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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, , antiastbematics, diuretics, anti enhancers have a major role in the rate and extent of absorp flatulents, antimigraine agents, antispasomodics, , 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 . 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. , cephalexin hydrochloride, cefdinir, and gatifloxa [0008] In certain aspects of this disclosure, the solvent or cin. Laxatives include 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, , cyclizine, chlor pirones, , , , validol, and , chlorodiphenhydramine, clemastine, cypro beta-blockers; , such as , brompri heptadine, desloratadine, dextrobrompheniramine, dexchlo dol, , , , , timi rpheniramine, , , ebastine, perone, , , pimazide, acepromazine, embramine, fexofenadine, hydroxyzine, levocetirizine, lora chlorpromazine, , , fluphenazene, tadine, meclozine, , olopatadine, orphenadrine, , , , pericyazine, phenindamine, pheniramine, phenyltoloxamine, promethaz , , , , prothipendyl, , , , ine, pyrilamine, , rutatadine, tripelennamine, and , , , , triprolidine. Antiastbmatics include albuterol sulfate, ipratro , , , , prothipendyl, pium bromide, salmeterol xinafoate, Zafirlukast, flunisolide, , clocaprarmine, , mosapromine, metaproterenol sulfate, terbutaline sulfate, formoterol, cro , , , , , molyn sodium, levalbuterol hydrochloride, zileuton, flutica , , , , , some propionate, triamcinolone acetonide, dimethylxanthine, , , , , paliperi and beclomethasone. Diuretics include spironolactone, done, , quetiapine, , , trimi hydrochlorothiazide, sprirolactone, butmetamide, torsemide, pramine, , , alstonine, , bitop chlorotiazide, furosemide, and hydrochlorothiazide. Anti ertin, , , , , flatulents include simethicone, enzyme-based dietary supple pomaglumeted methionil, xanomeline, and . ments, and herbal inhibitors. Antimigraine agents include Decongestants include , levo-, , , maratriptan, , , naphazoline, oxymetazoline, phenylephrine, phenylpro almetriptan, and . Antispasmodics panol-amine, propylhexadrine, synephrine, tetrahydrozoline, include dicyclomine, , mebeverine, papaverine, xylometazoline, pseudoephedrine, and tramazoline. These cyclobenzaprime, , orphenadrine, , pharmaceutically active agents are illustrative, and other , , chlorzoxazone, , dan active agents can be used in the disclosed film oral dosage trolene, and baclofen. Sedatives include barbiturates, such as , , , and ; forms. Such active agents can be used alone orin combination , such as , , , in the disclosed film oral dosage forms. , , , , [0015] Vitamins include Vitamin A (retinol, retinal, and , trizolam, , , and carotenoids), Vitamin B1 (thiamine), Vitamin B2 (riboflavin), ; , such as eszopicione, zale Vitamin 133 ( and niacinamide), Vitamin B5 (pan plon, and ; ; antihistamines, tothenic acid), Vitamin B6 (pyridoxine, pyridoxamine, pyri such as , dimenhydrinate, doxylamine, mir doxal), Vitamin B7 (biotin), Vitamin B9 (folic acid and folinic tazapine, and promethazine; metaqualones and methaqua acid), Vitamin B12 (cyanocobalamin, hydroxycobalamin, lone analogues, such as , , diprodua and methylcobalamin), Vitamin C (ascorbic acid), Vitamin D lone, , methylmethaqualone, mebroqualone, (cholecalciferol and ergocalciferol), Vitamin E (tocopherols, , and nitromethaqualone; 2-methyl-2-butanol: and tocotrienols), and Vitamin K (phylloquinone and hydrate; ; ; and . Anti menaquinones). hyperactives include , dextroamphedamine, [0016] Minerals (dietary minerals or mineral nutrients) methylphenidate, dexmethylphenidate, , atomox include potassium, sodium, calcium, magnesium, manga etine, and lisdexamfetamine. Antihypertensives include nese, iron, cobalt, nickel, copper, zinc, selenium, and molyb diuretics, such as bumetanide, ethacrynic acid, furosemide, denum, all of which are commercially available or can be torsemide, epitizide, hydrochlorothiazide, chlorothiasize, prepared in biologically absorbable forms. bendroflumethizide, idapamide, chlorthalidone, metolazone, amiloride, triamterene, and spironolactone; beta-blockers, [0017| Other possible nutrients include fatty acids, amino such as atenolol, metroplol, nadolol, nebivolol, , acids, chloride, iodine, and phosphorus. Examples of herbal , , and timolol; alpha blockers, such as supplements include extracts from cassia cinnamon, cran doxazosin, phentolamine, indoramin, , berry, garlic, ginger, ginkgo, ginseng, green tea, hoodia, milk prazosin, terazosin, and tolazoline; mixed alpha beta block thistle, saw palmetto, St. John’s wort and . ers, such as bucindolol, carvedilol, and labelalol; benzodiaz [0018] These nutritionally active agents (nutraceuticals) epines, such as those listed for the sedatives; calcium channel are illustrative, and other active agents can be used in the blockers, such as amlodipine, cilnidipine, felodipine, israd disclosed film oral dosage forms. Such active agents can be ipine, lercanidipene, levamlodipine, nicardipine, nifedipine, used alone orin combination in the disclosed film oral dosage nimodipine, nitrendipine, diltiazem and verapamil; rennin forms. inhibitors, such as aliskiren; ACE inhibitors, such as capto pril, enalapril, fosinopril, lisinopril, perindopril, quinapril, [0019] The film oral dosage forms of this disclosure can ramipril, trandolapril, and benazepril; angiotensin II receptor comprise one or more pharmaceutically active agent(s) in antagonists, such as candesartan, eprosartan, irbesartan, losa combination with one or more nutraceutically active agent(s) tan, olmesartan, telmisartan, and Valsartan; aldostrone recep to treat certain conditions or combinations of conditions. tor antagonists, such as eplerenone and spironolactone; [0020) The amounts of active agent(s) incorporated into the vasodilators, such as sodium nitroprusside; alpha-2 adrener film oral dosage forms can depend on a variety of factors gic receptor , such as , guanabenz, guanfa including the condition being treated, the characteristics of cine, methyldopa and moxonidine; and endothelin receptor the subject being treated (age, weight, gender, etc.), and the blockers, such as bosentan. Tranquilizers include particular active agent(s) being employed in the film oral agents, such as benzodiazepines, serotanergic, antipressants, dosage forms. Techniques for determining appropriate dose US 2016/0220480 A1 Aug. 4, 2016

levels of active agents for sublingual and/or buccal adminis 4379-455° F (225°-235° C); lactide/glycoli 85/15, believed tration are well known, and are not the subject of this disclo to be 85% lactide and 15% glycolide, having a melting point Sure within the range of 338°-347° F (170°-175°C.); and lactide/ [0021] The major component(s) of the film oral dosage glycolide 50/50, believed to be a copolymer of 50% lactide forms is at least one film forming polymer. Suitable film and 50% glycolide, having a melting point within the range of forming polymers are non-toxic, non-irritant and devoid of 338°-347° F (170°-175° C). leachable impurities. The film oral dosage form should also [0024] The film forming polymers typically represent 30% exhibit sufficient peel, shear and tensile strength to facilitate to 95% of the weight of the cast films prior to packaging, e.g., manufacture, packaging, storage and administration without 40% to 95%, 50% to 95%, 60% to 90%. losing their integrity. In accordance with this disclosure, the [0025] The film oral dosage forms disclosed herein can be selected film forming polymer(s) should be compatible with free or substantially free of surfactants and polyalcohols. The the selected organic solvent or solvent system included in the term “substantially free” of surfactants and polyalcohols specific wet blend preparation, which is further cast to pro means that the film oral dosage forms do not require deliber duce the film oral dosage form with a residual solvent(s) ately added surfactants or polyalcohols, although unavoid remaining after casting. Examples of film forming polymers able or incidental surfactants or polyalcohols can be present, that can be employed in the disclosed film oral dosage forms if at all, as impurities in other ingredients in amounts that do include hydroxypropylmethylcellulose, hydroxyethylcellu not affect measurable properties relating to wettability (e.g., lose, hydroxypropylcellulose, polyvinyl pyrrolidone, poly contact angle goniometer measurements), dissolution or dis mers of substituted vinylpyrrolidone, derivatives of polyvi integration rates by more than 10%, and do not adversely nylpyrrolidone, copolymers or polyvinylpyrrolidone, such as affect measurable stability properties. The term “free” of vinylpyrrolidone-vinyl acetate copolymers or copovidones, surfactants and polyalcohols means that incidental or poly(1-vinylpyrrolidone-co-2-dimethylamino-ethyl meth unavoidable surfactants and polyalcohol impurities are acrylate, poly(1-vinylpyrrolidone-co-styrene), poly(1-vi present in only inconsequential amounts that affect water nylpyrrolidone)-graft-(1-triacontene), poly (vinylpyrroli contact angle measurements and dissolution rate by less than done-co-methylacrylate), poly (vinylpyrrolidone-co-N,N' 1%. In certain embodiments, the presence of surfactants and dimethacrylamide), and poly (vinylpyrrolidone-co-maleate), polyalcohols are each limited to less than 1000 ppm (w/w), polyethylene oxide, carboxymethylcellulose, polyvinyl alco less than 500 ppm (w/w), less than 100 ppm (w/w), less than hol, natural gums, such as xanthan, tragacanth, guar, acacia 40 ppm (w/w), or less than 10 ppm (w/w). and arabic gums, polydextrose, pullulan, polyacrylic acid, [0026] The terms “surfactant” and “polyalcohol” are and polyacrylic polymers, such as methyl methacrylate poly intended to have their ordinary meanings. Specifically, the mers and copolymers. term “surfactant” is intended to mean an amphophilic com [0022] Other polymers useful for incorporation into the pound that lowers the surface tension of a liquid, the interfa film oral dosage forms of this disclosure include biodegrad cial tension between two liquids, or the interfacial tension able polymers, copolymers, block polymers and combina between a liquid and a solid. The term “polyalcohol” means a tions thereof. Among the known useful polymers or polymer sugar , which is a hydrogenated form of a carbohy are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly drate having a carbonyl group that has been reduced to a dioxanones, polyoxalates, poly(.alpha-esters), polyanhy primary or secondary hydroxyl group. Polyalcohols are also drides, polyacetates, polycaprolactones, poly(orthoesters), distinguishable based on their . Polyalco polyamino acids, polyaminocarbonates, polyurethanes, poly hols have the general formula H(HCHO), 1, whereas sugars carbonates, polyamides, poly(alkyl cyanoacrylates), and have the general formula H(HCHO), HCO. Common mixtures and copolymers thereof. Additional useful polymers examples of polyalcohols or sugar that can be include, stereopolymers of L- and D-lactic acid, copolymers avoided or eliminated from the disclosed films include glycol, of bis(p-carboxyphenoxy) acid and sebacic acid, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, manni sebacic acid copolymers, copolymers of caprolactone, poly tol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, iso (lactic acid)/poly(glycolic acid)/polyethylene glycol copoly malt, maltitol, lactitol, maltotritol and maltotetraitol. mers, copolymers of polyurethane and (poly(lactic acid), [0027| Titanium dioxide can be added in amounts from copolymers of polyurethane and poly(lactic acid), copoly about 0.05% to 5%, 0.1% to 3%, or 0.5% to 2% of the weight mers of alpha.-amino acids, copolymers of alpha.-amino of the film. The titanium dioxide can act as a disintegrant in acids, and caprioc acid, copolymers of alpha.-benzyl the disclosed films, as well as a texture modifier that improves glutamate and polyethylene glycol, copolymers of succinate mouth feel, and an opacifier or coloring agent. These amounts and poly(glycols), polyphosphazene, polyhydroxy-al are effective for increasing the rate at which the film will kanoates and mixtures thereof. Binary and ternary systems dissolve in an aqueous medium (e.g., saliva) upon buccal are contemplated. and/or sublingual administration. [0023] Other specific polymers that can be used in the film [0028] The residual solvent(s) is the remaining solvent con oral dosage forms of this disclosure include those marketed tained in the finished film product. The solvent is selected under the Medisorb and Biodel trademarks. The Medisorb based on its capacity to dissolve the film forming polymer(s) materials are marketed by the DuPont Company of Wilming that can be used to produce a wet blend from which a film can ton, DE and are generically identified as a “lactide/glycolide be obtained by removal (e.g., evaporation) of most of the co-polymer” containing propanoic acid, 2-hydroxy-polymer solvent(s). Examples of suitable organic solvents or solvent with hydroxyl-polymer with hydroxyacetic acid.” Such poly system include carboxylic acids, ketones, ethers, esters and/ mers include lactide-glycolide 100 L, believed to be 100% or their derivatives. Carboxylic acids that can be used as the lactide, having a melting point within the range of 338°-347° organic solvent include formic acid, acetic acid, propanoic F. (170°-175° C), lactide/clycolide 100 L, believed to be acid, butyric acid, and valeric acid. Alcohols that can be used 100% glycolide having a melting point within the range of as the organic solvent include 1-butanol, 2-butanol, ethanol, US 2016/0220480 A1 Aug. 4, 2016

3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, sion is obtained. Thereafter, the active ingredient(s) is (are) 1-propanol and 2-propanol. Ketones that can be used as the added. Eventually, the active ingredient(s) may be homoge organic solvent include , methylethyl ketone, and neously dissolved or suspended within the solvent or solvent methylisobutyl ketone. Esters that can be used as the organic system before the addition of any other required ingredients solvent include butyl acetate, ethyl acetate, ethyl formate, or after a specific ingredient, depending on the properties of isobutyl acetate, isopropyl acetate, propyl acetate, and methyl the wet blend preparation (e.g., viscosity) and the oral film acetate. Ethers that can be used as the organic solvent include dosage form (e.g., dimensions, air bubbles, residence time). tert-butylmethyl ether and ethyl ether. Combinations of these The solution or suspension is cast or coated onto a carrier or other organic solvents can be used. material and dried to form a film. Examples of suitable carrier [0029] In a single layer or monolayer film, the amount of materials include non-siliconized polyethylene terephthalate residual solvent is about 0.5% to 8% of the weight of the film. film, non-siliconized kraft paper, polyethylene-impregnated In a multiple layer film, at least one of the layers contains kraft paper and non-siliconized polyethylene film. The liquid residual organic solvent in an amount of about 0.5% to 8% of film composition can be coated onto the carrier material using the weight of the film layer. generally any conventional coating equipment, including [0030] In certain embodiments, the disclosed films may knife-over-roll, extrusion die, reverse roll, or Meyer roll coat include a plasticizer. The term “plasticizer” refers to a com ing equipment. ponent that reduces the glass-transition temperature of the [0034] Upon drying, the resulting solid film can have a film forming polymers (e.g., the water soluble polymer or thickness of generally 5 to 200 pum, such as 10 to 200 pum, 20 water soluble polymers in the film). The plasticizer increases to 150 pum or 20 to 100 pum. The film can be cut into individual the flexibility, enhances elasticity, and reduces brittleness of pieces having a suitable size to facilitate administration of a the film. Examples of plasticizers that can be used in the targeted dosage of active agent(s). disclosed film oral dosage forms include triacetin, triethyl [0035] The film oral dosage forms of this disclosure can be citrate, tributyl citrate, acetyl tributyl citrate, acetyl triethyl formulated without conventional penetration enhancers used citrate, trioctyl citrate, acetyl trioctyl citrate, trihexylcitrate, to promote buccal and/or sublingual transmucosal absorption dibutyl sebacate, etc. Other plasticizers include polyalkylene of active agent(s), such as sulfoxides (e.g., dimethylsulfox oxides, glycerol, glycerol monoacetate, diacetate or triac ide), azones (e.g., laurocapran), pyrrolidones (e.g., 2-pyrroli etate, polysorbate, cetyl alcohol, sorbitol and sodium dieth done), and glycols (e.g., propylene glycol). ylsulfosuccinate. Plasticizer may be added in an amount up to [0036] The amount of residual solvent in the film oral dos 25% of the total mass of the film oral dosage form, such as age forms can be controlled by selecting drying times and 0.5% to 25%, 1% to 20%, 2% to 15% or 5% to 10%. conditions (e.g. heating temperature, ventilation, and drying [0031] The amount of active agent(s) that can be incorpo sequence) that consistently provide the desired residual rated in the film oral dosage forms disclosed herein is gener amounts (e.g., 0.5 to 8%, 1% to 4%, or 1% to 3% of the weight ally from 0.01%to 50% by total weight of the film, such as 1% of the film), as may be determined using analytical techniques to 40%, 2% to 30%, or 5% to 20% by total weight of the film. such as gas chromatography. [0032] Conventional film oral dosage form additives, other [0037] Once the product is in its finished form, the film than surfactants and polyalcohols, can be added as needed or dosage forms are rapidly packaged individually to prevent desired, generally in amounts conventionally employed. evaporation of the residual solvent(s) during the normal shelf Examples of such additives include artificial sweeteners such life of the particular product. as sucralose, aspartame, acesulfame potassium and monoam [0038] The above description is considered that of the pre monium glycyrrhizinate; natural sweeteners such as sucrose ferred embodiment(s) only. Modifications of these embodi and fructose; flavorants such as , various fruit flavors ments will occur to those skilled in the art and to those who (e.g., citrus, cherry, grape, orange, etc.) or various mint fla make or use the illustrated embodiments. Therefore, it is vors (e.g., spearmint, peppermint, etc.); colorants; opacifiers understood that the embodiment(s) described above are (e.g., titanium dioxide); and antioxidants (e.g., butylhydroxy merely exemplary and not intended to limit the scope of this ). Other additives may also be incorporated in disclosure, which is defined by the following claims as inter amounts that do not adversely affect the film properties or preted according to the principles of patent law, including the film stability. Specifically, any such additives must not cause doctrine of equivalents. undesirable softening of the film and subsequent loss of dimensional stability, degradation of the active ingredient(s), 1. A film oral dosage form or film layer of an oral dosage or induce undesirable aesthetics such as discoloration of the form comprising: film or noticeable segregation and agglomeration of film at least one film forming polymer; components. at least one plasticizer in an amount of from 1% to 20% of [0033] In an embodiment, a method offorming a film of the the total mass of the film; present disclosure includes combining the various ingredi an optional surfactant in an amount that does not exceed ents in generally any order, employing a combination of water 1000 ppm (w/w); and water-miscible solvents such as alcohols (e.g., ethanol) or at least one active agent; and organic solvents alone or as a mixture. For example, the at least one residual organic solvent in an amount of from plasticizer and additives (e.g., sweetening agents, colorants, 0.5% to 8% of the weight of the film or film layer, flavorants, and opacifying agents) can be dissolved or dis wherein the oral dosage form is packaged to prevent persed in a sufficient amount of solvent that is agitated to form evaporation of the residual organic solvent. a homogenous solution or suspension to which the water 2. The film oral dosage form of claim 1, which does not soluble polymer(s) is (are) added. Heat, vacuum and agitation contain a surfactant. may be applied as needed during addition of the water soluble 3. The film oral dosage form of claim 1, which does not polymeruntilahomogenous solution orhomogenous suspen contain a mucosal penetration enhancer. US 2016/0220480 A1 Aug. 4, 2016

4. The film oral dosage form of claim 1, which does not contain either a surfactant or a mucosal penetration enhancer. 5. The film oral dosage form of claim 1, in which the at least one residual solvent is selected from alcohols, carboxylic acids, ketones, ethers, esters and their derivatives. 6. The film oral dosage form of claim 1, in which the film or film layer further comprises residual water. 7. A process for making a film oral dosage form or film layer for an oral dosage form, comprising: forming a wet blend of at least one film forming polymer, at least one plasticizer in an amount of from 1% to 20% of the total mass of the film; an optional surfactant in an amount that does not exceed 1000 ppm (w/w); and at least one active agent in a liquid including at least one organic solvent; applying at least one layer of the wet blend onto a substrate; casting a film by removing most of the liquid, while retain ing residual organic solvent in an amount of 0.5% to 8% of the weight of the film or film layer; and packaging the oral dosage form to prevent evaporation of the residual organic solvent. 8. The process of claim 7, in which the film does not contain a surfactant. 9. The process of claim 7, in which the film does not contain a mucosa penetration enhancer. 10. The process of claim 7, in which the film does not contain either a surfactant or a mucosa penetration enhancer. 11. The process of claim 7, in which the organic solvent is selected from alcohols, carboxylic acids, ketones, ethers, esters and/or their derivatives. 12-15. (canceled)