NOVEL DRUG DELIVERY SYSTEM

This patent application claims priority from Australian Provisional Patent Application No. 2010902059 titled "Novel drug delivery system" and filed 6 May 2010, the entire contents of which are hereby incorporated by reference.

FIELD

The present invention relates to pharmaceutical dosage forms and, more specifically, to patches for the transmucosal delivery of pharmacologically active agents. The present invention also relates to methods of treatment using the dosage forms. BACKGROUND

There is a constant need for methods for the safe and effective administration of drugs to humans and animals. It is also important that the administration regime is as simple and non-invasive as possible in order to maintain a high level of patient compliance. Oral administration is commonly used due to the ease, convenience, and relative lack of pain during administration. As a result, the majority of pharmaceutical dosage forms today are administered in the form of tablets, capsules, powders, granules or liquids.

Despite their popularity, conventional oral dosage forms are not necessarily the most efficacious. Some patients, particularly geriatrics and pediatrics, have difficulty ingesting solid oral dosage forms.

Moreover, the oral administration route is complicated because of the hostile environment presented by the gastro-intestinal (GI) tract where significant quantities of the administered drug are lost due to acid hydrolysis and the hepatic "first pass" effect. In addition, not all drugs can be incorporated into oral dosage forms due to their specific physicochemical properties. Most importantly, solid oral dosage forms are impractical for the treatment of acute conditions for which a rapid pharmacological action is required, since drug release from solid oral dosage forms is not immediate as it has to first undergo disintegration and/or dissolution in the GI tract prior to releasing the drug.

Transmucosal delivery is an attractive alternative to oral delivery as it provides a simple, non-invasive delivery regime and the dosage forms can be administered by a care-giver or patient with minimal discomfort. Further, transmucosal delivery leads to relatively rapid absorption and high bioavailability, thereby allowing for lower doses, and generating potentially fewer side effects.

Of the possible transmucosal delivery routes, buccal administration is attractive because the direct drainage of blood from the buccal cavity into the internal jugular vein means that the first pass effect can be avoided, thereby increasing the bioavailability of drugs that are poorly bioavailable. Also, the relatively low level of enzymatic activity and a relatively stable pH in the buccal cavity serves to provide a means, for administering sensitive drugs.

Dosage forms that provide local or systemic drug delivery in the buccal cavity typically contain drug and a mucoadhesive agent. Three different forms of buccal mucoadhesive patches are generally available based on their geometry, and details of these are shown in Figure 1 . In one form of patch, the direction of drug release includes bi-directional drug release, both into the oral cavity and the mucosa (diagrams a, b and f)- This type of dosage form suffers from significant drug loss due to swallowing. In another form, the patch contains an impermeable coating on every face except the one that is in contact with the buccal mucosa and, therefore, drug is released uni-directionally into the mucosa only (diagrams c, e and g); drug loss into the oral cavity is prevented in this type of patch. Finally, drug can also be released uni- directionally into the oral cavity only (diagram d).

Uni-directional drug release into the mucosa is desirable when drugs for systemic therapeutic effect are easily degraded in the gastric tract or suffer from hepatic pre-systemic metabolism. In addition, unidirectional drug release prevents drug release to the rest of the oral cavity, thereby avoiding any adverse drug taste and irritation and reducing other side effects caused by inaccurate dosage.

A water-impermeable backing layer is normally used to achieve uni-directional drug release into mucosa ( 1 , 2). Commonly, the drug is incorporated within a mucoadhesive matrix by dissolving the drug in a polymer solution which is then cast and dried to form patches or mixed together with polymer mixtures and compressed into mucoadhesive tablets. However, there are several disadvantages with this technique of drug incorporation. First, dosage uniformity is highly dependent on drug distribution within the polymer matrix, which is difficult to control, especially when prepared by solvent casting. Secondly, binding between drug molecules and polymer molecules can result in changes in the mucoadhesive properties of the mucoadhesive polymer and alter the appearance and performance of the final mucoadhesive product. Finally, an undesired and uncontrollable delay in drug release is quite common for patches where this drug incorporation technique is employed, since the drug must first diffuse from the mucoadhesive polymers before reaching the surface of the mucosa.

There is a need for dosage forms for buccal administration of drugs that overcome at least one of the problems associated with prior art dosage forms.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in any country before the priority date of each claim of this application. SUMMARY OF THE INVENTION

The present invention has arisen from research into solid dosage forms for buccal administration and, in particular, the discovery that drugs can be delivered uni-directionally to the oral mucosal surface from solid dosage forms that are incorporated into mucoadhesive patches.

In a first aspect, the present invention provides a transmucosal delivery device suitable for delivering a pharmacologically active agent to an oral mucosal surface of a subject, the device comprising: at least one solid core comprising the active agent; a bioadhesive layer; and an impermeable backing layer extending over the core with at least one surface of the core exposed and wherein the device is able to be placed on the oral mucosal surface with the exposed surface and the bioadhesive layer in contact therewith such that the backing layer substantially prevents release of the active agent into the oral cavity of the subject.

In some embodiments, the solid core is a tablet, pellet, powder, granule, film or capsule comprising the active agent. In some embodiments, the solid core is a compressed solid core, such as a tablet or a pellet. In some embodiments, the compressed solid core is a tablet comprising the active agent and suitable tabletting excipients. The tablet may be a single- or a multi-layered tablet.

In some embodiments, the bioadhesive layer and the impermeable backing layer extend over the core with at least one surface of the core exposed.

In some embodiments, the active agent is comprised within the core only and substantially no active agent is contained within the bioadhesive layer.

In some embodiments, the bioadhesive layer comprises a film-forming polymer and a bioadhesive polymer. In some embodiments, the bioadhesive layer comprises a polyacrylic acid polymer and a cellulose polymer.

In some embodiments, the impermeable backing layer is an ethylcellulose polymer. In a second aspect, the present invention provides a process for producing a transmucosal delivery device suitable for delivering a pharmacologically active agent to an oral mucosal surface of a subject, the process comprising:

- providing a solid core comprising the active agent;

- forming a bi-layer laminate patch comprising a bioadhesive layer and an impermeable backing layer extending over the bioadhesive layer;

- assembling the solid core and the bi-layer laminate patch to form a tri-layer laminate patch in which the bi-layer laminate patch extends peripherally over the core so as to leave at least one surface ,

4

of the core exposed and the backing layer is able to be sealed against a mucosal surface with the exposed surface of the core in contact therewith.

In some embodiments, the solid core is a compressed solid core and the step of providing a solid core comprises compressing the active agent and, optionally, excipients to form the compressed solid core.

In a third aspect, the present invention provides a kit of parts that can be used to form a transmucosal delivery device suitable for delivering a pharmacologically active agent to an oral mucosal surface of a subject, the kit comprising;

- at least one solid core comprising the active agent;

- a bi-layer laminate patch comprising a bioadhesive layer and an impermeable backing layer extending over the bioadhesive layer,

wherein the bi-layer laminate patch is capable of being positioned peripherally over the core so as to leave at least one surface of the core exposed and the backing layer is able to.be sealed against a mucosal surface with the exposed surface of the core in contact therewith.

In a fourth aspect, the present invention provides a method of treating or alleviating one or more symptoms associated with a health condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmacologically active agent using a transmucosal delivery device according to the first aspect.

In a fifth aspect, the present invention provides a method for the prophylaxis of a disease state or health condition in a subject, the method comprising administering to the subject an immunogically active agent capable of eliciting an immune response in the subject, wherein the administering comprises using a transmucosal delivery device according to the first aspect.

In a sixth aspect, the present invention provides a method of cancer vaccination to either prevent infections with cancer-causing viruses and treating existing cancer or prevent the development of cancer in certain high risk subjects, the method comprising administering to the subject tumor antigens using a transmucosal delivery device according to the first aspect.

In a seventh aspect, the present invention provides for the use of a transmucosal delivery device according to the first aspect for the preparation of a medicament for the treatment of one or more symptoms associated with a health condition in a subject.

In an eighth aspect, the present invention provides for the use of a transmucosal delivery device according to the first aspect for the preparation of a vaccine for the prevention of a disease state or health condition in a subject. In a ninth aspect, the present invention provides for the use of a transmucosal delivery device according to the first aspect for the preparation of a cancer vaccine for the prevention or therapy of a cancer. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows schematic cross sections of various prior art transmucosal delivery device configurations;

Figure 2 shows a schematic cross section of an embodiment of a transmucosal delivery device of the present invention;

Figure 3 shows a schematic of a tensile test jig;

Figure 4 provides graphical results showing the release of nicotine from tri-laminate patches containing nicotine base or nicotine polacrilex and release of nicotine from the backing layer side (* p <0.05, significant difference, paired samples t-tests);

Figure 5 provides graphical results showing the effect of adsorbents on drug release from nicotine tri- laminate patches; Figure 6 provides graphical results showing the effect of concentration on permeation of nicotine from aqueous solution through porcine buccal mucosa;

Figure 7 provides graphical results showing the permeation of nicotine from tri-laminate patches containing nicotine base or nicotine polacrilex;

Figure 8 provides graphical results showing the relationship between nicotine available in the donor compartment and the permeation flux.

DESCRIPTION OF EMBODIMENTS

The present invention provides a transmucosal delivery device, an embodiment of which is shown in Figure 2. The device 10 is suitable for delivering a pharmacologically active agent to an oral mucosal surface 12 of a subject. The device is suitable for the transmucosal delivery of a range of active agents. The term "transmucosal" and similar terms as used herein means entering through, or across, a mucous membrane. Transmucosal administration enables the active agent to enter the circulatory system thereby enabling it to have a systemic effect. The delivery device described herein may be particularly suitable for the buccal delivery of an active agent. The term "buccal delivery" and similar terms as used herein means a delivery of an active agent for absorption across one or more membranes in the mouth, including the buccal mucosa, buccal gingiva, mucous membrane of the tongue, sublingual membrane and the soft palate.

The device 10 is suitable for delivering a pharmacologically active agent in order to treat or alleviate one or more symptoms associated with a health condition in a subject. The term "health condition" as used herein means a state of altered physical or mental well-being in a subject. Health conditions include, but are not limited to: disease states, altered emotional states, substance dependence (eg nicotine

dependence), etc. The device 10 comprises a solid core 14 comprising the active agent and a bioadhesive layer 16. In the illustrated embodiment, the bioadhesive layer 16 extends peripherally over the core 14 so that a surface 1 8 of the core 14 is exposed. An impermeable backing layer 20 extends over the core 14 with the surface 1 8 of the core exposed. The device 10 is able to be placed on the oral mucosal surface 12 with the exposed surface 1 8 and the bioadhesive layer 16 in contact therewith such that the backing layer 20 substantially prevents release of the active agent into the oral cavity of the subject.

In an embodiment that is not illustrated, the bioadhesive layer may extend peripherally from the core but without covering the core. For example, the core may be positioned centrally on a patch comprising the backing layer, and the bioadhesive layer mayjse applied to the backing layer peripherally around the core.

As seen in Figure 2, when the device 10 is placed on the oral mucosal surface 18 the backing layer 20 substantially encases the core 14 and the bioadhesive layer 16 so that release of the active agent into the oral cavity is substantially prevented. Other configurations of the device (other than the illustrated configuration) are also possible. For example, the backing layer 20 may only cover the core 14 and the bioadhesive layer 1 may be external to the backing layer coated core. In this embodiment, diffusion of the active agent into the bioadhesive layer and the oral cavity is substantially prevented by the backing layer.

In some embodiments, the active agent is comprised within the core only and substantially no active agent is contained within the bioadhesive layer. As a result, there are no diffusion problems associated with transport of the active agent through the bioadhesive polymer as is the case with some prior art delivery devices. Furthermore, by having the active agent in the core only leads to better content uniformity and more consistent content uniformity than a standard patch in which the drug is mixed into the bioadhesive layer. Further, the drug release characteristics for the active agents are the same or similar to those observed for the particular dosage form used.

Despite these advantages, it is also contemplated that in some embodiments the bioadhesive layer may contain some active agent. These embodiments may provide a modified release dosage form in which the _η active agent is released from the core at a different rate than it is released from the bioadhesive layer. These embodiments may also provide the opportunity to include a different active agent in the bioadhesive layer than in the core. The term "solid core" and similar terms as used herein means a coated or uncoated particle comprising a mixture of one or more active agents and, optionally, excipients. The solid core may be a tablet, microparticle, film or capsule. The solid core may be shaped.

In some embodiments, the solid core is a compressed solid core. Compressed solid cores can be prepared by compressing solid ingredients together. The compressed solid core may be a tablet or pellet containing the active agent and suitable tabletting excipients.

To produce the solid core, the active agent may be dry blended with suitable excipients before being transferred to a press and pressed into tablets or pellets using standard procedures. In the case of tablets, the dry ingredients may be tabletted by using a single-punch tablet machine or a rotary type tablet machine.

In some embodiments, the compressed solid core is a tablet. As used herein, the term "tablet" includes minitablets within its scope. In some embodiments, the tablet is a unitary (or single-layer) tablet. In these embodiments, the active agent and suitable excipients are mixed and compressed together. In these embodiments, the active agent will normally be dispersed relatively uniformly throughout the tablet. In these embodiments, the core may have a diameter in the range of about 5 mm to about 10 mm. In some embodiments, the core has a diameter of about 7 mm. In some other embodiments, the tablet is a multi-layer tablet. Multi-layer tablets contain two or more distinct layers within a single compressed dosage form. Each distinct layer may contain a different active agent, different amounts of the same active agent, different excipient(s), and/or different amounts of excipient(s). The solid core may contain excipients that are added so as to provide a desirable drug release profile.

Alternatively, or additionally, the solid core may contain excipients or agents for permeation adjustment to achieve targeted drug permeability from the core.

Suitable tabletting excipients will be known to the person skilled in the art and may include, for example, permeation enhancers, disintegrants, diluents, fillers, lubricants, glidants, colourants and flavours.

A variety of materials may be used as diluents or fillers. Examples include lactose, starch,

dextrose, mannitol, sorbitol, microcrystalline cellulose and mixtures thereof. Permeation enhancers are known in the art and suitable permeation enhancers include: ethers such as diethylene glycol monoethyl ether and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231 , 182, 1 84), Tween (20, 40, 60, 80) and lecithin; alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyols and esters thereof such as polyethylene glycol, and polyethylene glycol monolaurate; amides and other nitrogenous compounds such as urea, dimethylacetamide, dimethylformamide, 2-pyrrolidone, 1 -methyl -2 -pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly citric acid and succinic acid.

Suitable disintegrants may include crosslinked polymers such as crospovidone (crosslinked

polyvinylpyrrolidone) and croscarmellose (crosslinked sodium carboxymethylcellulose).

Lubricants and glidants are usually employed when producing tablets. Examples of lubricants and glidants are hydrogenated vegetable oils, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc, mixtures thereof, and others that are well known to the person skilled in the art.

Additives such as colouring agents and pigments may also be added. Suitable colouring agents and pigments include titanium dioxide and dyes suitable for food. Colouring agents or pigments may be used to provide a visual indicator of a certain property for individual transmucosal delivery devices. For example, different colours may be used to denote different dosages of active agent.

Instead of directly tabletting the active agent with excipients, the active agent and excipients may first be granulated to form core elements and then be blended with tablet excipients and pressed into a tablet. The granulation process may be a "wet granulation" process which means that water or other solvent is used in the granulation step. An alternative process for producing the core is to apply a layer of active ingredient over inert cores. The layer of active ingredient may be applied by spraying a solution of the active ingredient onto the inert cores. A drying step may be used to remove some or all of the solvent from the core.

In alternative embodiments that are not illustrated, the solid core comprises microparticles. Microparticles are formulations of the active agent in discrete particulate form! Microparticles include microspheres; spherical particles, microcapsules, particles, multiparticulates, granules, spheroids, beads, pellets and powders. A plurality of microparticles may be attached to the bioadhesive layer. Microparticles containing the active agent can be prepared using standard methods and, optionally, standard excipients. For example, pellets may be formed by compressing a mixture of active agent and excipients. Granules may be formed using granulation processes known to the person skilled in the art, such as wet granulation, dry granulation (e.g. slugging, roller compaction), direct compression, extrusion, spheronisation, melt granulation, and rotary granulation. Powders may be formed by grinding solid active agents to a desired particle size.

In some embodiments, the solid core is a capsule. As used herein, the term "capsule" includes

"minicapsules" within its scope. Capsules may be formed using methods known to the person skilled in the art. Capsules may be soft or hard capsules and suitable capsules include gelatin, starch or HPMC capsules. Capsules may contain a liquid carrier such as polyethylene glycol Or a fatty oil. Capsules are particularly suitable for use with active agents that are in a liquid form or in the form a solution or suspension. However, capsules may also be filled with microparticles, such as pellets, granules of powders, containing the active agent.

A core formed by any of the methods described above may be incorporated directly into the transmucosal delivery device or may first be coated with a pharmaceutically-acceptable coating layer. The coating step may be performed to confer controlled release or other properties to the core. Suitable methods for coating cores, such as tablets, are known to the person skilled in the art.

The "pharmacologically active agent" may be any compound that has a therapeutic effect on the human or animal body in the treatment or prevention of a condition. Pharmacologically active agents include pharmaceutical, nutraceutical, cosmetic or veterinary active agents. The term "pharmacologically active" is used herein in a broad sense to include agents that have a direct pharmacological effect on a host, as well as those that have an indirect or observable effect on a host. As such, it will be appreciated that the term includes prodrugs of an agent which, in vivo, exerts the pharmacological effect.

A benefit of the dosage form of the present invention is that an active agent with unstable

physicochemical properties, such as a highly volatile or light sensitive compound, can be incorporated into the core. Alternatively, or additionally, an active agent with a certain drug release requirement, such as fast drug release or sustained drug release can be incorporated into the core and the drug release may be similar to that achieved from known tablets. Alternatively, or additionally, vaccines can be incorporated into the core and be delivered without the requirement of needles. Suitable pharmacologically active agents may be selected from:

Alimentary system antidiarrhoeals such as diphenoxylate, loperamide and hyoscyamine; , _Q

Cardiovascular system agents including:

• Antihypertensives such as hydralazine, minoxidil, captopril, enalapril, clonidine, prazosin,

debrisoquine, diazoxide, guanethine, methyldopa, reserpine and trimetaphan;

• Calcium channel blockers such as diltiazem, felodopine, amlodipine, nitrendipine, nifedipine and verapamil;

• Proton pump inhibitors such as lansoprazole, omeprazole and pantaprazole;

• Antiarrhythmics such as amiodarone, flecainide, disopyramide, procainamide, mexiletene and quinidine;

• Antiangina agents such as glyceryl trinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate, perhexilene, isosorbide dinitrate and nicorandil;

• Beta-adrenergic blocking agents such as alprenolol, atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol, nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol and timolol maleate;

• Cardiotonic glycosides such as digoxin and other cardiac glycosides and theophylline derivatives; · Adrenergic stimulants such as adrenaline, ephedrine, fenoterol, isoprenaline, orciprenalihe, rimeterol, salbutamol, salmeterol, terbutaline, dobutamine, phenylephrine, phenylpropanolamine, pseudoephedrine and dopamine;

• Vasodilators such as cyclandelate, isoxsuprine, papaverine, dipyrimadole, isosorbide dinitrate, phentolamine, nicotinyl alcohol, co-dergocrine, nicotinic acid, glyceryl trinitrate, pentaerythritol tetranitrate and xanthinol; and

• Antimigraine preparations such as ergotamine, dihydroergotamine, methysergide, pizotifen and sumatriptan;

Drugs affecting blood and haemopoietic tissues including:

· Anticoagulants and thrombolytic agents such as warfarin, dicoumarol, low molecular weight heparins such as enoxaparin, and streptokinase and its active derivatives; and

• Haemostatic agents such as aprotinin, tranexamic acid and protamine;

Drugs affecting the central nervous system including:

· Analgesics;

• Antipyretics including the opioid analgesics such as buprenorphine, dextromoramide,

dextropropoxyphene, fentanyl, alfentanil, sufentanil, hydromorphone, methadone, morphine, oxycodone, papaveretum, pentazocine, pethidine, phenoperidine, codeine and dihydrocodeine. Others include acetylsalicylic acid (aspirin), paracetamol and phenazone;

· Hypnotics and sedatives such as the barbiturates, amylobarbitone, butobarbitone and

pentobarbitone and other hypnotics and sedatives such as choral hydrate, chlormethiazole, hydroxyzine and meprobamate; and • Antianxiety agents such as the benzodiazepines, alprazolam, bromazepam, chlordiazepoxide, elobazam, chJorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam, temazepam and triazolam; Agents to treat food allergies such as sodium cromoglicate;

Neuroleptic and antipsychotic drugs such as the phenothiazines, chlorpromazine, fluphenazine, pericyazine, perphenazine, promazine, thiopropazate, thioridazine and trifluoperazine and the butyrophenones, droperidol and haloperidol, and other antipsychotic drugs such as pimozide, thiothixene and lithium;

Antidepressants such as the tricyclic antidepressants amitryptyline, clomipramine, desipramine, dothiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline and trimipramine; tetracyclic antidepressants such as mianserin; monoamine oxidase inhibitors such as isocarboxazid, phenelizine, tranylcypromine and moclobemide; selective serotonin re-uptake inhibitors such as fluoxetine, paroxetine, titalopram, fluvoxamine and sertraline; and tetracyclic antidepressants such as mirtazapine and any metabolites, salts enantiomers (including esmirtazapine), solvents, non-covalent complexes, chelates, hydrates, crystalline or amorphous forms thereof; Central nervous system stimulants such as caffeine;

Anti-Alzheimer's agents such as tacrine;

Anti-Parkinson agents such as amantadine, benserazide, carbidopa, levodopa, benztropine, biperiden, benzhexol, procyclidine and dopamine-2 agonists such as S(-)-2-(N-propyl-N-2thienylethylamino)-5- hydroxytetralin (N- 0923);

Lipid regulating drugs such as statins; Drugs affecting bone metabolism such as calcitonin and bisphosphonates;

Anticonvulsants such as phenytoin, valproic acid, primidone, phenobarbitone, methylphenobarbitone and carbamazepine, ethosuximide, methsuximide, phensuximide, sulthiame and clonazepam; Antiemetics and antinauseants such as the phenothiazines, prochloperazine, thiethylperazine and 5HT-3 receptor antagonists such as ondansetron and granisetron and others such as dimenhydrinate,

diphenhydramine, metoclopramide, dompehdone, hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, clebopride and brompride; ^• Musculoskeletal system drugs including:

• Non-steroidal anti-inflammatory agents including their racemic mixtures or individual

enantiomers where applicable, such as ibuprofen, flurbiprofen, ketoprofen, aclofenac, diclofenac, aloxiprin, aproxen, aspirin, diflunisal, fenoprofen, indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxicam, salicylamide, salicylic acid, sulindac, desoxysulindac, tenoxicam, tramadol, ketoralac, salicylamide, salicylic acid, flufenisal, salsalate, triethanolamine salicylate, aminopyhne, antipyhne, oxyphenbutazone, apazone, cintazone, flufenamic acid, clonixeril, clonixin, meclofenamic acid, flunixin, colchicine, demecolcine, allopurinol, oxypurinol, benzydamine hydrochloride, dimefadane, indoxole, intrazole, mimbane hydrochloride, paranylene hydrochloride, tetrydamine, benzindopyrine hydrochloride, fluprofen, ibufenac, naproxol, fenbufen, cinchophen, diflumidone sodium, fenamoie, flutiazin, metazamide, Ietimide hydrochloride, nexeridine hydrochloride, octazamide, molinazole, neocinchophen, nimazole, proxazole citrate, tesicam, tesimide, tolmeti, and trifiumidate;

• Antirheumatoid agents such as penicillamine, aurothioglucose, sodium aurothiomalate,

methotrexate and auranofin;

• Muscle relaxants such as baclofen, diazepam, cyclobenzaprine hydrochloride, dantrolene,

methocarbamol, orphenadrine and quinine; and

• Agents used in gout and hyperuricaemia such as allopurinol, colchicine, probenecid and

sulphinpyrazone;

Hormones and steroids including:

• Estrogens such estradiol, estriol, estradiol benzoate, estradiol 17 beta.- cypionate, estradiol

enanthate, estradiol propionate, estrone, ethinylestradiol, fosfestrol, dienestrol mestranol, stilboestrol, dienoestrol, epioestriol, estropipate diethylstilbestrol, chlorothanisene, conjugated estrogenic hormones, Polyestradiol phosphate and zeranol and mixtures thereof;

• Progesterone and progestins such as norethisterone, norethisterone acetate, gestodene,

levonorgestrel, allylestrenol, anagestone, desogestrel, dimethisterone, dydrogesterone, ethisterone, ethynodiol, Ethynodiol diacetate, Etonogestrel, gestodene, ethinylestradiol, haloprogesterone, 17-hydroxy-16- methylene-progesterone, 17. alpha.- hydroxyprogesterone, lynestrenol, medroxyprogesterone, melengestrol, norethindrone, norethynodrel, norgesterone, Gestonorone, Norethisterone, norgestimate, norgestrel, Levonorgestrel, norgestrienone, norvinisterone, pentagestrone, MENT (7-methyl- 19-testosterone); Norelgestromin, and trimigestone Drospirenone, Tibolone, and megestrol and mixtures thereof;

• Antiandrogens such as cyproterone acetate and danazol;

• Antiestrogens such as tamoxifen- and epitiostanol and the aromatase inhibitors, exemestane and 4- hydroxy-androstenedione and its derivatives; • Androgens and anabolic agents such as androisoxazole, androstenediol, bolandiol, bolasterone, clostebol, ethylestrenol. formyldienolone, 4-hydroxy-19- nortestosterone, methandriol, methenolone, methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone and trenbolone. Androgenic steroids can include boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17. alpha.- methyltestosterone 3- cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone 1 7-chloral hemiacetal, testosterone propnonate, testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA), androstenedione (Andro): an androstenediol, androsterone, dihydrotestosterone (DHT) and androstanolone and derivatives thereof;

• 5-alpha reductase inhibitors such as finasteride, turosteride, LY-191704 and MK-306;

• Corticosteroids such as betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21 -phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21 - acetate methylprednisolone, prednisolone, prednisolone 21 -phosphate, prednisone,

triamcinolone, triamcinolone acetonide;

• Steroidal antiinflammatory agents such as cortodoxone, fluoracetonide, fludrocortisone,

difluorsone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and its other esters, chloroprednisone, clorcortelone, descinolone, desonide, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide, flucortolone,

fluoromethalone, fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, cortisone acetate, hydrocortisone cyclopentylpropionate, cortodoxone, flucetonide, fludrocortisone acetate, flurandrenolone acetonide, medrysone, amcinafal, amcinafide, betamethasone, betamethasone benzoate, chloroprednisone acetate, clocortolone acetate, descinolone acetonide, desoximetasone, dichlorisone acetate, difluprednate, flucloronide, flumethasone pivalate, flunisolide acetate, fluperolone acetate, fluprednisolone valerate, paramethasone acetate, prednisolamate, prednival, triamcinolone hexacetonide, cortivazol, formocortal and nivazol;

• Pituitary hormones and their active derivatives or analogs such as corticotrophin, thyrotropin, follicle stimulating hormone (FSH), luteinising hormone (LH) and gonadotrophin releasing hormone (GnRH);

• Hypoglycaemic agents such as insulin, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide and metformin;

• Thyroid hormones such as calcitonin, thyroxine and liothyronine and antithyroid agents such as carbimazole and propylthiouracil; and

• Other miscellaneous hormone agents such as octreotide; Pituitary inhibitors such as bromocriptine;

Ovulation inducers such as clomiphene; Genitourinary system drugs including:

• Diuretics such as the thiazides, related diuretics and loop diuretics, bendrofluazide,

chlorothiazide, chlorthalidone, dopamine, cyclopenthiazide, hydrochlorothiazide, indapamide, mefruside, methycholthiazide, metolazone, quinethazone, bumetanide, ethacrynic acid and frusemide and potassium sparing diuretics, spironolactone, amiloride and triamterene;

· Antidiuretics such as desmopressin, lypressin and vasopressin including their active derivatives or analogs;

e Obstetric drugs including agents acting on the uterus such as ergometrine, oxytocin and

gemeprost; and

• Prostaglandins such as alprostadil(PGEi), prostacyclin (PGI2), dinoprost (prostaglandin F2-alpha) and misoprostol;

Antimicrobials including:

• Cephalosporins such as cephalexin, cefoxytin and cephalothin;

• Penicillins such as amoxycillin, amoxycillin with clavulanic acid, ampicillin, bacampicillin, benzathine penicillin, benzylpenicillin, carbenicillin, cloxacillin, methicillin, phenethicillin, phenoxymethylpenicillin, flucloxacillin, mezlocillin, piperacill in, ticarcillin and azlocillin;

• Tetracyclines such as minocycline, chlortetracycline, tetracycline, demeclocycline, doxycycline, methacycline and oxytetracycline and other tetracycline-type antibiotics;

• Aminoglycosides such as amikacin, gentamicin, kanamycin, neomycin, netilmicin and

tobramycin;

• Antifungals such as amorolfine, isoconazole, clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate, thacetin, zinc, pyrithione and sodium pyrithione;

• Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin, enoxacin and norfloxacin;

· Sulphonamides such as phthalylsulphthiazole, sulfadoxine, sulphadiazine, sulphamethizole and sulphamethoxazole;

• Sulphones such as dapsone; and

• Other miscellaneous antibiotics such as chloramphenicol, clindamycin, erythromycin,

erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin ethylsuccinate, erythromycin lactobionate, roxithromycin, lincomycin, natamycin, nitrofurantoin, spectinomycin, vancomycin, aztreonam, coiistin IV, metronidazole, tinidazole, fusidic acid and trimethoprim; 2-thiopyridine N-oxide; halogen compounds, particularly iodine and iodine compounds such as iodine-PVP complex and iodohydroxyquinone; hexachlorophene;

chlorhexidine; chloroamine compounds; benzoylperoxide;

Antituberculosis drugs such as ethambutol, isoniazid, pyrazinamide, rifampicin and clofazimine;

Antimalarial drugs such as primaquine, pyrimethamine, chloroquine, hydroxychloroquine, quinine, mefloquine and halofantrine;

Antiviral agents such as acyclovir and acyclovir prodrugs, famciclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, ndocosanol, tromantadine and idoxuhdine;

Anthelmintics such as mebendazole, thiabendazole, niclosamide, praziquantel, pyrantel embonate and diethylcarbamazine;

Cytotoxic agents such as plicamycin, cyclophosphamide, dacarbazine, fluorouracil and its prodrugs, methotrexate, procarbazine, 6- mercaptopurine and mucophenolic acid;

Metabolism agents including:

• Anorectic and weight reducing agents including dexfenfluramine, fenfluramine, diethylpropion, mazindol and phentermine; and

• Agents used in hypercalcaemia such as calcitriol, dihydrotachysterol and their active derivatives or analogs;

Respiratory system agents including:

• Antitussives such as ethylmorphine, dextromethorphan and pholcodine;

• Expectorants such as acetylcysteine, bromhexine, emetine, guaiphenesin, ipecacuanha and

saponins;

• Decongestants such as phenylephrine, phenylpropanolamine and pseudoephedrine; and

• Bronchospasm relaxants such as ephedrine, fenoterol, orciprenaline, rimiterol, salbutamol,

sodium cromoglycate, cromoglycic acid and its prodrugs, terbutaline, ipratropium bromide, salmeterol and theophylline and theophylline derivatives;

Allergy and immune system agents including antihistamines such as meclozine, cyclizine, chlorcyclizine, hydroxyzine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine, diphenhydramine, diphenylamine, doxylamine, mebhydrolin, pheniramine, tripolidine, azatadine, diphenylpyraline, methdilazine, terfenadine, astemizole, loratidine and cetirizine; Local anaesthetics such as bupivacaine, amethocaine, lignocaine, cinchocaine, dibucaine, mepivacaine, prilocaine and etidocaine;

H2-receptor antagonists such as cimetidine and ranitidine;

Neuromuscular blocking agents such assuxamethonium, alcuronium, pancuronium, atracurium, gallamine, tubocurarine and vecuronium;

Smoking cessation agents such as nicotine, bupropion and ibogaine;

Insecticides and other pesticides which are suitable for local or systemic application;

Nutraceutically active compounds including: carotenoids such as lycopene, lutein, astaxanthin and [beta]- carotene; Glucosamine or N- acylglucosamine; Ubiquinone; Vitamins such as vitamins A, C, D and E; Rosmarinic acid; Honokiol; Magnolol; Chlorogenic acid; Oleuropein; Methylsulphonylmethane ("MSM") ; Collagen and Chon.droitin; Boswellin and boswellic acid;

Keratolyses such as the alpha-hydroxy acids, glycollic acid and salicylic acid; Psychic energisers, such as 3-(2-aminopropyl) indole, 3-(2- aminobutyl)indole, and the like;

Biologies, such as sugars, peptides, proteins, nucleic acids, cells, tissues, and combinations thereof; and immunologically active agents (such as vaccine active agents) for preventable diseases, including:

· anthrax vaccine;

• human papillomavirus (HPV) vaccine;

• vaccines to prevent diphtheria, tetanus (lockjaw) and pertussis (whooping cough), such as DTaP, Tdap, DT and Td;

• hepatitis A vaccine;

· hepatitis B vaccine;

• haemophilus influenzae type b (Hib) vaccine;

• influenza (flu) vaccine;

• Japanese encephalitis (JE) vaccine;

• lyme disease vaccine;

· vaccines to prevent measles, mumps, rubella and varicella (M RV), such as measles, mumps and rubella (MMR) vaccine, varicella vaccine, and measles, mumps, rubella and varicella vaccine; vaccines to prevent meningococcal disease, such as meningococcal polysaccharide vaccine and meningococcal conjugate vaccine;

smallpox vaccine;

vaccines to prevent pneumococcal, such as pneumococcal conjugate vaccine and pneumococcal polysaccharide vaccine;

vaccines to prevent polio, such as inactivated polio vaccine (IPV) and oral polio vaccine (OPV); rabies vaccine;

vaccines to prevent rotavirus, such as RotaTeq* (RV5) and Rotarix (RV1 );

shingles (herpes zoster) vaccine;

typhoid fever vaccine;

BCG, a vaccine for tuberculosis (TB);

varicella (chickenpox) vaccine;

yellow fever vaccine;

nucleic acid or DNA vaccines; and

vaccines against existing cancers.

The active agent may be incorporated in the core in any suitable amount, and for instance may be provided in an amount from 5 to 95% by weight, preferably from 20 to 80% by weight, based on the total weight of the core.

The active agent may be adsorbed onto a solid adsorbent prior to formation of a tablet. This may be particularly useful in the case of liquid active agents as it allows them to be used in a solid dosage form. A range of pharmaceutically acceptable adsorbents are well known to the person skilled in the art. For example, adsorbents such as calcium sulphate dihydrate, calcium phosphate, magnesium oxide, and β- cyclodextrin may be used alone or in combination. The ratio of active agent to adsorbent may be from about 1 : 1 to about 1 : 10 (w/w). In some embodiments, the ratio of active agent to adsorbent is about 1 :4 (w/w).

In some embodiments, the pharmacologically active agent is a smoking cessation agent. In some specific embodiments, the pharmacologically active agent is nicotine. The amount of nicotine in the tablet may be from about 2 wt% to about 7 wt%. These embodiments therefore provide a delivery device suitable for delivering nicotine to an oral mucosal surface of a subject whilst delivering substantially no nicotine to the oral cavity of the subject, the device comprising: a solid core comprising nicotine and

pharmaceutically-acceptable excipients; a bioadhesive layer extending peripherally over the core so as to leave a surface of the core exposed; and an impermeable backing layer extending over the bioadhesive layer so that the backing layer is able to be sealed against a mucosal surface with the exposed surface of the core in contact therewith. _g

Nicotine may be used as the free base or as a nicotine polacrilex complex. When free base nicotine is used it may be adsorbed onto a solid adsorbent prior to tablet formation. In some embodiments, the solid adsorbent is calcium sulphate dihydrate. The bioadhesive layer comprises a bioadhesive agent. As used herein the term "bioadhesive" and similar terms means that a compound or agent is able to attach to a biological surface such as a mucous membrane and/or an endothelial surface. One specific type of bioadhesion is mucoadhesion and the term "mucoadhesive" and similar terms means that a compound or agent is able to attach to the mucosal tissue. The bioadhesive agent may be a mucoadhesive agent that is capable of absorbing water to achieve a water content so that the device autoadheres to the oral mucosal surface. Mucoadhesive agents are well known to the person skilled in the art and they are typically natural or synthetic polymers or biopolymers including adhesive proteins or glycoproteins or polysaccharides. In the case of the present invention, there is, preferably, substantially no active agent in the bioadhesive layer itself and, therefore, the range of bioadhesive agents that could be used may be less restricted than in some prior art transmucosal delivery patches for which compatibility and interactions between the active agent and the mucoadhesive agent need to be considered. A range of bioadhesive and mucoadhesive agents are discussed in Salamat-Miller et al. (3) and any of the classes or specific agents disclosed therein may be used in the present invention. The bioadhesive layer may comprise a number of mucoadhesive agents to achieve a desired appearance, hardness, mucoadhesive properties, desirable duration of retention at the buccal site and other properties.

In some embodiments, the bioadhesive layer comprises a film-forming polymer and a bioadhesive polymer.

Examples of suitable film-forming polymers include cellulose based polymers such as methyl cellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxyethyl methylcellulose (HEMC), hydroxypropyl methylcellulose (HPMC), and other cellulose derivatives alone or in combination. The film-forming polymer may be crosslinked and/or plasticised.

Examples of bioadhesive polymers include polyacrylic acid polymers (carbomers) such as Carbopol™, which may or may not be partially crosslinked, sodium carboxymethyl cellulose (NaCMC), and polyvinylpyrrolidone (PVP), alone or in combination. These bioadhesive polymers are known to exhibit good instantaneous bioadhesive properties in the dry, film state. Other bioadhesive polymers or combination of bioadhesive polymers well known to the person skilled in the art may also be used.

The ratio of bioadhesive polymer to film-forming polymer in the bioadhesive layer can be varied and depends upon the type and amount of active ingredient used and other factors. However, the content of combined components in the bioadhesive layer is between 5 and 95% by weight, preferably between 10 and 80% by weight. The ratio of bioadhesive polymer to film-forming polymer may be from about 10: 1 to about 10:2. In some embodiments, the ratio of bioadhesive polymer to film-forming polymer is about 10: 1 .5.

In some embodiments, the bioadhesive layer comprises a polyacrylic acid polymer and a cellulose polymer. In some embodiments, the polyacrylic acid polymer is Carbopol 934P. In some embodiments, the cellulose polymer is HPMC. The bioadhesive layer may also contain a plasticiser. Plasticisers that are suitable for this purpose are well known to the person skilled in the art and include propylene glycol, polyethylene glycol and glycerine. In some embodiments, the plasticiser is PEG 300.

To form the transmucosal delivery device, the bioadhesive layer may be cast onto a suitable flat surface, such as a glass surface. Solvent casting may be used for this purpose, in which case a solution of the bioadhesive agent(s) and, optionally, a plasticiser in a suitable solvent is prepared and the solution cast onto the glass surface. The solution may be prepared by dissolving the bioadhesive agent in an amount of about 3% to about 6% (w/v) and the plasticiser in an amount of about 1 % to about 2% (v/v) in an aqueous ethanol blend (ethanol: water 3:2). After casting, the material may be dried prior to casting the impermeable backing layer onto the exposed face of the bioadhesive layer (described in more detail hereinafter).

Other methods for forming the bioadhesive layer include hot-melt extrusion and direct milling. After formation of the bioadhesive layer, it is typically laminated with the impermeable backing layer to form a bi-layer laminate patch. In some embodiments, the bi-layer patch is a "blank", meaning that is does not contain a pharmacologically active agent.

The impermeable backing layer may be any biologically compatible material that is substantially impermeable to saliva. The impermeability of the backing layer means that release of the active agent into the oral cavity is minimised. Suitable materials for this purpose include hydrophobic polymers. Eudragit polymers, ethyl cellulose polymers and methyl cellulose polymers may be suitable. In some

embodiments, the impermeable backing layer is an ethylcellulose polymer. Optionally, the impermeable backing layer may also include a water soluble polymer such as polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol or any other water soluble polymer. Additives may be included in the impermeable backing layer to improve its aesthetics or the physical properties. In some embodiments, the impermeable backing layer contains a plasticising agent in order to improve the flexibility of the delivery device in the mouth. Suitable plasticisers include dibutyl sebacate. Other additives that could be used include, but are not limited to, humectants, colours, dyes, and opacifiers. Suitable humectants include hyaluronic acid, glycolic acid, and other alpha hydroxyl acids. Colours, dyes and/or opacifiers may be added to help distinguish the impermeable backing layer from the bioadhesive layer. Opacifers that could be used include titanium dioxide, zinc oxide, zirconium silicate, etc. The bi-layer laminate patch may be formed by casting the impermeable backing layer onto the exposed face of the bioadhesive layer. Solvent casting may be used. Thus, a hydrophobic polymer and, optionally, plasticiser and/or other additives may be dissolved in a suitable solvent and the solution cast over the bioadhesive layer. The solvent may be any volatile organic solvent in which the hydrophobic polymer is soluble. Alcohols may be suitable for this purpose. In some embodiments, the solvent is ethanol.

The backing layer casting solution may contain from about 1 % to about 10% (w/w) of the hydrophobic polymer. In some embodiments, the backing layer casting solution contains from about 3% to about 7% (w/w) of the hydrophobic polymer. In some embodiments, the backing layer casting solution contains about 5% (w/w) of the hydrophobic polymer. The backing layer casting solution may contain from about 0.1% to about 2% (w/v) of the plasticiser. In some embodiments, the backing layer casting solution contains about 0.4% (w/v) of the plasticiser.

After casting the backing layer, the bi-layer laminate may be dried and then cut into predetermined sized patches. The laminate may be cut to a size and thickness that achieves desirable duration of retention at the buccal site. In some embodiments, the laminate is cut in 20mm diameter circular patches. The patches can be stored until required.

The backing layer may be of greater area than the bioadhesive layer so that the backing layer extends peripherally from the bioadhesive layer. In these embodiments, the section of the backing layer that extends peripherally from the bioadhesive layer will contact the mucosal surface when the device is in place.

In a second aspect, the present invention provides a process for producing a transmucosal delivery device suitable for delivering a pharmacologically active agent to an oral mucosal surface of a subject, the process comprising:

- forming a solid core comprising the active agent by compressing the active agent and, optionally, excipients; - forming a bi-layer laminate patch comprising a bioadhesive layer and an impermeable backing layer extending over the bioadhesive layer;

- assembling the solid core and the bi-layer laminate to form a tri-layer laminate patch in which the bi-layer laminate patch extends peripherally over the core so as to leave at least one surface of the core exposed and the backing layer is able to be sealed against a mucosal surface with the exposed surface of the core in contact therewith.

To form the transmucosal delivery device, the bi-layer laminate patch is placed over the core so that the core sits, preferably, centrally in contact with the bioadhesive layer and at least one face of the core is exposed on the bioadhesive layer side of the device. In this way, a tri-layer laminate patch is formed. Typically, the bioadhesive layer will be adhesive enough to stick to the core. Thus, the device can be manufactured by pressing the core into contact with the bioadhesive layer. If necessary, a section of the bioadhesive layer to which the core is to be attached may be moistened with a suitable solvent prior to the core being pressed into contact. Suitable solvents for this purpose include ethanol. When the core is in the form of microparticles, such as powder, pellets or granules, the microparticles may be sprayed onto the bioadhesive layer. In this form, individual granules or pellets will adhere to the bioadhesive layer.

The transmucosal delivery device may be provided to a patient with the core attached thereto or it may be provided to a patient as a kit containing a blank bi-layer laminate patch and a core with instructions for the patient to place the core on the bi-layer laminate patch to form a tri-layer laminate patch and then administer the patch in the usual manner. The bioadhesive layer may contain markings to assist the patient with positioning the core on the bi-layer laminate patch.

In a third aspect, the present invention provides a kit of parts that can be used to form a transmucosal delivery device suitable for delivering a pharmacologically active agent to an oral mucosal surface of a subject, the kit comprising:

- a solid core comprising the active agent;

- a bi-layer laminate patch comprising a bioadhesive layer and an impermeable backing layer extending over the bioadhesive layer,

wherein the bi-layer laminate patch is capable of being positioned peripherally over the core so as to leave at least one surface of the core exposed and the backing layer is able to be sealed against a mucosal surface with the exposed surface of the core in contact therewith.

As best shown in Figure 2, the bi-layer laminate patch extends peripherally over the core. In this way, when the device is placed in position in the mouth, the bioadhesive layer contacts the mucosal surface and adheres thereto. The impermeable backing layer is substantially co-terminus with the bioadhesive layer and, therefore, substantially none of the bioadhesive layer is exposed to the oral cavity. In a fourth aspect, the present invention provides a method of treating or alleviating one or more symptoms associated with a health condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmacologically active agent using a transmucosal delivery device according to the first aspect.

In a fifth aspect, the present invention provides a method for the prophylaxis of a disease state or health condition in a subject, the method comprising administering to the subject an immunogically active agent capable of eliciting an immune response in the subject, wherein the administering comprises using a transmucosal delivery device according to the first aspect.

In a sixth aspect, the present invention provides a method of cancer vaccination to either prevent infections with cancer-causing viruses and treating existing cancer or prevent the development of cancer in certain high risk subjects, the method comprising administering to the subject rumor antigens using a transmucosal delivery device according to the first aspect.

In a seventh aspect, the present invention provides for the use of a transmucosal delivery device according to the first aspect for the preparation of a medicament for the treatment of one or more symptoms associated with a health condition in a subject. In an eighth aspect, the present invention provides for the use of a transmucosal delivery device according to the first aspect for the preparation of a vaccine for the prevention of a disease state or health condition in a subject.

In a ninth aspect, the present invention provides for the use of a transmucosal delivery device according to the first aspect for the preparation of a cancer vaccine for the prevention or therapy of a cancer.

The invention is hereinafter described by reference to the following non-limiting example and accompanying figures. EXAMPLE

Example 1 Nicotine tri-Iaminate transmucosal delivery device

Materials

Nicotine base, hypromellose (HPMC 2910), calcium sulphate dihydrate, calcium phosphate, light magnesium oxide and 0-cyclodextrin were purchased from Sigma-Aldrich Pty Ltd (Castle Hill, NSW, Australia). Nicotine polacrilex was purchased from ShaanXi Tianze Biological Technology Co Ltd Carbopol 934P was a gift from Bronson & Jacobs (Villawood, Australia). Acetonitrile (HPLC grade) was purchased from BioLab Ltd (Australia). Krebs bicarbonate Ringer (KBR) buffer (pH 7.4) was prepared with 1 15:5 mM NaCl, 4.2mM C1, 21 .9 mM NaHCO}, 12.2 mM glucose, 4.0 mM HEPES, 1 .2 mM MgS0 ₄ -7H ₂ 0, 2.5 mM CaCl2-2H ₂ 0, and 1 .6 mM Nal^PO^ ^O. Water was obtained from a Milli-Q purification system (Millipore, Milford, MA), and other chemicals were of analytical grade and were used as received.

Preparation of nicotine tri-laminate transmucosal delivery device

A tri-laminate transmucosal delivery device incorporating nicotine was obtained by attaching a medicated tablet to a blank bioadhesive bi-laminate patch. The blank bioadhesive bi-laminate patch and the medicated tablet were prepared separately.

Preparation of the blank bioadhesive bi-laminate patch

The blank bioadhesive bi-laminate patch was prepared .by solvent casting the following polymeric solutions onto glass trays, drying in an oven and then cutting into predetermined sizes (20mm diameter).

The bioadhesive layer was comprised of Carbopol 934P and HPMC 2910 in the ratio of 10: 1 .5, prepared as follows: 4.6% (w/v) of the polymer and 1 .6% (v/v) plasticizer (PEG 300) was dissolved in an aqueous ethanol blend (ethanol: water 3:2) by overhead stirring at 600rpm for 30 mins. For the backing layer, a 5% (w/w) solution of ethylcellulose in ethanol with different test ratios of dibutyl sebacate added as plasticiser (0.2, 0.33, 0.4, 0.6, 0.8, 1.0 % w/v) was sprayed onto one side of the dry bioadhesive layer and allowed to dry.

The blank bioadhesive bi-laminate patches were stored in airtight containers until required.

Determination of optimum ratio of plasticiser for ethylcellulose layer

The blank bioadhesive bi-laminate patch was swelled in milli-Q water to determine the optimal amount of plasticiser for the ethylcellulose layer. The study measured the time to loss of integrity after placing the bi-laminate patch onto the surface of 5 ml of milli-Q water in a plastic weighing boat. With the bioadhesive layer contacting water, the time taken for the bioadhesive layer to degrade or detach from the ethylcellulose layer was noted. A minimum of 2 hours before the loss of integrity or the separation of the two layers was required for satisfactory performance.

Preparation of the medicated tablets

For the medicated tablets, the drug and excipients were mixed homogenously and then compressed in a 7- mm diameter die, using a Korsch XP-1 tablet press ( orsch AG, BreitenbachstraBe 1 -6, 13509 Berlin, Germany). Medicated tablets were made either with nicotine base or nicotine polacrilex. Prior to the preparation of the medicated tablets with nicotine base, the active was firstly adsorbed to a solid adsorbent in a ratio of 1 :4 (w/w). Calcium sulphate dihydrate, calcium phosphate, light magnesium oxide, and 0-cyclodextrin were trialled to determine the best adsorbent. For the nicotine polacrilex tablet, each tablet contained 8 mg nicotine polacrilex which is equivalent to 2.4 mg nicotine base. Surface pH measurement

The patches were left to swell on the surface of porcine buccal mucosa fixed in position by standard Franz diffusion cells (diffusion area 1.77 cm ² , receptor cell volume 15 ml) for 15 minutes. The porcine buccal mucosa was pre-wet with 0.1 ml artificial saliva (pH = 6.5), and the temperature was controlled at 37 °C. The surface pH was measured by means of a universal indicator paper (pH range = 1 -14) placed on the surface of the swollen patch. The mean of three readings was recorded.

Analysis of nicotine tri-laminate drug delivery device

HPLC analysis method

Analysis of nicotine in diffusion medium was performed after chromatographic separation on a reversed phase C I 8 column ( 150 * 4.6 mm I.D. packed with 5 μπι octadecylsilyl-modified silica). The HPLC system comprised a chromatography pump and a UV variable wavelength UV-vis detector.

Quantification of detector response was performed at 254 run. The mobile phase was acetonitrile - water (30: 70 % v/v) and triethylamine (1 % v/v), apparent pH 6.8, the flow rate was 1 .0 ml/min, and the injection volume was 20 μΐ. Precision of the method was assessed by regression from six point calibration lines, within one day and on five consecutive days. The results varied by 1 % R.S.D. (within day) and by 2.5% R.S.D. (day to day), which demonstrated the precision of the method.

Measurement of ex vivo bioadhesive strength

Preparation of blank tri-laminate drug delivery device

Blank tri-layered patches were prepared in the same way as the nicotine tri-laminate patches, only with no active agent added.

Tissue preparation

Porcine buccal mucosa was used for the evaluation. Pig cheek tissue was obtained from a local abattoir as soon as possible after slaughter and transported to the laboratory in ice-cold KBR buffer (pH 7.4). The epithelium of the buccal mucosa was carefully separated from the underlying tissues using forceps and surgical scissors. The epithelium was then stored at -20°C until required.

Modified tensile test

The evaluation of bioadhesive strength was carried out using a specially designed two part jig and a tensile tester. A schematic figure of the jig is shown in Figure 3. The jig consists of a lower support, an upper support and a ring secured onto the lower support by two screws. The lower support has a surface area of around 380 mm^ (diameter: 22 mm). A cotton pad of suitable size was affixed to the lower support (underneath the tissue) by double-sided tape to provide a cushioning effect. Tissue of suitable size was fixed into position on the cotton pad by the plastic ring and further secured by the screws. The ring has a circular hole of 20 mm diameter allowing the exposure of the tissue for contact with the patches. The lower support was positioned at the bottom of the instrument and fixed in place. The patches to be evaluated were attached to the upper support (diameter: 20 mm) by double-sided tape.. The upper support was then fixed to the upper probe of the tensile tester. The two supports were aligned to ensure that the patches would come into direct contact with the exposed buccal membrane when the upper support was lowered.

During measurement, the upper support was lowered at a speed of 0.5 mm/s to contact with the tissue at a contact force of 100 N and a contact time of 60s. It was then withdrawn at a speed of 1 .0 mm/s. The measurements were conducted at room temperature of 20 ± 0.5 °C. The maximum force of detachment was recorded as the peak detachment force. All tests were carried out with three replicates and the mean values were calculated. The ex vivo bioadhesive strength was evaluated for both the bi-laminate patch and the tri-laminate patch.

In vitro drug release evaluation

Drug release was evaluated using standard Franz diffusion cells. Tri-laminate patches were clamped between donor and receptor compartments with the medicated tablet facing the receptor compartment. The receptor compartment (volume 15 ml) was filled with dissolution medium ( BR buffer) and maintained at 37 °C with constant stirring by a magnetic stirrer. Drug release at each time point and the total drug released were determined by removing aliquots from the receptor compartments through the sampling arm of the receptors at fixed intervals and immediately replacing the same volume of dissolution medium. Samples were filtered through 0.45 μπι Acrodisc® Syringe Filters with Supor® membrane and analysed by HPLC analysis as described above. All experiments with either nicotine or nicotine polacrilex tri-laminate patches were conducted with six replicates, and the results expressed as mean ± SD. Uni-directional drug release was tested by the evaluation of drug release from the backing layer side of the patches, and the patches were clamped between donor and receptor compartments with the ethylcellulose layer facing the receptor compartment during the evaluation.

When controlled drug release was observed, Peppas equation (Equation 1 ), a simple exponential relation introduced to describe general solute release behaviour, was used to explore the mechanism of the first 60% of fractional drug release from the mucoadhesive patches (20).

= k t Equation 1 where the fraction of drug released up to time / (h), k is the kinetic constant and n is the release exponent describing the mechanism of drug release. A plot of log {M M^ versus log / gives a linear trendline of gradient n and intercept log k. Evaluation of ex vivo drug permeation

Tissue preparation

Porcine buccal mucosa was used for the ex vivo drug permeation studies. Tissue was prepared in the same way as described above. The tissue obtained was mounted between the donor and receptor cells filled with KBR solution, maintained at 37 °C and allowed to equilibrate for 1 hour before the permeation study.

Evaluation of ex vivo permeation of nicotine from an aqueous solution

Ex vivo permeation of nicotine from an aqueous solution was conducted in Franz diffusion cells (diffusion area 0.64 cm^, receptor cell volume 5 ml). The receptor cells were maintained at 37 °C and the KBR buffer stirred continuously using magnetic stirrers. After equilibration of the mucosa, 0.1 ml of donor cell KBR buffer was removed and replaced with 0.1 ml nicotine solution (2.5, 9, 12.5, 25 g/L), Samples (0.07 ml) were removed from the receptor cell at fixed intervals over 4 hours and replaced with fresh KBR buffer. The cumulative amount of drug per unit area of mucosa (Q/A) reaching the receptor phase was determined. The steady-state flux of nicotine permeating through the porcine buccal mucosa (Js) was calculated using Equation 2:

dp

Js = Equation 2

A d r

Where dQ is the amount of drug permeated through the porcine buccal mucosa during time dt, and A is the diffusional area. All experiments were conducted with six replicates and the results expressed as mean ± SD.

Evaluation of ex vivo permeation of tri-laminate transmucosal drug delivery devices

Ex vivo permeation tests of nicotine and nicotine polacrilex tri-laminate patches were conducted in the same manner except that the patch was placed over the external side of the mucosa by gentle pressing with the medicated tablet facing the mucosa. Samples (0.1 ml) were removed from the receptor cell

(diffusion area 1 .77 cm^, receptor cell volume 5 ml) at fixed intervals over 2 hours and replaced with fresh KBR buffer. The permeation studies were conducted with six replicates and results were expressed as mean ± SD. The fraction of nicotine permeated through the mucosa was plotted as a function of time. The flux of nicotine permeation through porcine buccal mucosa (Js) at each interval was further calculated using Equation 2 and plotted versus the drug amount (as a percentage of the loading dose) available in the donor compartment at that time (Md). Md was calculated by the subtracting the permeated percentage (Mp) from the released percentages (Mr) (Equation 3). _2?

Md = Mr - Mp Equation 3 where Md is the drug amount available in the donor compartment as a percentage of loading dose at time t, Mr is the percentage of loading dose released up to time t from in vitro drug release evaluation, and Mp is the percentage of loading dose permeated through the buccal mucosa up to time t from ex vivo drug permeation evaluation.

Statistical analysis

All statistical analysis was performed using SPSS Statistics Version 17 for Windows. Data were transformed and t-tests were performed to determine the p-value. A p-value of <0.05 was considered to be statistically significant.

Results

Nicotine tri-laminate transmucosal delivery devices

By assessing the swelling of the bi-laminate patch in contact with water, a 0.4% concentration of plasticiser in the ethylcellulose layer was found to be optimal with no loss of integrity of the device or separation of the bioadhesive layer from the ethylcellulose layer during the 120-minute test. The physiochemical properties of patches with the optimal composition are reported in Table 1. Patch dimensions were specified with consistent diameter and thickness, and each device contained 2.03 ± 0.03 mg nicotine. The surface pH was neutral and close to the oral conditions of around pH 6.5. Ex vivo bioadhesive strength for the blank tri-laminate patches was 84.61 ± 0.74 N after a contact time of 60 seconds (Table 1 ). The bi-laminate patch had an ex vivo bioadhesive strength of 89.92 ± 3.12 N and no significant difference was found between it and the blank tri-laminate patch.

Table 1 : Physicochemical Properties of nicotine tri-laminate transmucosal delivery devices*

* Each value represents the mean ± SD of 3 replicates

Evaluation of in vitro drug release

Drug release rate from or across the backing layer was negligible for 1 20 minutes (Figure 4), thus confirming uni-directional drug release for the tri-laminate patch.

Drug release rate from the tablet was significantly higher when CaS04-2H20 was used as the adsorbent compared to other adsorbents (p 0.05, Figure 5). Therefore, CaS04-2H20 was selected as the adsorbent for further study. As shown in Figure 5, drug release from the nicotine tri-laminate transmucosal delivery patches with optimum composition was rapid, approaching a steady rate within 40 minutes. By comparison, drug release from nicotine polacrilex tri-laminate patches for the initial 30 minutes was significantly lower, while no significant difference was found in the later 90 minutes (Figure 4). By the use of the Peppas equation, the n value of nicotine polacrilex patch was calculated to be 0.79, falling in the range of 0.45- 0.89, which indicates an anomalous non-Fickian release mechanism (4).

Ex vivo drug permeation evaluation

Ex vivo drug permeation evaluation of nicotine solution

Transmucosal flux of nicotine aqueous solution increased proportionally with the given nicotine concentration, and linearity was observed, with R-squared approaching 1 (R2= 0.9975) (Figure 6).

Ex vivo drug permeation of nicotine tri-laminate transmucosal delivery devices

Nicotine permeation was plotted against time, as shown in Figure 7. The permeation rate was around 21 % at 30 minutes, nearly 30% at one hour, and close to 40% at two hours. This indicates that permeation is relatively rapid initially, followed by constant and slow permeation. A remarkable decrease in the flux rate was observed from 0.081 g/m ² min at 30 minutes to 0.031 g/m ² min at 120 minutes (Figure 8). Nicotine polacrilex tri-laminate patches were also investigated, and less than 3% of the dosage could permeate through the buccal mucosa (Figure 7).

Discussion

The delivery devices described herein can be easily manufactured with constant physicochemical properties and have a neutral surface pH, which is unlikely to cause irritation to the buccal mucosa. Drug release in a uni-directional manner, with the hydrophobic ethylcellulose backing layer preventing drug loss to the oral cavity, was confirmed by the drug release study (Figure 4). Potential drug interaction with the mucoadhesive polymers was avoided, preventing the disadvantages of the direct drug incorporation technique, and confirmed by the identical ex vivo mucoadhesive strength for patches with or without the medicated tablet (Table 1 ) and the rapid initial drug release (Figure 4).

By the use of the tri-laminate design and incorporating liquid nicotine base to adsorbents and formulating into tablet form, drug content uniformity was easily achieved. However, different adsorbents show different effects on drug release from the patches (Figure 5). A nicotine replacement therapy (NRT) product should preferably give rapid relief from nicotine craving. Therefore, CaSCV2H ₂ 0 is considered as the optimal adsorbent for nicotine in this study, generating the most rapid and complete drug release, and nicotine adsorbed to CaS0 ₄ -2H ₂ 0 to form the nicotine tri-laminate patches is more suitable than the nicotine polacrilex tri-laminate patches, with more rapid initial drug release. Nicotine- polacrilex is a weak carboxylic cation-exchange resin complex composed of nicotine and polacrilin, and appears as a white powder with a fine particle size. The binding of nicotine to the resin improved the stability under normal storage conditions and has been widely used as a nicotine active for the production of nicotine polacrilex chewing gum and lozenges.

However, drug release from nicotine polacrilex patches was characterized by a delay and was found to follow an anomalous non-Fickian release mechanism. This type of drug release has been used to describe diffusion of hydrophilic solute from swollen matrix, which in this case describes the drug release controlled by the desorption of nicotine from resin and the diffusion of nicotine through the matrix.

The benefit of using nicotine base rather than its salt as the active is also supported by the transmucosal absorption mechanism of nicotine. The transport of nicotine through buccal mucosa is via the transcellular pathway by a passive diffusion mechanism, which has been confirmed in this study by the linearity achieved between the nicotine transmucosal flux rate and the donor concentration (5-7). Also, the absorption of nicotine via buccal mucosa is believed to be dependent on the concentration of nicotine present in its non-ionised form (8).

Moreover, when comparing the pharmacokinetics of nicotine base and nicotine salt following intravenous administration in rats (9), the salt showed more extensive conversion to the inactive metabolite cotinine, and nicotine base produced a higher and more sustained plasma nicotine level within 3 hours after dosage than the salt.

To help overcome nicotine addiction, the combined use of a nicotine transdermal patch and fast acting products have been investigated and found to be more effective than any single product. Significantly improved success in helping quitting has been reported with the combination of a nicotine patch and inhaler (10), nicotine patch and nasal spray ( 1 1 ), or nicotine transdermal patch and chewing gum ( 12). The incremental efficiency of the combined approach can be explained by the simulation of the pattern of smoking. The early onset provides the required pleasurable sensation and quick relief of nicotine symptoms with abstinence from tobacco, and the later plateau level of nicotine plays an important role in further suppressing the craving. Craving is also prevented from recurring after a short interval. The permeation profile of the nicotine tri-laminate device described herein combines a rapid initial peak of nicotine with a sustained level of transmucosal permeation, thus offering potential for improved effectiveness in overcoming nicotine addiction.

As nicotine permeates through the mucosa via a passive diffusion mechanism, theoretically a linear relationship can be observed between the transmucosal flux and the concentration difference between the donor and receptor compartments, can be described by Equation 4.

^■ ) Equation 4

, _3Q where Js is the transmucosal flux at time t, Md is the drug amount available in the donor compartment as a percentage of loading dose at time t, Vd is the volume of the solution in the donor compartment, Mrp is the drug amount available in the receptor compartment as a percentage of loading dose at time t, Vrp is the volume of the solution in the receptor compartment, and k is the constant incorporating the permeability of the permeant.

Since Vrp » Vd, Equation 5 can be simplified as:

Js =— * Md Equation 5

Substituting for Md from Equation 3 into Equation 5, one obtains the following expression:

Js =— * (Mr - Mp) Equation 6

Equation 6 can be further simplified:

When t T, ,

Mr

Js =— * k Equation 7

When t >T ₂ ,

M * Mp

Js = (— -— ) * k Equation 8 where D is the loading dose, M» is the amount of drug released as time approaches infinity, T| is the time when Mr » Mp, and T ₂ is the time when drug release steady state is achieved. Theoretically, maximal Js can be achieved when T| = T ₂ . It is obvious from Equation 7 and Equation 8 that drug permeation from a buccal mucoadhesive product is initially dominated by the drug release step from the product (t ≤ΐ>), later determined by the permeation mechanism of the permeant (t >T ₂ ), and controlled by both when T, < t < T ₂ . Therefore, the property of the active and the desired treatment effect should be considered in formulation design, since selection of suitable designs are of significant importance to obtain high clinical efficacy. For the active requiring quick onset, such as nicotine, quick initial drug permeation can be achieved by a rapid release product. And when drug release steady state is reached early, T ₂ close to T ₍ , initial high transmucosal flux can be obtained and it decreases after t > T ₂ , which results in rapid transport followed by slower permeation.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be Understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that . any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in any country before the priority date of each claim of this application.

REFERENCES

Unless specifically stated otherwise in this specification, the following references are incorporated herein in their entirety.

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