Technical Field of the Invention

The present invention relates to a multiple-compression tablet comprising an immediate release inner core containing a sulfonylurea and an extended release outer coat containing a biguanide, wherein one surface of the inner core is exposed. Also provided are processes for the preparation of the tablet.

Background of the Invention

Diabetes mellitus of type II is a progressive metabolic disorder with diverse pathologic manifestations and is often associated with lipid metabolism and glycometabolic disorders. The long-term effects of diabetes result from its vascular complications: the microvascular complications of retinopathy, neuropathy and nephropathy and the macrovascular complications of cardiovascular, cerebrovascular and peripheral vascular diseases. Initially, diet regulation and exercise are the preliminary course of treatment for type II diabetes; however, these are generally followed by the administration of oral hypoglycemic agents. The current drugs used for managing type II diabetes and its precursor syndromes, such as insulin resistance, include biguanides and sulfonylureas, among others.

Biguanides, which include metformin, phenformin and buformin, help control the blood glucose level by decreasing hepatic glucose production and reducing the intestinal absorption of glucose. Sulfonylureas, which include glipizide, glimepiride, glyburide, glibonuride, glisoxepide, gliclazide acetohexamide, chlorpropamide, tolazamide, and tolbutamide, among others, help in controlling or managing NIDDM by stimulating the release of insulin from the pancreas.

Biguanides and sulfonylureas are individually commercially available in the form of tablets as either oral immediate-release (IR) formulations or controlled-release (CR) formulations. These are typically administered orally to patients in need thereof, in protocols calling for the single administration of the individual ingredient.

Approximately 20% to 25% percent of patients with type 2 diabetes demonstrate primary failure to sulfonylurea therapy. Gerich JE (1989), "Oral hypoglycemic agents," N. Engl. J. Med. 321(18):1231-1245. Secondary failure with sulfonylureas is known to occur in approximately 5% to 10% of the patients per year. Most sulfonylurea monotherapy patients (91.3%) typically progress to the addition of metformin. Brown JB et al., "The burden of treatment failure in type 2 diabetes", Diabetes Care, 27(7): 1535-40 (2004). Similarly, most metformin monotherapy patients (91.6%) eventually require the addition of a sulfonylurea.

Biguanides, particularly metformin, improve glucose tolerance but do not stimulate insulin secretion. Sulfonylureas lower blood glucose levels acutely by stimulating the release of insulin from the pancreas, an effect that is dependent upon properly functioning beta cells in the pancreatic islets. A combination therapy of a biguanide and sulfonylurea has a synergistic effect on glucose control, since both agents act by different, but complementary, mechanisms.

This combination therapy plays an important therapeutic role, since it allows an effective metabolic control in NIDDM. patients in whom the therapy with only sulfonylureas or only biguanides has become ineffective.

The use of combinations of metformin (a biguanide) and a sulfonylurea has been demonstrated to be synergistic in clinical trials when compared with the use of the individual agents separately. Physician's Desk Reference 2000, page 832. The monograph also advocates the use of combinations of metformin and sulfonylureas for patients not controlled on metformin alone. Several references pertain to pharmaceutical compositions having combinations of biguanides and sulfonylureas providing for controlled or immediate-release of both of the drugs. In order to formulate a single dosage form for the combination of a biguanide and a sulfonylurea, the biguanide, which has a shorter half-life, needs to be administered in a controlled or extended-release form; whereas the sulfonylurea, particularly glimepiride, which has a longer half-life, needs to be administered in immediate-release form. Further, a large disparity between the doses of the two agents and differences in their solubility and permeability profiles pose difficulties in their formulation into a single dosage form. Although combinations of two antidiabetic agents are well known in the art and are convenient to formulate, a combination requiring an extended-release of a high dose, water-soluble active, i.e., biguanide, and immediate-release of low-dose, water-insoluble or sparingly soluble active, i.e. sulfonylurea is difficult to achieve using a simple and cost- effective process.

WO 04/ 45622 discloses a dosage form which includes one layer or a core from which one high-dose, water-soluble active is released on a prolonged basis and a coating or layer from which low-dose, water-insoluble active is released on an immediate-release basis can be prepared in a manner that provides a high degree of uniformity. This application is incorporated herein in its entirety by reference.

At present, fixed dose combination ("FDC") therapy represents a largely unexplored opportunity to improve the management of type 2 diabetes. It has been observed that administering glimepiride along with metformin in Type 2 diabetics resulted in superior glycemic control compared to glimepiride or metformin monotherapy. Charpentier G et ah, "Improved glycemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients", Diabet. Med. 18: 828-834 (2001).

Summary of the Invention

It has now been discovered that a dosage form that includes a core from which one low-dose, water-insoluble active, i.e. the SU, is released on an immediate-release basis and an outer layer from which high-dose, water-soluble active, i.e. the biguanide, is released on an extended basis can be prepared in a manner that provides a high degree of uniformity.

This objective has been achieved by preparing a multiple-compression tablet comprising an inner core of SU and an outer coat of biguanide; wherein one surface of the inner core is exposed. These types of tablets are also referred to as inlay or bull's-eye tablets and these are similar to compression-coated tablets except that one surface of the coating is eliminated.

In one general aspect there is provided a pharmaceutical tablet dosage form of a biguanide and a sulfonylurea. The dosage form includes an extended release portion comprising a biguanide, one or more rate-controlling polymers and one or more pharmaceutically acceptable excipients and an immediate release core comprising a sulfonylurea and one or more pharmaceutically acceptable excipients, wherein the immediate release core is covered by the extended release portion from all sides except one surface. Emobidments of the pharmaceutical tablet dosage form may include one or more of the following features. For example, the biguanide, maybe metformin, phenformin or buformin and the sulfonylurea may be glipizide, glimepiride, glibonuride, glyburide, gliclazide, acetohexamide, chlorpropamide, tolazamide or tolbutamide.

The biguanide may be present from about 20% to about 80% by weight of the tablet. The sulfonylurea comprises from about 0.05% to about 10% by weight of the tablet. The sulfonylurea is released within about 2 hours and the biguanide is released within about 12 to about 16 hours.

The one or more rate controlling polymers may be hydrophilic polymers, hydrophobic polymers and combinations thereof. The one or more pharmaceutically acceptable excipients may be one or more of diluents, binders, lubricants, glidants, colorants and flavoring agents. The immediate release core of sulfonylurea may include one or more of disintegrants, surfactants and colorants.

The tablet dosage form may also include one or more of glitazones, insulin, alpha- glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors. In another embodiment, the dosage form further comprises one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin - converting enzyme inhibitors.

In another general aspect there is provided a process for the preparation of a pharmaceutical tablet dosage form which includes a sulfonylurea and a biguanide. The process includes granulating a sulfonylurea and one or more pharmaceutically acceptable excipients to form granules, compressing the sulfonylurea granules into tablets to form an immediate-release core, granulating a biguanide, one or more rate-controlling polymers and one or more pharmaceutically acceptable excipients to form granules, and compressing the biguanide granules around the sulfonylurea tablets such that one surface of the sulfonylurea tablets remains exposed.

In another general aspect there is provided a method of treating non-insulin dependent diabetes mellitus in a patient in need thereof. The method includes administering a pharmaceutical tablet dosage form which includes an extended release portion comprising a biguanide, one or more rate-controlling polymer(s) and one or more phaπnaceutically acceptable excipients and an immediate release core comprising a sulfonylurea and one or more pharmaceutically acceptable excipients. The immediate release core is covered by the extended release portion from all sides except one surface.

Embodiments of the method may include one or more of the following features.

For example, the dosage form further include one or more of glitazones, insulin, alpha- glucosidase inhibitors, meglitinides, fibrates, statins and squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors synthesis inhibitors and angiotensin - converting enzyme inhibitors.

The method may also include concurrently or sequentially administering one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors synthesis inhibitors and angiotensin - converting enzyme inhibitors.

Detailed Description of the Invention

The inventors have no surprisingly developed a pharmaceutical tablet dosage form for the combination of biguanide and sulfonylurea. The tablet includes an extended release portion comprising biguanide, one or more rate-controlling polymers and one or more pharmaceutically acceptable excipients. The tablet also includes an immediate release core comprising sulfonylurea and one or more pharmaceutically acceptable excipients, wherein the immediate release core is covered by the extended release portion from all sides except one surface.

Suitable biguanides include one or more of metformin, phenformin, buformin and other pharmaceutically acceptable forms of the biguanide class. For example, metformin may be used. The metformin include free base or a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts of metformin include hydrochloride, fumarate, hydrobromide, succinate and embonate. The daily effective dose of metformin may range from about 500 mg to about 2550 mg; particularly, the dose is a single dose of 250 mg to about 1000 mg. The metformin in the present dosage form may be present at a concentration of about 20% to about 80% by weight of the dosage form.

Suitable sulfonylureas may include one or more of glipizide, glimepiride, glibonuride, glyburide, gliclazide, acetohexamide, chlorpropamide, tolazamide, and tolbutamide. Also included are pharmaceutically acceptable forms of sulfonylureas including their salts, solvates, hydrates, polymorphs, complexes and other such products. For example, glimepiride may be used. The daily effective dose of glimepiride may range from about 1 mg to about 8 mg once a day. In the present dosage form, the glimepiride may be present from about 0.05% to about 10% by weight of the dosage form.

The biguanide may be incorporated in an extended-release portion by dispersing in a rate-controlling polymer matrix, as described in WO 03/028704 and WO 03/039527.

The term matrix, as used herein, refers to a uniform mixture of a biguanide, one or more rate-controlling polymers and one or more pharmaceutically acceptable excipients.

Suitable rate-controlling polymers may be hydrophilic, hydrophobic or mixtures thereof. These rate-controlling polymers may be present at a concentration of from about 5% to about 75% by weight of the dosage form. The rate-controlling polymers are uniformly dispersed throughout the matrix to achieve uniform drug release.

Suitable hydrophilic rate-controlling polymers may include one or more of cellulose derivatives, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl, cellulose hydroxymethyl cellulose, carboxy methyl cellulose, methyl cellulose, sodium carboxymethyl cellulose and mixtures thereof; polyvinyl pyrrolidone, microcrystalline cellulose, polysaccharides, polyalkylene glycols, starch and starch derivatives, alginic acid and salts of alginic acid and mixtures thereof.

Suitable hydrophobic polymers may be include one or more of ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, copolymers of acrylic or methacrylic acid esters, waxes, shellac, hydrogenated vegetable oil and mixtures thereof.

In addition to the active ingredient and one or more rate controlling polymers, the extended release portion may also include one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include one or more of diluents, binders, lubricants, glidants, colorants and flavoring agents.

Suitable diluents may include one or more of microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose, dextrose, maltodextrin and mixtures thereof. Suitable binders may include one or more of polyvinyl pyrrolidone, hydroxyl propylcellulose, hydroxyl ethyl cellulose, hydroxyl propyl methylcellulose, gums, waxes, polyvinylalcohol and mixtures thereof.

Suitable lubricants may include one or more of silicon dioxide, colloidal silicon dioxide, talc, stearic acid, magnesium stearate, magnesium trisilicate, sodium benzoate, polyethylene glycol, sodium lauryl sulphate, fumaric acid, zinc stearate, paraffin, glyceryl behenate and mixtures thereof.

Suitable glidants may include one or more of talc, silicon dioxide, colloidal silicon dioxide, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate. The extend release portion may be formulated by any pharmaceutically acceptable technique including dry granulation, wet granulation, compaction, fluidized bed granulation and extrusion-spheronization.

The inner portion of the present invention may include one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include diluents, binders, lubricants, surfactants, disintegrants and pigments/colorants.

The inner portion of the present invention may include one or more pharmaceutically acceptable excipients including diluents, binders, lubricants, surfactants, disintegrants and pigments/colorant.

Suitable disintegrants may include one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose and mixtures thereof.

Suitable surfactants may include one or more of amphoteric, non-ionic, cationic or anionic. For example, the surfactant may be sodium lauryl sulphate, monoleate, monolaurate, monopalmitate, monostearate or other esters of polyoxyethylene sorbitan, polyethylene glycol laurate, lecithins, propylene glycol alginate, bile acids, phospholipids, propylene glycol laurate and mixtures thereof.

The dosage form may also include one or more of glitazones, insulin, alpha- glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors. In another embodiment, the dosage form further comprises one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin - converting enzyme inhibitors.

The compression-coated tablets of the present invention may be manufactured by a three-step procedure involving: (1) preparation of the immediate release core and extended release portion granulations from SU and biguanide, respectively, (2) compressing the immediate release core granulation to provide the immediate release core tablet, and subsequently (3) compressing an extended release portion granulation around the core tablet, in such a manner that one surface of the inner core remains exposed.

Also provided are processes for preparing a pharmaceutical tablet dosage form for the combination of biguanide and sulfonylurea. The process includes the steps of:

(a) granulating sulfonylurea and one or more pharmaceutically acceptable excipients to form granules,

(b) compressing the sulfonylurea granules into tablets to form immediate- release core,

(c) granulating biguanide, one or more rate-controlling polymers and one or more pharmaceutically acceptable excipients to form granules,

(d) compressing biguanide granules around sulfonylurea tablets such that one surface of the sulfonylurea tablets remains exposed.

Also provided herein are methods for the treatment of non-insulin dependent diabetes mellitus in a patient in need thereof. The method includes administering a pharmaceutical tablet dosage form which include an extended release portion comprising biguanide, one or more rate-controlling polymer and one or more pharmaceutically acceptable excipients, and an immediate release core comprising sulfonylurea and one or more pharmaceutically acceptable excipients, wherein the immediate release core is covered by the extended release portion from all sides except one surface.

The methods may include one or more of the following embodiments. For example in one embodiment, the method further includes concurrently or sequentially administering one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitimdes, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors. In another embodiment, the dosage form further comprises one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin - converting enzyme inhibitors. The following non-limiting examples illustrate the process for making the oral dosage form disclosed in various embodiments of the specification. Example 1

Procedure: 1. Glimepiride, microcrystalline cellulose (Part I), lactose, polyvinyl pyrrolidone, colour (Part I) and croscarmellose sodium were blended and granulated with purified water. 2. The granules were Sried, sized, blended with sodium starch glycolate, microcrystalline cellulose (Part II), colour (Part II) and magnesium stearate and compressed to form tablets. 3. Metformin hydrochloride was milled and mixed with microcrystalline cellulose and purified water was added to the blend to wet the mass.

4. Sodium carboxymethyl cellulose, hypromellose and a part of magnesium stearate were mixed with blend of step 3.

5. Granules were prepared by roller compaction of the blend of step 4.

6. The granules were lubricated with magnesium stearate and filled into the" die of the tabletting machine.

7. One glimepiride tablet was placed over these metformin granules and compressed to form the inlay tablet of an immediate release SU in an extended release matrix of a biguanide.

Tables 1 and 2 provide the in- vitro release profiles of the metformin and the glimepiride respectively from the inlay tablets prepared by the composition and process of Example 1, in phosphate buffer 7.8 (900 ml), USP 2 at 75 rpm.

Table 1: Release profile of metformin from inlay tablets prepared as per Example 1 in Phosphate buffer pH 7.8 (900ml), USP 2 at 75 rpm.

Table 2: Release profile of glimepiride from inlay tablets prepared as per Example 1 in Phosphate buffer pH 7.8 (900ml), USP 2 at 75 rpm.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.