(2) Patent Application Publication (10) Pub. No.: US 2016/0220480 A1 Bilal Et Al
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US 20160220480A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2016/0220480 A1 Bilal et al. (43) Pub. Date: Aug. 4, 2016 (54) ORAL DOSAGE FILM EXHIBITING A61 K 47/34 (2006.01) ENHANCED MUCOSAL PENETRATION A61 K 47/38 (2006.01) A61.J 3/00 (2006.01) (71) Applicant: IntelGenx Corp., Saint-Laurent (CA) A61 K 47/12 (2006.01) (72) Inventors: Mobarik Bilal, Montreal (CA); Nadine CPC A6 IK 9/006 (2013.01); A61.J 3/00 (2013.01); Paiement, Saint-Laurent (CA) A61K 47/08 (2013.01); A61K 47/12 (2013.01); - - - A61K 47/32 (2013.01); A61K 47/34 (2013.01); (73) Assignee: IntelGenx Corp., Saint-Laurent (CA) A61K 47/38 (2013.01); A61K 47/10 (2013.01) (21) Appl. No.: 14/612,433 (57) ABSTRACT (22) Filed: Feb. 3, 2015 A film oral dosage form useful for buccal or sublingual Publication Classification administration of an active agent(s), which exhibits excellent bioabsorption and rate of mucosal penetration of the active (51) Int. Cl. agent(s) without requiring a conventional penetration A6 IK 9/{}{} (2006.01) enhancer, includes at least one film forming polymer, at least A6 IK 47/08 (2006.01) one plasticizer, at least one active agent, and a residual A6 IK 47/10 (2006.01) organic solvent in an amount of from 0.5% to 8% of the A6 IK 47/32 (2006.01) weight of the film. US 2016/0220480 A1 Aug. 4, 2016 ORAL DOSAGE FILM EXHIBITING hols, carboxylic acids, ketones, ethers, esters and/or their ENHANCED MUCOSAL PENETRATION derivatives or from aqueous solventora combination of aque ous and organic solvents. CROSS-REFERENCE TO RELATED [0009] These and other features, advantages and objects of APPLICATIONS the various embodiments will be better understood with ref [0001] Not Applicable. erence to the following specification and claims. DETAILED DESCRIPTION FIELD OF THE DISCLOSURE [0010] The film oral dosage forms of this disclosure are [0002] This disclosure relates to oral dosage forms and useful for buccal and sublingual administration of active more particularly to film oral dosage forms that exhibit agents. Sublingual administration refers to the absorption of enhanced mucosal penetration of at least one pharmaceuti an active agent through the mucosa under the tongue, and cally active agent. buccal administration refers to the absorption of an active agent through the mucosa located between the gums and the BACKGROUND OF THE DISCLOSURE cheeks. The active agent(s) can be any pharmaceutically [0003] Oral films are known to have a great potential for active agent or nutraceutically active agent that is capable of buccal and sublingual absorption of active agents and have a being absorbed through the sublingual or buccal mucosa. large advantage for onset of action by bypassing the liver and Buccal and sublingual oral dosage forms are particularly potential first pass metabolization and also bypassing the useful for administering active agents that are susceptible to gastrointestinal tract (degradation due to pH and digestive degradation in the gastrointestinal tract, avoiding the first pass enzymes. Although buccal and sublingual absorption have effect of drug metabolism by the liver, or when rapid absorp potential advantages, the barriers to penetrate the mucosal tion of the active agent is desired. membrane and enter the systemic circulation to generate an [0011] Pharmaceutically active agents refer to any sub efficacious level of active agents in the blood in a short period stance used in a finished pharmaceutical product and that is of time are numerous. intended to provide pharmacological activity or otherwise [0004] Multiple parameters impact on the amount of drug have a direct effect on the diagnosis, cure, mitigation, treat that penetrates the mucosal membrane. The oral dosage prod ment or prevention of disease, or have a direct effect in restor uct formulation, the residence time, the surface area on the ing, correcting or modifying physiological functions in mucosa, the presence of penetration enhancer, the pH of the human beings or other animals. micro environment, and the size of the active molecule, all [0012] Nutraceutically active agents refer to dietary vita have an impact on the final amount of the drug?s) absorbed. mins and minerals, and to chemicals extracted from herbs. [0013) Pharmaceutically active agents that can be incorpo SUMMARY OF THE DISCLOSURE rated into the film oral dosage forms of this disclosure include analgesics, anti-inflammatories, antipyretics, antibiotics, [0005] It is usually expected that surfactant and penetration laxatives, antihistamines, antiastbematics, diuretics, anti enhancers have a major role in the rate and extent of absorp flatulents, antimigraine agents, antispasomodics, sedatives, tion of a drug. Surprisingly, it was observed during develop antihyperactives, antihypertensives, tranquilizers, deconges ment activities that the best rate and extent of drug absorption tants, beta blockers, peptides, proteins, or oligonucleotides. was obtained from a formulation containing neither of those, Film oral dosage forms for buccal and sublingual administra but rather a very limited quantity of solvent. tion of an active agent are especially beneficial for treating [0006] Producing an oral film involves the preparation of a indications where a fast onset of action is required or greatly wet blend into which all ingredients are dissolved, suspended desired, such as acute repetitive seizures, febrile seizures, or both dissolved and suspended, including a film forming acute pain, cluster headaches, agitation, acute post-operative polymer, a plasticizer, at least one active material and any pain, post-operative nausea and vomiting, vertigo, motion other required ingredients. Then, the wet blend is cast into at sickness, anaphylaxis, angina, and breakthrough cancer pain. least one thin layer and the selected solvent or solvent system [0014] Analgesics include opiates and opiate derivatives, is removed. A controlled and minor quantity of the solvent or such as oxycodone, ibuprofen, aspirin and acetaminophen. solvent system remains in the film after drying, termed Anti-inflammatory agents include hydroxychloroquine sul residual solvent(s). Active agent penetration tests using mul fate, fluticasone, amcinonide, methylprednisolone, budes tiple distinct films showed a better rate and extent of drug onide, anakinra, diflorasone diacetate, and entanercept. Anti penetration using the films containing no surfactant or pen pyretics include metamizole, nabumetone, phenazone and etration enhancer but rather residual solvent(s), as demon quinine. Antibiotics include amoxicillin, ampicillin, moxi strated using Franz cells set up with ex-vivo porcine and/or floxacin hydrochloride, clarithromycin, ceftibuten, cefurox artificial mucosa. Surprisingly, the same film produced using ine axetil, cefprozil, ciprofloxacin hydrochloride, clindamy water as the unique solvent, and containing water as the only cin phosphate, doxycycline hyclate, dirithromycin, residual solvent, resulted in a lower amount of active agent(s) erythromycin, gemifloxacin, ofioxacin, telithromycin, lom penetrating the mucosa. efloxacin hydrochloride, minocycline hydrochloride, fosfo [0007] The film oral dosage forms of this disclosure mycin tromethamine, penicillin, trimethoprim, ciprofloxacin includes at least one film forming polymer, at least one plas hydrochloride, rifampin, isoniazid, pyrazinamide, cefditeren, ticizer, at least one active agent, and one or several residual cefixime, tetracycline, tubramycin, rifaximin, azithromycin, solvent(s) representing in total between 0.5% to 8% of the linezolid, hydrocortisone, neomycin sulfate, thonzonium weight of the film. bromide, cephalexin hydrochloride, cefdinir, and gatifloxa [0008] In certain aspects of this disclosure, the solvent or cin. Laxatives include prucalopride and lubiprostone. Anti solvent system is selected from organic solvents such as alco histamines include acrivastine, azelastine, bilastine, bro US 2016/0220480 A1 Aug. 4, 2016 mpheniramine, buclizine, bromodiphenhydramine, mebicar, afobazole, selank, bromantane, emoxypine, aza carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlor pirones, barbiturates, hydroxyzine, pregabalin, validol, and pheniramine, chlorodiphenhydramine, clemastine, cypro beta-blockers; antipsychotics, such as benperidol, brompri heptadine, desloratadine, dextrobrompheniramine, dexchlo dol, droperidol, haloperidol, moperone, pipamperone, timi rpheniramine, dimenhydrinate, doxylamine, ebastine, perone, fluspirilene, penfluridol, pimazide, acepromazine, embramine, fexofenadine, hydroxyzine, levocetirizine, lora chlorpromazine, cyamemazine, dixyrazine, fluphenazene, tadine, meclozine, mirtazapine, olopatadine, orphenadrine, levomepromazine, mesoridazine, perazine, pericyazine, phenindamine, pheniramine, phenyltoloxamine, promethaz pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, ine, pyrilamine, quetiapine, rutatadine, tripelennamine, and triflupromazine, chlorprothixene, clopenthixol, flupentixol, triprolidine. Antiastbmatics include albuterol sulfate, ipratro tiotixene, zuclopenthixol, clotiapine, loxapine, prothipendyl, pium bromide, salmeterol xinafoate, Zafirlukast, flunisolide, carpipramine, clocaprarmine, molindone, mosapromine, metaproterenol sulfate, terbutaline sulfate, formoterol, cro sulpiride, sultopride, veralipride, amisulpride, amoxapine, molyn sodium, levalbuterol hydrochloride, zileuton, flutica aripiprazole, asenapine, clozapine, blonanserin, iloperidone, some