WO2006117803A2

WO2006117803A2 - Transmucosal drug delivery systems

Info

Publication number: WO2006117803A2
Application number: PCT/IN2006/000089
Authority: WO
Inventors: Milind Rajaram Redkar; Rahul Ramesh Shelke
Original assignee: Devarajan, Padma, Venkitachalam
Priority date: 2005-03-14
Filing date: 2006-03-13
Publication date: 2006-11-09
Also published as: WO2006117803A3

Abstract

Transmucosal drug delivery systems comprise an inert core and a coating layer comprising at least one active agent, at least one bioadhesive substance, at least one plasticizer, and optionally one or more pharmaceutically acceptable excipients. The transmucosal drug delivery systems are designed to remain localized on mucosal surfaces while providing high surface area for rapid release of the pharmaceutically active agent or rapid release of a fraction of the pharmaceutically active agent followed by sustained delivery.

Description

TRANSMUCOSAL DRUG DELIVERY SYSTEMS

INTRODUCTION TO THE INVENTION

The present invention relates to transmucosal drug delivery systems for delivering drug substances to mucosal surfaces, processes to prepare such delivery devices and their methods of use and treatment.

The oral route constitutes one of the routes initially favored on account of the ease of administration of the dosage form along with high patient compliance. But the pharmaceutically active agents administered by the oral route may undergo degradation due to the action of gastrointestinal (Gl) enzymes and/or pH of the Gl tract. In addition, metabolism in the liver often leads to partial inactivation of the pharmaceutically active agents. Moreover the onset of drug action is also slowed down.

Parenteral administration while providing rapid onset of action overcomes the limitations of oral administration. However pain due to injection, poor patient compliance, the need of trained personnel and sterility requirements proves to be limitations of this route.

Transmucosal administration through various mucosa namely oral mucosa, rectal mucosa, urethral mucosa, vaginal mucosa and nasal mucosa provides an alternative route, which could overcome the disadvantages of oral and parenteral route of administration. A major advantage offered by the mucosal route of administration is bypass of hepatic first pass metabolism, the pH and the enzymes of the gastrointestinal tract. Food effects associated with oral administration are also circumvented. Oral mucosal administration includes buccal, sublingual and gingival routes of administration. Oral mucosa offers thin, multicellular epithelium, weakly acidic pH and rich vascularization thus permitting a rapid absorption of drug through the mucosa to the blood stream.

Various transmucosal drug delivery systems are known in the art using different techniques such as U.S. Patent Nos. 5,135,757, 5,128,143, 4,994,276 and 4,915,948, which disclose uncoated tablets for transmucosal delivery, transmucosal (through vagina) delivery of bisphosphonates using vaginal devices such as tampon, ring, strip, capsule, tablet, pessary, cup or sponge (U.S. Patent No. 6,905,701) and iontophoretic transmucosal delivery (U.S. Patent No. 6,564,092). U.S. Patent No. 6,488,953 discloses an autoadhesive oral transmucosal delivery device, which comprises a cross-linked polyurethane hydrogel capable of absorbing water to achieve a water-content such that the device autoadheres to oral mucosal surface and the hydrogel comprises a pharmaceutically active agent. U.S. Patent No. 5,908,637 discloses a mucoadhesive drug delivery device comprising a gel, powder or tablet matrix comprising a therapeutically effective amount of a heparinic anticoagulant and an outer mucoadhesive portion disposed peripherally to the matrix, thereby forming a reservoir within which the matrix is disposed. U.S. Patent No. 5,780,045 describes a transmucosal drug delivery device in the form of a sheet material wherein the device contains an acid-containing particulate polymeric resin dispersed throughout a polytetrafluoroethylene support matrix, U.S. Patent No. 5762494 discloses a mucosal applicator for topical anesthetics comprising a delivery member for retaining and delivering the anesthetic to the mucosal tissue, an adhesive which adheres the delivery member to the tissue and a retention member connected to the delivery member which provides a biasing force against the delivery member to further secure the delivery member in position when the device is inserted into the patient's mouth. U.S. Patent No. 5,516,523 discloses a method for mucosally administering a macromolecular drug to the oral cavity comprising applying to the oral cavity mucosa a system comprising an inner drug or enhancer or polymer layer having one surface in contact with and adhering to the mucosal tissue of the oral cavity and an opposing surface in contact with and adhering to an overlying inert layer which contains a bile salt enhancer, a hydrophilic polymer and a macromolecular drug having a molecular weight of at least 500 Daltons. U.S. Patent No. 5,482,706 discloses a transmucosal composition comprising a peptide or protein, wherein the composition is a liquid dosage form which contains a cytidine nucleotide derivative in water and is administered through nasal or vaginal mucosa. U.S. Patent No. 5,288,498 discloses a transmucosal delivery device comprising a drug containing sponge-like-matrix which is not dissolvable by the saliva in the mouth and the drug being capable of absorption through mucosal tissues of the mouth, pharynx, and esophagus. U.S. Patent No. 4,649,075 discloses a device for delivery of medicaments to epidermal and mucosal surfaces, comprising a microporous outer portion and a macroporous inner portion made from polymeric foam incorporating a medicament.

U.S. Application Publication No. 2005/0142203 discloses a method of making a multiparticulate oral dosage form comprising cores, coated with a coating composition comprising active pharmaceutical ingredient, a binder and a dispersing agent. The coating mixture in the presence of a plurality of cores is atomized to produce a plurality of pellets.

U.S. Patent No. 5,958,458 describes a pharmaceutical multiple unit particulate formulation in the form of coated cores, which includes a pharmaceutically acceptable carrier and an active substance in a layer on the outer surface of the cores. The patent claims the particle size range of uncoated cores within 90-225 μm.

None of the documents disclose transmucosal drug delivery systems comprising an inert core coated with a layer wherein the layer consists of at least an active agent along with at least a bioadhesive substance, at least a plasticizer optionally with one or more pharmaceutically acceptable excipients.

Thus, the development of transmucosal drug delivery systems as described in context of the present invention would be a significant improvement in the field of clinical practice.

BRIEF DESCRIPTION OF THE DRAWING

Bioadhesion of the transmucosal delivery systems was measured using a modified two pan balance. One pan (A) was modified as a holder (C) by coating the bottom of the pan (A) with the bioadhesive substrate (E). The surface of an adjustable jack (F) served as the holder for the transmucosal delivery system. The pan (B) was used to load weights and apply a detachment force. The bioadhesive substrate selected was a film of sodium carboxymethyl cellulose (sodium CMC) as it was found to mimic animal tissue substrates. A film of sodium CMC was coated on pan (A) as a hydroalcoholic solution and allowed to air dry. Briefly the transmucosal drug delivery system (D) was affixed on (C) with an adhesive, wetted on the upper surface with 5 μl of water and held in contact with the bioadhesive substrate (B) for one minute. Weights were then added to pan (B) and the weight at which the bioadhesive substrate detached from the transmucosal delivery system was recorded as the bioadhesive force in grams.

SUMMARY OF THE INVENTION

The present invention relates to transmucosal drug delivery systems for delivering drug substances to mucosal surfaces, processes to prepare such delivery devices and their methods of use and treatment. The present invention also relates to transmucosal drug delivery systems comprising: a) a pharmacologically inert core b) coating layer comprising at least one active agent, at least one bioadhesive substance, and at least one plasticizer, optionally with one or more pharmaceutically acceptable excipients.

Further, transmucosal drug delivery systems of the present invention are designed to remain localized on mucosal surfaces while providing high surface area for rapid release of the pharmaceutically active agent or rapid release of a fraction of the pharmaceutically active agent followed by a controlled delivery.

DETAILED DESCRIPTION OF THE INVENTION

The present invention also relates to transmucosal drug delivery systems comprising: a) a pharmacologically inert core b) a coating layer comprising at least one active agent, at least one bioadhesive substance, and at least one plasticizer, optionally with one or more pharmaceutically acceptable excipients.

Further, transmucosal drug delivery systems of the present invention are designed to remain localized on mucosal surfaces while providing high surface area for rapid release of the pharmaceutically active agent or rapid release of a fraction of the pharmaceutically active agent followed by sustained delivery.

In context of the present invention, the terms like "active" or "active agent" or "active substance" or "pharmaceutically active agent" or "pharmacologically active agent" or "drug" or "drug substance" may be used synonymously for active ingredient.

The "pharmacologically inert core," "inert core," or "core" of the compositions of the present invention relates to a granule, a pellet, a bead, a spherule, a beadlet, a microcapsule, a microsphere, a platelet, a wafer, a rod, a minitablet, a tablet or a capsule, prepared using pharmaceutically acceptable excipients having a diameter or width typically not less than about 500 μm. The core typically will not contain an active agent.

In an embodiment, the transmucosal delivery systems comprise of a solid inert core that acts as an anchor for the drug-containing coat. The polymeric coating encapsulating the inert core provides enhanced surface area facilitating rapid release of the pharmaceutically active agent. The polymeric coating also promotes localization of said device on the mucosal surface.

In another embodiment, the transmucosal delivery systems comprise a solid inert core encapsulated with a polymeric coating comprising one or more pharmacologically active agents, and at least one bioadhesive polymer to enhance localization and retention on the mucosal surfaces.

Further the present invention also discloses the transmucosal delivery system composition optionally with a surface-active agent.

The transmucosal delivery systems of present invention can be formulated for oral mucosal delivery (buccal, gingival, sublingual), urethral, vaginal or rectal delivery.

Further, the transmucosal delivery devices form can be designed for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release.

The bioadhesive substances that can be used include but are not limited to polyacrylic polymers such as carbomer and its derivatives like polycarbophil, carbopol; ethylene oxide and its derivatives, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyt cellulose (HEC), hydroxypropyl cellulose (HPC) and sodium carboxymethyl cellulose (NaCMC); gelatin, sodium alginate, pectin; gums such as karaya gum, ghatti gum, guar gum, locust bean gum, psyllium seed gum and the like.

In the present invention pharmaceutically acceptable excipients may optionally be used. These pharmaceutically acceptable excipients may include but are not limited to: diluents such as microcrystalline cellulose (MCC), silicified MCC (e.g. Prosolv™ HD 90), microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like; binders such as acacia, guar gum, alginic acid, dextrin, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL^®), hydroxypropyl methylcellulose (e.g. METHOCEL^®), carboxymethylcellulose sodium, povidone (various grades of KOLLIDON^®, PLASDONE^®) starch and the like; disintegrants such as carboxymethyl cellulose sodium (e.g. Ac-Di-Sol^®, Primellose^®), crospovidone (e.g. Kollidon^®, Polyplasdone^®), povidone K-30, polacrilin potassium, starch, pregelatinized starch, sodium starch glycolate (e.g. Explotab^®) and the like; surfactants which can include anionic surfactants such as chenodeoxycholic acid, 1-octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxycholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium chelate hydrate, sodium lauryl sulfate (SLS) and sodium dodecyl sulfate (SDS); cationic surfactants such as cetylpyridinium chloride monohydrate and hexadecyltrimethylammonium bromide; nonionic surfactants such as N-decanoyl-N- methylglucamine, octyl a-D-giucopyranoside, n-Dodecyl b-D-maltoside (DDM), polyoxyethylene sorbitan esters like polysorbates and the like; plasticizers such as acetyltributyl citrate, phosphate esters, phthalate esters, amides, mineral oils, fatty acids and esters, glycerin, triacetin or sugars, fatty alcohols, polyethylene glycol, ethers of polyethylene glycol, fatty alcohols such as cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol and the like, buffering agents such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic acid, ascorbic acid, boric acid, citric acid, formic acid, fumaric acid, lactic acid, maleic acid, oxalic acid, amino acid, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide and the like; solubili∑ers such as ethylene glycol, polyethylene glycol, propylene glycol, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyvinylalcohol, cyclodextrins and. cyclodextrin derivatives; hydrophilic celluloses and their derivatives; amides, such as 2-pyrrolidone, 2-piperidone, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaproiactam, dimethylacetamide, polyvinylpyrrolidone; esters like ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, δ- valerolactone and its isomers, β-butyrolactone and its isomers; dimethyl acetamide, dimethyl isosorbide (Arlasolve DMl. RTM), monooctanoin, diethylene glycol monoethyl ether (Transcutol. RTM), water and the like; lubricants such as talc, magnesium stearate, fumed silica (Carbosil, Aerosil), micronized silica , polyethylene glycols, surfactants, waxes, stearic acid, stearic acid salts, stearic acid derivatives and the like; sweeteners such as natural sweeteners like maltose, sucrose, glucose, sorbitol, xylitol, maltitol, glycerin dextrins and the like, artificial sweeteners such as aspartame, saccharine saccharine salts and the like; preservatives such as mercurial, quaternary ammonium compounds and the like; solvents that may be used in granulation or layering or coating such as aqueous like water or alcoholic like ethanol, isopropanolol or hydro-alcoholic like a mixture of water with alcohol in any ratio or organic like acetone, methylene chloride, dichloromethane.

Pharmaceutical compositions of the present invention may further include but are not limited to pharmaceutically acceptable glidants, opacifiers, flavors, colorants and other commonly used excipients.

Rate controlling substances that can be used include but are not limited to: hydrophilic cellulose derivatives such as carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC); homopolymers or copolymers of N- vinylpyrrolidone; vinyl and acrylic polymers; polyacrylic acid; and the like; hydrophobic substances such as: celluloses like ethyl cellulose, low-substituted hydroxy Ip ropyl cellulose (L-HPC), cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate; polyalkyl methacrylates; polyalkyl acrylates; polyvinyl acetate (PVA); chitosan; crosslinked vinylpyrrolidone polymers; hydrogenated castor oil; and the like. Mixtures of two or more rate controlling substances are useful. Other classes of rate controlling substances or their mixtures in various ratios as required are also within the purview of this invention without limitation.

The commonly utilized processes for manufacture of solid inert core in the context of the present invention include but are not limited to extrusion (various types of extrusion devices such as screw, sieve and basket, roll, ram extruders and the like), encapsulation by extrusion (melt extrusion) spheronization, spray congealing, solvent dehydration (spray drying), supercritical fluid processes such as cryopelletization, direct blending, slugging, wet granulation, conventional tabletting, capsule manufacturing methods and the like.

The commonly utilized encapsulation processes for encapsulation of pharmaceutically active agent containing polymeric coatings on inert core include but are not limited to pan coating, fluidized bed coating, dip coating, tangential coating, top spray coating, bottom spray coating, Wurster coating and the like. The encapsulation process may further be conducted by using solvent based solution coating or solvent-free coating which further may include but is not limited to melt coating, compression coating and the like.

The pharmaceutical composition and/or the solid inert core can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compression coatings, fast disintegrating coatings or enzyme degradable coatings or combinations thereof.

The transmucosal delivery devices of the present invention have a weight ratio of solid inert core to the polymeric coating approximately in the range of about 1 :0.1 to 1 :2. The weight ratio of pharmaceutically active agent to polymeric coat, in the polymeric coat layer is approximately in the range of about 0.01 :1 to 1:0.2. The bioadhesive polymer represents approximately 0.1 % w/w to 50% w/w of the polymeric coat. The plasticizer represents approximately 0.1% w/w to 30% w/w of the coat. The solubilizers represent approximately 0.1 % w/w to 30% w/w of the polymeric coating.

In context of the present invention, the pharmaceutically active agents that may be used can be but are not limited to hydrophilic, hydrophobic, amphiphilic substances that may be in a solubilized state or dispersed or partially solubilized or partially dispersed state or both. Such pharmaceutically active agents may be selected from drugs or pharmaceuticals or nutraceuticals and may be formulated as a compound or mixture of compounds having therapeutic or nutritional value when administered to animals, particularly to mammals like humans.

The pharmaceutically active agents can be selected from but are not limited to the following classes of active agents such as analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anticoagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, beta-blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolyses, lipid regulating agents, anti-anginal agents, cox-2- inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti- osteoporosis agents anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids and the like.

Examples of useful pharmaceutical active agents include but are not limited to acetaminophen; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicid sodium; cefoperazone; cefotetan disodium; cefotoxime; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chrionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clondronate; colistimethate sodium; colistin sulfate; cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium; danaproid; deforoxamine; denileukin diftitox; desmopressin; diatrizoate megluamine and diatrizoate sodium; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; dornase alpha; doxacurium chloride; doxorubicin; editronate disodium; elanaprilat; enkephalin; enoxacin; enoxaprin sodium; ephedrine; epinephrine; epoetin alpha; erythromycin; esmol hydrochloride; factor IX; famiciclovir; fludarabine; fluoxetine; foscamet sodium; ganciclovir; granulocyte colony stimulating factor; granulocyte- macrophage stimulating factor; growth hormones-recombinant human; growth hormone- bovine; gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; hemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine; interIeukin-2; interleukin-3; insulin-human; insulin lispro; insulin procine; insulin NPH; insulin aspart; insulin glargine; insulin detemir; interferon alpha; interferon beta; ipratropium bromide; isofosfamide; Japanese encephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolide acetate; levofloxacin; lincomycin and lincomycin derivatives; lobucavir; lomefloxacin; loracarbef; mannitol; measles virus vaccine; meningococcal vaccine; menotropins; mephenzolate bromide; mesalmine; methanamine; methotrexate; methscopolamine; metformin hydrochloride; metroprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neutontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate; oxytocin; pamidronate disodium; pancuronium bromide; paroxetine; pefloxacin; pentamindine isethionate; pentostatin; pentoxifylline; periciclovir; pentagastrin; phentolamine mesylate; phenylalanine; physostigmine salicylate; plague vaccine; piperacillin sodium; platelet derived growth factor-human; pneumococcal vaccine polyvalent; poliovirus vaccine inactivated; poliovirus vaccine live (OPV); polymixin B sulfate; pralidoxine chloride; pramlintide; pregabalin; propofenone; propenthaline bromide; pyridostigmine bromide; rabies vaccine; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine; salmetrol xinafoate; sincalide; small pox vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase; streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumor necrosis factor; typhoid vaccine live; urea; urokinase; vancomycin; valaciclovir; valsartan; varicella virus vaccine live; vasopressin and vasopressin derivatives; vecoronium bromide; vinblastin; vincristine; vinorelbine; vitamin Bi₂; warfarin sodium; yellow fever vaccine; zalcitabine; zanamavir; zolandronate; zidovudine; their pharmaceutically acceptable salts, isomers and derivatives thereof.

Useful pharmaceutical active agents further include but are not limited to aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethasone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulfan, butenafine, calcifediol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin, cetirizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine,clonazβpam, clopidogrel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporin, danazol, dantrolene, dexchlorpheniramine, diazepam,diclofenac, dicoumarol, digoxin, dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donezepil, efavirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenytoin, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lansoprazole, leflunomide, lisinopril, loperamide, loratadine.lorazepam, lovastatin, L- thryroxine, lutein, lycopene, medroxyprogesterone, mifepristone, mefloquine, megestrol acetate, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratriptan, nelfinavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin, oestradiol, oxaprozin, paclitaxel, paracalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudoephedrine, pyridostigmine, rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terazosin, terbutaline tetrahydrocannabinol, tiagabine, ticlopidine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglita∑one, trovafloxacin, ubidecarenone, valsartan, venlafaxine, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, ∑olmitriptan, Zolpidem, zopiclone, their pharmaceutically acceptable salts, isomers and derivatives thereof.

Further, the pharmaceutically active agent can be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid and the like.

Useful nutraceuticals include but are not limited to vitamins such as carotenoids, vitamin E, vitamin D, vitamin C, thiamine, riboflavin, niacin, folic acid, pyridoxine, biotin, pantothenic acid, cyanocobalamin and the like; minerals such as magnesium, manganese, zinc, selenium, chromium, copper and the like; nutritional elements such as alpha lipoic acid, lutein beta carotenoids and the like.

The following examples will further illustrate certain aspects and embodiments of the invention in greater detail and are not intended to limit the scope of the invention.

EXAMPLES

Example 1 Transmucosal delivery systems of valdecoxib

Process of manufacture of inert cores:

Lactose (100 g) was mixed with povidone K29-32 (10 g) and granulated using isopropyl alcohol. The granules were dried and passed through an ASTM 20 mesh sieve. The dried granules were lubricated with talc (1%) and magnesium stearate (1%). The blend so obtained was compressed on a Cadmach™ (India) single stroke tablet press using 10 mm * 4 mm caplet shaped punches. The final weight of the inert core tablets was 64 mg.

Table No. 1

Coating process:

100 inert tablets were loaded in a coating pan of diameter 6 inches (15 cm) and were spray coated using polymeric coating solution mentioned in table no. 1. The coating was performed at a bed temperature of 45 °C-50 °C. The polymeric coating was applied to the inert core until a coating quantity equivalent to 10 mg of valdecoxib per tablet was achieved.

Example 2

Transmucosal delivery systems of cetirizine dihydrochoride

The inert cores were prepared using the similar process as discussed in example 1. The punches used were 5 mm round biconvex and the average weight of the inert core tablet was 64 mg.

Table No. 2

Coating process:

50 core tablets were loaded in a coating pan of diameter 6 inches (15 cm) and were coated using the polymeric coating solution. The coating was performed at a bed temperature of 70°C-75°C.The polymeric coating was applied to the inert core until a coating equivalent to 2.5 mg of cetrizine dihydrochoride per tablet core was achieved. Example 3 Transmucosal delivery device of zolmitriptan

Table No. 3

Inert core: Process of manufacture of inert core tablets is similar as described for example 1.

Coating process:

50 core tablets were loaded in a coating pan of diameter 6 inches (15 cm) and were coated using polymeric coating solution. The coating was performed at a bed temperature of 45°C-50°C.The polymeric coating was applied to the inert core until a coating equivalent to 2.5 mg of zolmitriptan per tablet core was achieved. Example 4

Transmucosal delivery device of zolmitriptan

Dissolution profile:

Media: pH 6.8 phosphate buffer maintained at 37⁰C ± 0.5⁰C

Stirring rpm: 75

Volume: 250 ml

Apparatus: USP Type 2 (Paddle type)

The results of dissolution test were as follows:

Table No. 4

Example 5

Bioadhesion testing of transmucosal delivery systems

The results of the bioadhesion test were as follows:

Table No. 5

Results of the study indicate that the inert cores showed poor bioadhesion while the transmucosal delivery systems showed good adhesion. Transmucosal delivery systems of cetirizine and zolmitriptan which contained HPMC in combination with L-HPC showed greater bioadhesive force than the transmucosal delivery systems of valdecoxib which contained only HPMC as a bioadhesive.

Claims

1. A transmucosal delivery system comprising an inert core having a coating comprising: a) a therapeutically effective amount of at least one pharmaceutically active agent; b) at least one bioadhesive polymer; c) at least one plasticizer; and d) optionally, one or more pharmaceutically acceptable excipients.

2. The transmucosal delivery system of claim 1 , wherein the weight ratio of inert core to coating is 1 :0.1 to 1 :2.

3. The transmucosal delivery system of claim 1 , wherein the weight ratio of pharmaceutically active agent to coating in the coating layer is 0.005:1 to 1 :0.2.

4. The transmucosal delivery system of claim 1 , wherein the active ingredient comprises a drug, a nutrient, a cosmeceutical, a diagnostic agent, a salt thereof, an isomer thereof, a derivative thereof, or mixture of any two or more thereof.

5. The transmucosal delivery system of claim 1 , wherein the active ingredient comprises an analgesic, anti-inflammatory agent, antihelminthic, anti-arrhythmic agent, anti-bacterial agent, anti-viral agent, anti-coagulant, anti-depressant, anti-diabetic, anti- epileptic, anti-fungal agent, anti-gout agent, anti-hypertensive agent, anti-malarial, antimigraine agent, anti-muscarinic agent, anti-neoplastic agent, erectile dysfunction improvement agent, immunosuppressant, anti-protozoal agent, anti-thyroid agent, anxiolytic agent, sedative, hypnotic, neuroleptic, beta blocker, cardiac inotropic agent, corticosteroid, diuretic, anti-parkinsonian agent, gastro-intestinal agent, histamine receptor antagonist, keratolytic, lipid regulating agent, anti-anginal agent, COX-2 inhibitor, leukotriene inhibitor, macrolide, muscle relaxant, nutritional agent, opioid analgesic, protease inhibitor, sex hormone, stimulant, muscle relaxant, anti-osteoporosis agent, anti-obesity agent, cognition enhancer, anti-urinary incontinence agent, nutritional oil, anti-benign prostate hypertrophy agent, essential fatty acid, non-essential fatty acid, or a mixture of any two or more thereof.

6. The transmucosal delivery system of claim 1 , wherein the concentration of bioadhesive polymer in the coating is 0.1 % w/w to 50% w/w of the coating.

7. The transmucosa! delivery system of claim 1 , wherein the bioadhesive polymer is a pharmaceutically acceptable polymer having bioadhesive characteristics.

8. The transmucosal delivery system of claim 1, wherein the bioadhesive polymer comprises a carbomer, carbomer derivative; copolymer of methyl vinyl ether and maleic anhydride, cellulose derivative, natural polymer, hydrophilic polysaccharide gum or a mixture of any two or more thereof.

9. The transmucosal delivery system of claim 1 , wherein a bioadhesive polymer comprises a cellulose derivative.

10. The transmucosal delivery system of claim 1, wherein a bioadhesive polymer comprises hydroxypropyl methylcellulose.

11. The transmucosal delivery system of claim 1 , wherein a bioadhesive polymer comprises hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose.

12. The transmucosal delivery system of claim 1, wherein the coating further comprises a water-soluble polymer, a water insoluble polymer, or a combination thereof.

13. The transmucosal delivery system of claim 1, wherein the plasticizer in the coating comprises 0.1% w/w to 50% w/w of the coating.

14. The transmucosal delivery system of claim 1 , wherein a plasticizer in the coating comprises polyethylene glycol, triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate, an acetylated monoglyceride, glycerin, triacetin, propylene glycol, polyethylene glycol 400, a phthalate ester, diethyl phthalate, dibutyl phthalate, castor oil, sorbitol, dibutyl sebacate, or a mixture of any two or more thereof.

15. The transmucosal delivery system of claim 1 , wherein the coating comprises a solubilizer.

16. The transmucosal delivery system of claim 1 , wherein the coating contains a solubilizer comprising dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidone, monooctanoin, diethylene glycol monoethyl ether, N,N-dimethyl formamide, cyclodextrin, a cyclodextrin derivative, or a mixture of any two or more thereof.

17. The transmucosal delivery system of claim 1 , wherein the inert core comprises a hydrophilic material at a concentration of at least 80 % w/w of said inert core.

18. The transmucosal delivery system of claim 1 , for oral mucosal, buccal, gingival, sublingual, vaginal, urethral or rectal administration.

19. A transmucosal delivery system for administration of pharmaceutically active agents to mucosal surfaces substantially as described herein and illustrated in reference to the examples.