patient a composition comprising: a polypeptide; and iodothyronine and thyroxine covalently attached to said polypeptide.

22. The method of claim 21 wherein iodothyronine and thyroxine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein iodothyronine and thyroxine is released from said composition by a pH-dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.

CXL The present invention provides several benefits for active agent delivery. First, the invention can stabilize codeine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of codeine. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.

The composition of the invention comprises codeine covalently attached to a polypeptide.

Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

In the present invention, codeine is covalently attached to the polypeptide via a ketal bond.

Preferably, the resultant peptide-codeine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.

1. A pharmaceutical composition comprising: a polypeptide; and codeine covalently attached to said polypeptide.

2. The composition of claim 1 wherein said polypeptide is an oligopeptide.

3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.

4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.

5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.

6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.

7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

8. The composition of claim 1 wherein codeine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

9. The composition of claim 1 further comprising a microencapsulating agent.

10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.

11. The composition of claim 1 further comprising an adjuvant.

12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.

13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.

15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.

16. The composition of claim 1 wherein said composition is in the form of an oral suspension.

17. The composition of claim 1 wherein codeine is conformationally protected by folding of said polypeptide about said active agent.

18. The composition of claim 1 wherein said polypeptide is capable of releasing codeine from said composition in a pH-dependent manner.

19. A method for protecting codeine from degradation comprising covalently attaching said active agent to a polypeptide.

20. A method for controlling release of codeine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching codeine to said polypeptide.

21. A method for delivering codeine to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine covalently attached to said polypeptide.

22. The method of claim 21 wherein codeine is released from said composition by an enzyme-catalyzed release.

23. The method of claim 21 wherein codeine is released from said composition by a pH- dependent unfolding of said polypeptide.

24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.

25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.