Oral film compositions and dosage forms with precise active dissolution profiles

Abstract

The present application relates to oral film compositions and dosage forms with precise active dissolution profiles. Disclosed herein are oral membranes for delivering individual unit doses of one or more actives, the membranes having precisely calculated and controlled active dissolution profiles. A wide variety of actives may be used, including, for example, clobazam, diazepam, or riluzole. Also disclosed are methods of treating various diseases and conditions, such as epilepsy and seizures, by administering the oral membranes disclosed herein.

Description

[0001] This application is a divisional application of the Chinese patent application with the application date of September 5, 2019, the application number of “201980073077.2”, and the invention title of “Oral film compositions and dosage forms with precise active substance dissolution profiles”, the original application is the Chinese national stage application of international application PCT / US2019 / 049725. TECHNICAL FIELD

[0002] The present disclosure relates to oral films for delivering individual unit doses of one or more actives, such as clobazam, having a mean particle size D90 of less than about 160 microns, wherein the oral films have a precise, controlled active substance dissolution rate, and methods of treating a variety of diseases including epilepsy and seizures by administering the oral films to a patient in need thereof. BACKGROUND

[0003] Active ingredients, such as drugs or pharmaceuticals, can be prepared in tablet form to allow accurate and consistent dosing. However, this form of preparing and dispensing drugs has a number of drawbacks, including the necessity of adding a large proportion of excipients to obtain a size that can be handled, the additional storage space required for larger drug forms, and dispensing including counting the tablets, which has a tendency to be inaccurate. In addition, it is estimated that up to 28% of the population has difficulty swallowing tablets. While as a way to overcome swallowing difficulties, tablets can be broken into smaller pieces or even crushed, this is not a suitable solution for many tablet or pill forms. For example, crushing or breaking down tablet or pill forms, alone or in combination with food, to facilitate ingestion can also destroy the controlled release properties.

[0004] As an alternative to tablets and pills, films can be used to carry active ingredients, such as drugs, pharmaceuticals, and the like. However, both the films and the process of utilizing this dosage form to prepare drug delivery systems have historically presented a number of unique challenges in the areas of formulation, processing, and pharmacokinetics. In particular, films and oral dosage units cut from them have a number of unfavorable properties that have made them impractical to use in practice until recent advances have made films a highly desirable dosage form.

[0005] Like traditional tablets and pills, the absorption of a drug administered in the form of an oral film depends on a number of factors, including the release of the drug substance from the film, the dissolution and solubilization of the drug substance under physiological conditions. In one way, in vitro dissolution is a relevant predictor of in vivo performance. In vitro dissolution testing of immediate release oral dosage forms is used to assess the quality of drug products between batches; to guide the development of new formulations; and to ensure consistent product quality, bioequivalence, and performance as the product changes over time.

[0006] Because oral films dissolve rapidly, there is a need for improved dissolution testing for these rapidly dissolving products that can be performed accurately almost immediately after being placed in a liquid and at very small time intervals. SUMMARY

[0007] Oral films for delivering a desired amount of an active having a mean particle size D90 of less than about 160 microns in individual unit doses are disclosed. The films comprise: a water-soluble, a water-swellable, or a water-soluble and water-swellable polymer matrix; and an additive. The active can be selected from a wide variety of actives, such as those disclosed herein, including lobenzarit, riluzole, diazepam, or any combination thereof. The additive can be selected from: a sweetener, a flavoring agent, a taste enhancer, a filler, a plasticizer, a dye, a pigment, a permeation enhancer, a buffer, a preservative, silicon dioxide, an anti-tack agent, and any combination thereof. More than about 2% of the active dissolves in the medium after about 3 minutes after the film is placed in the medium.

[0008] The mean particle size D90 of the active is less than about 160 microns, less than about 120 microns, less than about 100 microns, less than about 80 microns, less than about 50 microns, less than about 20 microns, less than about 10 microns, or D90 is about 8 microns. Optionally, the mean particle size D50 of the active is also less than about 30, less than about 20, less than about 10, less than about 4, or D50 is about 3, and / or the mean particle size D10 is less than about 10, less than about 5, less than about 2, or D10 is about 1.

[0009] When the active is lobenzarit, the individual unit dose can comprise about 2 mg to about 20 mg, about 5 mg, or about 20 mg of lobenzarit. Optionally, less than about 10% of the active dissolves in the oral film. In certain embodiments, more than about 20% of the active dissolves after about 3 minutes, about 30% of the active dissolves after about 3 minutes, about 30% of the active dissolves after about 1 minute, more than about 50% of the active dissolves after about 1 minute, more than about 95% of the active dissolves after about 2.5 minutes, more than about 40% of the active dissolves after about 3.5 minutes, more than about 55% of the active dissolves after about 5 minutes, more than about 75% of the active dissolves after about 5 minutes, more than about 85% of the active dissolves after about 6.5 minutes, or more than about 95% of the active dissolves in the medium after about 10 minutes after the film is placed in the medium. In certain embodiments thereof, the dissolution of the active is measured after the film is stored at about 20 °C to about 60 °C, and / or up to about 75% relative humidity (RH), or about 60% RH, for more than 0 months to about 36 months.

[0010] The oral film can include a sweetener selected from the group consisting of sucralose, stevia, acesulfame K, saccharin, fructose, aspartame, and any combination thereof, optionally present in an amount of about 0.5% to about 5% by weight of the composition. The oral film can include a berry flavorant, optionally present in an amount of about 0.1% to about 15% by weight of the composition.

[0011] Also disclosed are methods of treating epilepsy and epileptic seizures by administering an oral film comprising an active in a single unit dose to a person in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 and Figure 2 is an exemplary configuration of a system for PION technology.

[0013] Figure 3 is a graph showing the dissolution of active in oral films containing 5 mg milled clobazam (D90 = 106 microns) and 5 mg clobazam (D90 = 8.3 microns) and in an oral tablet containing clobazam.

[0014] Figure 4 is a graph showing the average active dissolution profiles of oral films containing 5 mg and 15 mg of diazepam as measured by conventional dissolution method.

[0015] Figure 5 is a graph of the average active dissolution profiles of oral films containing 5 mg and 15 mg diazepam measured by PION technology.

[0016] Figure 6 is a graph showing the average active ingredient dissolution profile of an oral film containing 50 mg of riluzole measured by a conventional dissolution method.

[0017] Figure 7 is a graph of the average active dissolution profile of an oral film containing 50 mg of riluzole measured by PION technology.

[0018] Figure 8 is a graph showing the average active dissolution profile of an oral film containing 5 mg of clobazam after storage at about 25° C. and about 40° C. at 60 RH for about 24 months as measured by a traditional dissolution method.

[0019] Figure 9 is a graph of the average active dissolution profiles measured by PION technology for oral films containing 5 mg and 20 mg of clobazam after storage at about 25°C and about 40°C.

[0020] Figure 10 yes Figure 9 , which shows the curves of the active dissolution profiles of oral films containing 5 mg and 20 mg of clobazam after storage at about 25° C. and about 40° C. from 1 minute to 10 minutes.

[0021] Figure 11 Is an oral film containing 5mg of clobazam Figure 9 A plot of the second derivative values ​​and inflection points of the results.

[0022] Figure 12 is an oral film containing 5mg and 20mg of clobazam Figure 9 Plot of the resulting second derivative values ​​and inflection points.

[0023] Figure 13 and Figure 14 is a graph of the average active dissolution profiles of oral films containing 5 mg, 10 mg, and 20 mg of clobazam after storage at about 25°C and about 40°C, 60 RH, for about 24 months.

[0024] Figure 15 yes Figure 13 The first derivative graph of the active ingredient dissolution profile.

[0025] Figure 16 is a graph showing the active dissolution profiles of oral films containing 5 mg, 10 mg and 20 mg of clobazam after storage at about 25° C. and 60 RH for about 24 months and at about 40° C. and 60 RH for about 24 months as measured by PION technology.

[0026] Figure 17 yes Figure 16 The first derivative graph of the active ingredient dissolution profile.

[0027] Figure 18 is a graph showing the active dissolution profiles of oral films containing 5 mg, 10 mg and 20 mg of clobazam after storage at about 25° C. and 60 RH for about 24 months, as well as after manufacture (ie, without storage), as measured by PION technology.

[0028] Figure 19 yes Figure 18 The first derivative graph of the active ingredient dissolution profile.

[0029] Figure 20 The graph is a graph of the active ingredient dissolution profiles of oral films containing 5 mg, 10 mg and 20 mg of clobazam in different media measured by PION technology.

[0030] Figure 21 yes Figure 20 The first derivative graph of the active ingredient dissolution profile.

[0031] Figure 22 is a graph showing the active ingredient dissolution profiles of a liquid mixture containing clobazam, an oral film containing 5 mg of clobazam, and a placebo measured by PION technology.

[0032] Figure 23 is Figure 22 a first derivative plot of the active dissolution profile. DETAILED DESCRIPTION

[0033] Dissolution profiles, and more specifically, dissolution rates, of drug products, including oral films, are established to ensure consistency between batches and to identify any potential issues with respect to bioavailability of the drug active. An unexpected new way for more precise and accurate testing of dissolution profiles has been developed using the PION technology fiber optic UV monitoring system.

[0034] Disclosed herein are oral films for delivering a desired amount of active in individual unit doses with an average particle size D90 of less than about 160 microns, the active dissolution profile of the oral films having improved precision, more sampling points, and enhanced rate of change evaluation compared to the current known existing dissolution testing and dissolution profiles for film dosage forms.

[0035] The individual unit dose (i.e., dosage unit) oral films disclosed herein comprise: a water-soluble, a water-swellable, or a water-soluble and water-swellable polymer matrix; optionally a micronized active; and one or more additives. The films are self-supporting and the active is substantially uniformly distributed within the film. Substantially uniform distribution is measured by individual unit doses of substantially equal size that vary by no more than 10% of the desired amount of active. The films comprising the active can be manufactured by, for example, the casting methods described in U.S. Patents 7,666,337; 8,603,514; 8,765,167; 9,855,221; and 9,931,305, all of which are incorporated by reference in their entirety herein. Alternatively, the individual unit doses can be made into individual wells or strips, such as disclosed in U.S. Patent 8,956,685; U.S. Patent 8,936,825; and U.S. Publication US2012 / 0263865, all of which are incorporated by reference in their entirety herein.

[0036] The term "film" can include films and sheets in any shape, including rectangular, square, or other desired shape. The film can be any desired thickness and size. In one embodiment, the film can have a thickness and size such that it can be administered to a patient, for example, by placing into the oral cavity. The film can be relatively thin, from about 0.0025 mm to about 0.250 mm, or the film can be somewhat thicker, from about 0.250 mm to about 1.0 mm. Some films can even be thicker, for example, greater than about 1.0 mm, or thinner, for example, less than about 0.0025 mm. The film can be a single layer or the film can be multiple layers, including a laminated film or a multi-layer cast film. When multiple layers, the active can be present in one layer, in more than one layer but not all layers, or in all layers. The active can be present in the mucosa-contacting layer. The active can be combined with one or more additives in a single layer, each included in a separate layer, or each can be additionally included in a discrete region of the same dosage form.

[0037] Active

[0038] The film can be treated to ensure that any active is substantially uniformly distributed throughout the film. For example, when the film, such as a cast film, is cut into individual unit doses of substantially the same size, the amount of active in the unit dose can be known very accurately. When the active is a medicament, i.e., a drug, the accuracy of the dose is particularly advantageous and, in fact, is required by government regulatory agencies such as the U.S. FDA.

[0039] Actives that can be incorporated into the film of the present application include, without limitation, pharmaceutical and cosmetic actives, drugs, medicaments, antigens or allergens (e.g., timothy grass pollen), spores, microorganisms including bacteria, seeds, mouthwash components (e.g., chlorite or chlorite salts), flavorants, fragrances, enzymes, preservatives, sweeteners, colorants, spices, vitamins, and combinations thereof.

[0040] As will be readily appreciated by one of ordinary skill in the art, the amount of active in the film depends on many factors, including, for example, the active selected, the desired therapeutic strength, the number of layers of the film, and the formulation selected. The pharmaceutically active can comprise from about 0.001% to about 99%, from about 0.003% to about 75%, or from about 0.005% to about 50%, by weight of the film composition, including greater than about 0.005%, greater than about 0.05%, greater than about 0.5%, greater than about 1%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, about 50%, greater than about 50%, less than about 50%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, less than about 0.05%, or less than about 0.005%. The amount of other components can vary depending on the active and other components, but generally these components comprise no more than about 50%, no more than about 30%, or no more than about 15%, by total weight of the film composition.

[0041] Active agents suitable for the films herein include, but are not limited to, the following therapeutic classes: ace inhibitors; adrenergics; adrenocortical steroids; adrenocortical suppressants; aldosterone antagonists; alkaloids; amino acids; anabolics; analgesics; anesthetics; anorexics; anti-acne agents; anti-adrenergics; anti-allergic agents; anti-amoebics; anti-anemic agents; anti-anginal agents; anti-anxiety agents; anti-arthritic agents; anti-arrhythmic agents; anti-asthmatics; anti-atherosclerotic agents; anti-cholesterolemic agents; anti-bacterial agents; antibiotics; anti-cholinergics; anti-coagulants; anti-convulsants; anti-depressants; anti-diabetic agents; anti-diarrheals; anti-diuretics; antidotes; anti-epileptics; anti-fibrinolytic agents; anti-fungals; anti-hemorrhagic agents; anti-histamines; anti-hyperlipidemic agents; anti-hypertensive agents; anti-hypotensive agents; anti-infective agents (both systemic and non-systemic); anti-inflammatory agents; anti-lipid agents; anti-manics; anti-microbials; anti-migraine agents; anti-mitotic agents; anti-mycotics; anti-nauseants; anti-neoplasties; anti-neutropenic agents; anti-obesity agents; anti-parasitic agents; anti-Parkinson agents; anti-proliferatives; anti-psychotics; anti-pyretics; anti-rheumatic agents; anti-seborrheic agents; anti-secretion agents; anti-spasmodics; anti-stroke agents; anti-thrombotic agents; anti-thyroid agents; anti-tumor agents; anti-tussives; anti-ulcer agents; anti-uremic agents; anti-viral agents; appetite suppressants; appetite stimulants; biological response modifiers; blood glucose modifiers; blood modifiers; blood metabolite modifiers; bone resorption inhibitors; bronchodilators; cardiovascular agents; central nervous system stimulants; cerebral dilators; contraceptives; coronary dilators; cholinergics; cough suppressants; decongestants; depressants; diagnostic aids; dietary supplements; diuretics; dopaminergics; enzymes; estrogen receptor agonists; endometriosis management agents; expectorants; erectile dysfunction therapies; erythropoietic agents; ibrinolytic agents; fertility agents; fluorescent agents; free oxygen radical scavengers; gastric acid inhibitors; gastrointestinal motility effect agents; genetic modifiers; glucocorticoids; hair growth promoters; hemostatic agents; histamine H2 receptor antagonists; homeopathic agents; hormones; hypercalcemia management agents; hypocalcemia management agents; hypocholesterolemic agents; hypoglycemic agents; hypolipidemic agents; hypotensive agents; ion exchange resins; imaging agents; immunization agents; immunomodulators; immunoregulators; immunostimulants; immunosuppressants; keratolytics; laxatives; LHRH agonists; mood management agents; motion sickness preparations; mucolytics; muscle relaxants; mydriatics; nasal decongestants; neuromuscular blocking agents; neuroprotective agents; NMDA antagonists; non-hormonal sterol derivatives; osteoporosis therapies; pain management agents; parasympatholytics; parasympathomimetics; plasminogen activators; platelet activating factor antagonists;Platelet aggregation inhibitors; prostaglandins; psychotherapeutic agents; psychotropic agents; radioactive agents; respiratory agents; scabicides; sclerosing agents; sedatives; sedative hypnotics; selective adenosine Al antagonists; serotonin antagonists; serotonin inhibitors; serotonin receptor antagonists; smoking cessation therapy agents; steroids; stimulants; sympatholytics; terine relaxants; thyroid hormones; thyroid inhibitors; thyromimetic agents; tranquilizers; tremor therapy agents; amyotrophic lateral sclerosis agents; cerebral ischemia agents; Paget's disease agents; unstable angina agents; vasoconstrictors; vasodilators; weight management agents; wound healing agents; xanthine oxidase inhibitors; and combinations thereof.

[0042] Examples of active agents suitable for use herein include antacids, H2- antagonists, and analgesics. For example, antacid doses can be prepared using the ingredients of calcium carbonate alone or in combination with magnesium hydroxide and / or aluminum hydroxide. In addition, antacids can be used in combination with H2- antagonists.

[0043] Analgesics include opiates and opiate derivatives, such as oxycodone (available as OxyContin® (Purdue Pharma LP, Stamford, CT), which is a controlled release formulation of oxycodone hydrochloride), hydrocodone (available as Vicodin® (Knoll Pharmaceuticals, Mount Olive, NJ), which is a combination of hydrocodone bitartrate and acetaminophen), and codeine (available as Tylenol with Codeine® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of codeine phosphate and acetaminophen). Motrin® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of ibuprofen and pseudoephedrine hydrochloride), and Advil® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of ibuprofen and pseudoephedrine hydrochloride). Advil® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of ibuprofen and pseudoephedrine hydrochloride). Motrin® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of ibuprofen and pseudoephedrine hydrochloride), and Advil® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of ibuprofen and pseudoephedrine hydrochloride). Midol Cramp® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of ibuprofen, pyrilamine maleate, and acetaminophen), and Midol Complete® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of ibuprofen, pyrilamine maleate, and acetaminophen). Motrin Migraine® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of ibuprofen and pseudoephedrine hydrochloride), and Advil® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of ibuprofen and pseudoephedrine hydrochloride). and Tylenol® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride), and Tylenol® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride). Genuine Loperamide® (Janssen Pharmaceutica, Titusville, NJ), which is a combination of loperamide hydrochloride and pseudoephedrine hydrochloride), and Imodium® (Janssen Pharmaceutica, Titusville, NJ), which is a combination of loperamide hydrochloride and pseudoephedrine hydrochloride). Silapap® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride), and Tylenol® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride). Tylenol Extra Strength® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride), and Tylenol Infants’® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride). Tylenol® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride), and Tylenol® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride). Tylenol® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride), and Tylenol® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride). and Tylenol® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride), and Tylenol® (McNeil Consumer Healthcare, Fort Washington, PA), which is a combination of acetaminophen and pseudoephedrine hydrochloride). ​​​​​​​​​​Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as

[0044] The films disclosed herein can also comprise a pharmaceutical agent such as an NSAID, including etodolac (available as Lodine®, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Dolophine® (available as Methadone Hydrochloride, available as Commercially available), Oxaprozin (available as Commercially available), piroxicam (available as Commercially available), indomethacin (available as Commercially available), Meloxicam (available as Commercially available), mefenamic acid (available as Commercially available), Tolmetin sodium (available as Commercially available), choline magnesium trisalicylate (available as Commercially available), diclofenac sodium (available as Commercially available), diclofenac potassium (available as or commercially available) and misoprostol (available as Opioid agonists and antagonists (eg, buprenorphine and naloxone) are further examples of drugs useful in the present invention.

[0045] Other drugs useful as active ingredients herein include antidiarrheals such as loperamide (available as Imodium QC Health Care America Leader and Commercially available), nitazoxanide (available as commercially available) and diphenoxylate hydrochloride / atropine sulfate (available as Common medications used alone or in combination for colds, aches, fevers, coughs, congestion, runny noses, and allergies, such as acetaminophen, ibuprofen, chlorpheniramine maleate, dextromethorphan, dextromethorphan HBr, phenylephrine HCl, pseudoephedrine HCl, diphenhydramine, and combinations thereof (e.g., dextromethorphan HBr and phenylephrine HCl (available as Commercially available)).

[0046] Other active substances that can be used herein include, but are not limited to, alcohol dependence treatment drugs, such as acamprosate calcium (which can be used as commercially available); allergy treatment drugs, such as promethazine hydrochloride (available as Commercially available), Bepotastine besylate (available as commercially available), hydrocodone sulfonated divinylbenzene-vinylbenzene copolymer (hydrocodone polistirex) / chlorophenylpyramine sulfonated divinylbenzene-vinylbenzene copolymer (available as Commercially available), Cetirizine hydrochloride (available as Commercially available), Cetirizine Hydrochloride / Pseudoephedrine Hydrochloride (available as Commercially available), promethazine hydrochloride / codeine phosphate (available as Commercially available, containing codeine), pemirolast (available as Commercially available), fexofenadine hydrochloride (available as Commercially available), meclizine hydrochloride (available as Commercially available), hydrochloric acid nitrogen Azelastine hydrochloride (available as Commercially available), Nizatidine (available as Commercially available), desloratadine (available as Commercially available), sodium cromoglycate (available as Commercially available), epinastine hydrochloride (available as Commercially available), hydrochloric acid nitrogen Sting (available as Commercially available), prednisolone sodium phosphate (available as Orapred Commercially available), Olopatadine hydrochloride (available as Commercially available), ketotifen fumarate (available as commercially available) and montelukast sodium (available as commercially available); and antihistamines, such as diphenhydramine HCl (available as Commercially available), loratadine (available as Commercially available), astemizole (available as Commercially available), nabumetone (available as Commercially available), diphenhydramine HCL (available as commercially available) and clemastine (available as commercially available).

[0047] The films of the present disclosure may also contain Alzheimer's disease therapeutic drugs, such as tacrine hydrochloride (which can be used as Commercially available), Galantamine (available as Commercially available), donepezil hydrochloride (available as Commercially available), rivastigmine tartrate (available as Commercially available), octyne (available as commercially available) and memantine (available as commercially available); anemia drugs, such as cyanocobalamin (available as commercially available) and ferumoxytol (available as commercially available); anesthetics such as antipyrine with benzocaine (available as and commercially available); angina drugs, such as amlodipine besylate (available as Commercially available), nitroglycerin (available as Commercially available), isosorbide mononitrate (available as Commercially available) and isosorbide dinitrate (available as commercially available); antitussives, such as guaifensin; anti-Alzheimer's agents, such as nicergoline; and Ca H - antagonists, such as nifedipine (which can be used as and commercially available).

[0048] Actives useful in the present disclosure may also include antiasthmatics, such as salbutamol sulfate (available as Commercially available), ipratropium bromide (available as Commercially available), salmeterol xinafoate (available as Commercially available), zafirlukast (available as Commercially available), flunisolide (available as Commercially available), orphenadrine sulfate (available as Commercially available), salbutamol inhaler (available as Commercially available), terbutaline sulfate (available as Commercially available), Formoterol (available as Commercially available), sodium cromoglycate (available as Commercially available), salbutamol hydrochloride (available as Commercially available), Qiliutong (available as Commercially available), fluticasone propionate / salmeterol (available as Commercially available), salbutamol sulfate / triamcinolone acetonide (available as Commercially available), dimethylxanthine (available as commercially available) and beclomethasone (available as commercially available); angioedema drugs, such as C1 esterase inhibitor (human) (available as Commercially available) and ecallantide (available as commercially available); and antibacterial drugs such as trimethoprim / sulfamethoxazole Azoles (can be used as Commercially available), mupirocin (available as Commercially available), metronidazole (available as commercially available), acetylsulfonamide Azoles (can be used as commercially available), bismuth subsalicylate, and metronidazole / tetracycline hydrochloride (available as Helidac commercially available as Alphora®, Alphora® Plus, Alphora® Plus commercially available as Noroxin®, Noroxin® Plus, Noroxin® Plus commercially available as Erycette®, Erycette® Plus, Erycette® Plus commercially available as Zithromax®, Zithromax® Plus, Zithromax® Plus commercially available as Levaquin®, Levaquin® Plus, Levaquin® Plus commercially available as Avelox®, Avelox® Plus, Avelox® Plus.

[0049] The films of the present disclosure can also include one or more antibiotics, including amoxicillin (commercially available as Amoxil®, Amoxil® Plus, Amoxil® Plus commercially available as Ampicin®, Ampicin® Plus, Ampicin® Plus and commercially available as Augmentin®, Augmentin® Plus, Augmentin® Plus commercially available as Avelox®, Avelox® Plus, Avelox® Plus commercially available as Besivance®, Besivance® Plus, Besivance® Plus commercially available as Biaxin®, Biaxin® Plus, Biaxin® Plus commercially available as Bristacin®, Bristacin® Plus, Bristacin® Plus commercially available as Cefzil®, Cefzil® Plus, Cefzil® Plus commercially available as Cefprozil®, Cefprozil® Plus, Cefprozil® Plus commercially available as Cetraxone®, Cetraxone® Plus, Cetraxone® Plus and commercially available as Cleocin®, Cleocin® Plus, Cleocin® Plus commercially available as Doryx®, Doryx® Plus, Doryx® Plus commercially available as Dynacin®, Dynacin® Plus, Dynacin® Plus commercially available as Erycette®, Erycette® Plus, Erycette® Plus and commercially available as Erycette®, Erycette® Plus, Erycette® Plus commercially available as Gemiflox®, Gemiflox® Plus, Gemiflox® Plus commercially available as Levaquin®, Levaquin® Plus, Levaquin® Plus commercially available as Maxaquin®, Maxaquin® Plus, Maxaquin® Plus commercially available as Maxaquin®, Maxaquin® Plus, Maxaquin® Plus commercially available as Minocin®, Minocin® Plus, Minocin® Plus commercially available as Monu-Mycin®, Monu-Mycin® Plus, Monu-Mycin® Plus commercially available as Penicillin®, Penicillin® Plus, Penicillin® Plus commercially available as Primaquine®, Primaquine® Plus, Primaquine® Plus commercially available as Proquin®, Proquin® Plus, Proquin® Plus commercially available as Rifadin®, Rifadin® Plus, Rifadin® Plus commercially available as Simpiox®, Simpiox® Plus, Simpiox® Plus Commercially available), cefixime (available as Commercially available), tetracycline (available as Achromycin and Commercially available), tobramycin (available as Commercially available), rifaximin (available as Commercially available), azithromycin (available as Commercially available), azithromycin suspension (available as Commercially available), linezolid (available as commercially available), benzoyl peroxide, and clindamycin (available as commercially available), erythromycin, and benzoyl peroxide (available as Commercially available), dexamethasone (available as commercially available), ciprofloxacin and dexamethasone (available as Commercially available), polymyxin B sulfate / neomycin sulfate / hydrocortisone (available as Commercially available), colistin sulfate / neomycin sulfate / hydrocortisone acetate / tongzolamine bromide (available as Cortisporin-TC Commercially available), cephalexin hydrochloride (available as Commercially available), Cefdinir (available as commercially available) and gatifloxacin (available as commercially available).

[0050] Other active ingredients that may be used include cancer treatment drugs, including cyclophosphamide (available as Commercially available), methotrexate (available as and Commercially available), tamoxifen citrate (available as Commercially available), bevacizumab (available as Commercially available), everolimus (available as Commercially available), pazopanib (available as commercially available) and anastrozole (available as commercially available); leukemia therapeutics, such as ofatumumab (available as commercially available); antithrombotic drugs, such as antithrombin recombinant lyophilized powder (available as Commercially available), Prasugrel (available as commercially available); anticoagulants, such as aspirin with sustained-release dipyridamole (available as Commercially available), warfarin sodium (available as Commercially available), dipyridamole (available as Commercially available), dalteparin (available as Commercially available), danaparin (available as Commercially available), enoxaparin (available as commercially available), heparin (available as Hep-Lock, Hep-Pak, Hep-Pak CVC, Heparin Lock Flush), tinzaparin (available as commercially available) and clopidogrel bisulfate (available as commercially available); antiemetics, such as granisetron hydrochloride (available as commercially available) and nabilone (available as Commercially available), trimethobenzylamine hydrochloride (available as Commercially available) and ondansetron hydrochloride (available as commercially available); antifungal treatments such as ketoconazole (available as Commercially available), posaconazole (available as Commercially available), Ciclopirox (available as Commercially available), griseofulvin (available as Commercially available), Oxiconazole nitrate (available as Commercially available), fluconazole (available as Commercially available), sertaconazole nitrate (available as Commercially available), terbinafine hydrochloride (available as Commercially available), Ciclopirox (available as commercially available), nystatin / triamcinolone acetonide (available as Commercially available), econazole nitrate (available as Commercially available), itraconazole (available as commercially available) and terconazole (available as commercially available).

[0051] Active ingredients may also include anti-inflammatory drugs, such as hydroxychloroquine sulfate (available as Commercially available), fluticasone propionate (available as Commercially available), Canakinumab (available as Commercially available), amcinonide (available as Commercially available), methylprednisolone (available as Commercially available), budesonide (available as Entocort Commercially available), anakinra (available as business

[0052] Purchase), diflorasone diacetate (available as commercially available) and etanercept (available as commercially available); antispasmodics such as phenobarbital / hyoscine sulfate / atropine sulfate / scopolamine hydrobromide (available as commercially available); antiviral therapeutics, such as oseltamivir phosphate (available as commercially available); antiparasitic drugs, including tinidazole (available as appetite suppressants, such as megestrol acetate (available as Megace Commercially available), phentermine hydrochloride (available as Commercially available) and diethylaminopropiophenone hydrochloride (available as commercially available); arthritis drugs, including leflunomide (available as Commercially available), Certolizumab (available as Commercially available), diclofenac sodium (available as Commercially available), golimumab (available as commercially available) and tocilizumab (available as commercially available); bladder control drugs, such as trospium chloride (available as Commercially available), desmopressin acetate (available as Commercially available), tolterodine tartrate (available as Commercially available), oxybutynin chloride (available as or Commercially available), darifenacin (available as commercially available) and solifenacin succinate (available as commercially available); vasoconstrictor drugs, such as methylergonovine maleate (available as commercially available); plasma uric acid control agents, such as rasburicase (available as commercially available); iron deficiency anemia drugs, such as Felimod (available as commercially available); lymphoma drugs such as pralatrexate (available as Commercially available), romidepsin (available as commercially available); malaria drugs such as artemether / lumefantrine (available as commercially available); hyponatremia drugs, such as tolvaptan (available as commercially available); drugs for the treatment of von Willebrand disease (available as commercially available); antihypertensive drugs, such as treprostinil (available as Commercially available), tadalafil (available as commercially available); cholesterol-lowering drugs, including paricalcitol (available as Commercially available), Pitavastatin (available as commercially available), lovastatin, niacin (available as Commercially available), colestipol hydrochloride (available as Commercially available), rosuvastatin calcium (available as Commercially available), Fluvastatin sodium (available as Commercially available), atorvastatin calcium (available as Commercially available), lovastatin (available as Commercially available), niacin (available as Commercially available), pravastatin sodium (available as commercially available), pravastatin sodium with buffered aspirin (available as Pravigard Commercially available), cholestyramine (available as commercially available), simvastatin and niacin (available as Commercially available), atenolol, chlorthalidone (available as Commercially available), atenolol (available as Commercially available), fenofibrate (available as Commercially available), fenofibrate (available as Commercially available), Ezetimibe / Simvastatin (available as Commercially available), colesevelam (available as Commercially available), bisoprolol fumarate (available as Commercially available), Ezetimibe (available as Commercially available), bisoprolol fumarate / hydrochlorothiazide (available as commercially available) and simvastatin (available as commercially available).

[0053] Actives included herein may also include chronic kidney disease medications such as paricalcitol (available as commercially available); contraceptives, including etonogestrel (available as commercially available), norethindrone acetate, ethinyl estradiol (available as Loestrin 24 Commercially available), ethinyl estradiol, norgestrel (available as Ortho Commercially available), levonorgestrel (available as Plan commercially available), levonorgestrel and ethinylestradiol (available as Commercially available), levonorgestrel, ethinylestradiol (available as commercially available) and medroxyprogesterone acetate (available as commercially available); COPD medications such as arformoterol tartrate (available as Commercially available) and ipratropium bromide, salbutamol sulfate (available as commercially available); cough suppressants, including benzonatate (available as commercially available), guaifenesin, codeine phosphate (available as Tussi-Organidin commercially available) and acetaminophen, codeine phosphate (available as Tylenol with commercially available); drugs for the treatment of diabetes, including pioglitazone hydrochloride, metformin hydrochloride (available as ACTOplus Commercially available), bromocriptine mesylate (available as Commercially available), liraglutide (available as Commercially available), saxagliptin (available as Commercially available), pioglitazone hydrochloride (available as Commercially available), glimepiride (available as Commercially available), rosiglitazone maleate, metformin hydrochloride (available as Commercially available), rosiglitazone maleate (available as Commercially available), rosiglitazone maleate (available as Commercially available), Exenatide (available as Commercially available), Exenatide (available as Commercially available), chlorpropamide (available as Commercially available), pioglitazone hydrochloride, glimepiride (available as Commercially available), metformin hydrochloride (available as Commercially available), glipizide (available as Commercially available), glibenclamide, metformin (available as and Commercially available), dimethoate hydrochloride (available as Commercially available), sitagliptin (available as Commercially available), detemir (available as Commercially available), glipizide, metformin hydrochloride (available as Commercially available), glibenclamide (available as Commercially available), repaglinide (available as Commercially available), acarbose (available as Commercially available), nateglinide (available as Commercially available), Pramlintide acetate (available as Commercially available), canagliflozin (available as commercially available), linagliptin (available as Commercially available), dapagliflozin (available as Commercially available), insulin glargine (available as or Commercially available), insulin aspart (available as Commercially available), insulin lispro, empagliflozin (available as commercially available) and tolazamide (available as commercially available).

[0054] Other active ingredients that can be used include digestive agents such as sulfasalazine (available as Commercially available), rabeprazole sodium (available as Commercially available), lubiprostone (available as Commercially available), dicyclomine hydrochloride (available as Commercially available), sucralfate (available as Commercially available), lactulose (available as Diovol® (available as Diovol® 250 mg tablets, available from Bactrim® (available as Bactrim® DS, available from Hyzaar® (available as Hyzaar® 50 / 12.5 mg tablets, available from Colazal® (available as Colazal® 375 mg tablets, available from Zofran® (available as Zofran® 8 mg tablets, available from Clistin® (available as Clistin® 10 mg tablets, available from Nexium® (available as Nexium® 40 mg capsules, available from Prilosec® (available as Prilosec® 20 mg tablets, available from Prevacid® (available as Prevacid® 30 mg tablets, available from Prevacid® (available as Prevacid® 30 mg tablets, available from Triozin® (available as Triozin® 500 mg tablets, available from Prilosec® (available as Prilosec® 20 mg tablets, available from Pepcid® (available as Pepcid® 20 mg tablets, available from Reglan® (available as Reglan® 5 mg tablets, available from or Tagamet® (available as Tagamet® 200 mg tablets, available from Pepcid® (available as Pepcid® 20 mg tablets, available from Pepcid® (available as Pepcid® 20 mg tablets, available from Zantac® (available as Zantac® 150 mg tablets, available from Hydrodiuril® (available as Hydrodiuril® 25 mg tablets, available from Diovol® (available as Diovol® 250 mg tablets, available from Bumex® (available as Bumex® 5 mg tablets, available from Lasix® (available as Lasix® 20 mg tablets, available from Hydrodiuril® (available as Hydrodiuril® 25 mg tablets, available from Lasix® (available as Lasix® 20 mg tablets, available from Hydrodiuril® (available as Hydrodiuril® 25 mg tablets, available from Hydrodiuril® (available as Hydrodiuril® 25 mg tablets, available from

[0055] Active agents useful herein can also include therapeutic agents for emphysema, such as tiotropium bromide (available as Spiriva® 18 μg capsules, available from Active agents useful herein can also include therapeutic agents for emphysema, such as tiotropium bromide (available as Spiriva® 18 μg capsules, available from Active agents useful herein can also include therapeutic agents for emphysema, such as tiotropium bromide (available as Spiriva® 18 μg capsules, available from Active agents useful herein can also include therapeutic agents for emphysema, such as tiotropium bromide (available as Spiriva® 18 μg capsules, available from Colazal® (available as Colazal® 375 mg tablets, available from Active agents useful herein can also include therapeutic agents for emphysema, such as tiotropium bromide (available as Spiriva® 18 μg capsules, available from Active agents useful herein can also include therapeutic agents for emphysema, such as tiotropium bromide (available as Spiriva® 18 μg capsules, available from Active agents useful herein can also include therapeutic agents for emphysema, such as tiotropium bromide (available as Spiriva® 18 μg capsules, available from​ Commercially available), Primidone (available as Commercially available), oxcarbazepine (available as Commercially available), zonisamide (available as Commercially available), levetiracetam (available as commercially available) and phenytoin sodium (available as commercially available).

[0056] Actives useful herein may also include ophthalmic drugs and therapeutic agents, such as dipivefrin hydrochloride (available as Commercially available), valganciclovir (available as Commercially available), ganciclovir eye gel (available as commercially available); Bepotastine besylate (available as Commercially available), besifloxacin (available as Commercially available), bromfenac (available as Commercially available), fluorometholone (available as Commercially available), pilocarpine hydrochloride (available as Commercially available), cyclosporine (available as Commercially available), brimonidine tartrate (available as Alphagan Commercially available), Dorzolamide hydrochloride / Timolol maleate (available as Commercially available), bimatoprost (available as Commercially available), timolol maleate (available as Commercially available), travoprost (available as Commercially available), latanoprost (available as commercially available), iodinated phosphocholine (available as Phospholine commercially available) and ranibizumab (available as commercially available); flow control agents such as acetazolamide (available as commercially available); gallstone medications, including ursodiol (available as commercially available); drugs used to treat gingivitis, including chlorhexidine gluconate (available as headache medications, including butalbital / codeine phosphate / aspirin / caffeine (available as Commercially available, containing codeine), naratriptan hydrochloride (available as Commercially available), almotriptan (available as Commercially available), ergotamine tartrate / caffeine (available as Commercially available), butalbital / acetaminophen / caffeine (available as commercially available), butalbital / aspirin / caffeine (available as Commercially available), frovatriptan succinate (available as Commercially available), Rizatriptan benzoate (available as Commercially available), Isometheptene Mucate / Chloralphenazone / Acetaminophen (available as Commercially available), dihydroergotamine mesylate (available as Commercially available), elatriptan hydrobromide (available as commercially available) and zolmitriptan (available as commercially available); influenza drugs, such as Haemophilus influenzae b conjugate vaccine; tetanus toxoid conjugate (available as commercially available); and cardiac therapeutic agents, including quinidine sulfate, isosorbide dinitrate / hydralazine hydrochloride (available as Commercially available), digoxin (available as Commercially available), Flecainide acetate (available as Commercially available), mexiletine hydrochloride (available as Commercially available), disopyramide phosphate (available as Commercially available), procainamide hydrochloride (available as commercially available) and propafenone (available as commercially available).

[0057] Other active ingredients available include hepatitis treatments, including entecavir (available as Commercially available), hepatitis B immune globulin (available as HepaGam commercially available) and ribavirin (copegus / rebetol / ribasphere / vilona / virazole) (available as commercially available); herpes therapeutic agents, including valacyclovir hydrochloride (available as Commercially available), penciclovir (available as Commercially available), acyclovir (available as commercially available) and famciclovir (available as commercially available); therapeutic agents for hypertension, including enalaprilat (available as Commercially available), Captopril (available as commercially available) and lisinopril (available as Commercially available), Verapamil hydrochloride (available as Commercially available), Ramipril (available as Olmesartan medoxomil (available as Commercially available), amlodipine / atorvastatin (available as Commercially available), Nicardipine hydrochloride (available as Commercially available), diltiazem hydrochloride (Can be used as Commercially available), Quinapril Hydrochloride (available as quinapril / hydrochlorothiazide (available as Accupril® commercially available), perindopril (available as Aceon® commercially available), candesartan cilexitil (available as Atacand® commercially available), candesartan cilexitil / hydrochlorothiazide (available as Atacand® commercially available), irbesartan / hydrochlorothiazide (available as Hyzaar® commercially available), irbesartan (available as Avapro® commercially available), olmesartan medoxomil (available as Benicar® commercially available), levobunolol hydrochloride (available as Betagan® commercially available), betaxolol hydrochloride (available as Kerlone® commercially available), nebivolol (available as Teveten® commercially available), captopril / hydrochlorothiazide (available as Capozide® commercially available), doxazosin mesylate (available as Cardura® commercially available), clonidine hydrochloride (available as Catapres® commercially available), carvedilol (available as Dilacor® commercially available), nadolol (available as Corgard® commercially available), nadolol / bendroflumethiazide (available as Corzide® commercially available), valsartan (available as Diovan® commercially available), isradipine (available as DynaCirc® commercially available), guanabenz acetate (available as Wytensin® commercially available), guanfacine hydrochloride (available as Tenex® or commercially available), losartan potassium / hydrochlorothiazide (available as Hyzaar® commercially available), propranolol hydrochloride (available as Inderal® commercially available), propranolol hydrochloride / hydrochlorothiazide (available as Inderide® commercially available), eplerenone (available as Inspra® commercially available), ambrisentan (available as Letairis® commercially available), enalapril maleate / felodipine (available as Lexxel® commercially available), metoprolol tartrate (available as Lopressor® commercially available), benazepril hydrochloride (available as Lotensin® commercially available), benazepril hydrochloride / hydrochlorothiazide (available as Lotensin HCT® commercially available), amlodipine besylate / benazepril hydrochloride (available as Lotrel® commercially available), indapamide (available as Lozol® commercially available), trandolapril (available as Mavik® commercially available), telmisartan (available as Micardis® commercially available), telmisartan / hydrochlorothiazide (available as Micardis HCT® commercially available), prazosin hydrochloride (available as Minipress® (available as Ziac®, Wyeth), amiloride, hydrochlorothiazide (available as (available as Ziac®, Wyeth), fosinopril sodium (available as Monopril® (available as Ziac®, Wyeth), fosinopril sodium / hydrochlorothiazide (available as (available as Ziac®, Wyeth), propranolol (available as Inderal® (available as Ziac®, Wyeth), felodipine (available as Plendil® (available as Ziac®, Wyeth), sildenafil citrate (available as Viagra® (available as Ziac®, Wyeth), nisoldipine (available as Sular® (available as Ziac®, Wyeth), trandolapril / verapamil hydrochloride (available as (available as Ziac®, Wyeth), aliskiren (available as Tekturna® (available as Ziac®, Wyeth), eprosartan mesylate (available as Teveten® (available as Ziac®, Wyeth), eprosartan mesylate / hydrochlorothiazide (available as (available as Ziac®, Wyeth), moexipril hydrochloride / hydrochlorothiazide (available as (available as Ziac®, Wyeth), moexipril hydrochloride (available as Univasc® (available as Ziac®, Wyeth), enalapril maleate / hydrochlorothiazide (available as (available as Ziac®, Wyeth), and lisinopril / hydrochlorothiazide (available as Prinzide® (available as Ziac®, Wyeth).

[0058] The films of the present disclosure can include active of a drug useful in the treatment of HIV / AIDS, such as amprenavir (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® (available as Agenerase® Tenofovir disoproxil fumarate (available as VIREAD® Stavudine (available as ZERIT® Zidovudine (available as RETROVIR® Homocysteine removers, including anhydrous betaine (available as Drugs, such as insulin (available as HUMALOG® and HPV treatments, such as human papillomavirus vaccine (available as GARDASIL® bivalent (available as CERVARIX® Immunosuppressants, including cyclosporine (available as SANDIMMUNE® and

[0059] Active materials useful in the present disclosure can also include prolactin inhibitors, such as bromocriptine mesylate (available as PARLDEL® Drugs to aid in stress testing, such as regadenoson (available as LEXICAN® Drugs for baldness, including finasteride (available as PROPECIA® and Pancreatitis treatments, such as gemfibrozil (available as LOPIPTOR® Hormonal drugs, such as norethindrone acetate / ethinyl estradiol (available as ORTH-EST® Goserelin acetate (available as ZOLADEX® Progesterone gel (available as CRINALEN® Progesterone (available as PROVERA® Salmon calcitonin (available as Miacalcic® Calcitriol (available as ROCALTROL® Levothyroxine sodium (synthroid) (available as LEVO-T® Testosterone (available as ANDROGEL® and Menopausal drugs, such as estradiol / norethindrone acetate (available as CLIMARA® Drospirenone / estradiol (available as YASMIN® Estradiol / levonorgestrel (available as CLIMARA® Estradiol / norethindrone acetate (available as ORTH-EST® Estradiol (available as ESTRACE® and Estradiol (available as ESTRACE® Estradiol (available as ESTRACE® ​Commercially available), estrone sulfate piperazine (estropipate) (available as Commercially available), conjugated estrogens (available as commercially available) and medroxyprogesterone acetate (available as commercially available); menstrual medications, including leuprolide acetate (available as Lupron Depot), tranexamic acid (available as commercially available) and norethindrone acetate (available as commercially available); and muscle relaxants, including cyclobenzaprine hydrochloride (available as Commercially available), tizanidine (available as Commercially available) and hyoscyamine sulfate (available as commercially available).

[0060] Actives useful herein may also include osteoporosis medications, including ibandronate sodium (available as Commercially available), risedronate (available as Commercially available), raloxifene hydrochloride (available as commercially available) and alendronate sodium (available as commercially available); ovulation enhancers, including clomiphene citrate (available as Paget's disease treatment agents, such as etidronate disodium (available as commercially available); pancreatic enzyme deficiency drugs, such as pancreatic lipase (available as or drugs used to treat Parkinson's disease, such as pramipexole dihydrochloride (available as Commercially available), ropinirole hydrochloride (available as Commercially available), carbidopa / levodopa (available as Sinemet Commercially available), carbidopa / levodopa / entacapone (available as Commercially available), selegiline hydrochloride (available as Commercially available), Rasagiline (available as Commercially available), Entacapone (available as Commercially available) and selegiline hydrochloride (available as multiple sclerosis drugs, such as dalfampridine (available as Commercially available) and interferon beta-Ib (available as commercially available); prostate drugs, including flutamide (available as Commercially available), Nilutamide (available as Commercially available), dutasteride (available as Commercially available), tamsulosin hydrochloride (available as Commercially available), terazosin hydrochloride (available as (available as (available as

[0061] The films of the present disclosure can also comprise psychotropic drugs, including alprazolam (available as Xanax®, and salt of alprazolam (available as Xanax XR®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Haldol®, and haloperidol decanoate (available as Haldol Decanoate®). (available as Prozac®, and fluoxetine hydrochloride (available as Prozac Weekly®). (available as Lexapro®, and escitalopram oxalate (available as Lexapro CR®). (available as Abilify®, and aripiprazole lauroxil (available as Abilify Maintena®). (available as Seroquel®, and quetiapine fumarate (available as Seroquel XR®). (available as Saphris®, and iloperidone (available as Saphris XR®). (available as Paxil®, and paroxetine hydrochloride (available as Paxil CR®). (available as Aristda®, and aripiprazole (available as Aristda Meltada®). (available as Wellbutrin®, and bupropion hydrochloride (available as Wellbutrin SR®). (available as Elavil®, and amitriptyline hydrochloride (available as Elavil CR®). (available as Buspar®, and buspirone hydrochloride (available as Buspar CR®). (available as Buspar®, and buspirone hydrochloride (available as Buspar CR®). (available as Celexa®, and citalopram hydrobromide (available as Celexa CR®). (available as Ritalin®, and methylphenidate hydrochloride (available as Ritalin SR®). (available as Depakote®, and divalproex sodium (valproic acid) (available as Depakote ER®). (available as Depakene®, and valproate semisodium (valproic acid) (available as Depakene ER®). (available as Effexor®, and venlafaxine hydrochloride (available as Effexor XR®). (available as Eldepryl®, and selegiline hydrochloride (available as Eldepryl CR®). (available as Equetro®, and carbamazepine (available as Equetro CR®). (available as Lithobid®, and lithium carbonate (available as Lithobid CR®). (available as Luvox®, and fluvoxamine maleate / dexmethylphenidate hydrochloride (available as Luvox CR®). (available as Seroquel®, and quetiapine fumarate (available as Seroquel XR®). (available as Inderal®, and propranolol hydrochloride (available as Inderal LA®). (available as Inderal®, and propranolol hydrochloride (available as Inderal LA®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). (available as Zyprexa®, and olanzapine pamoate (available as Zyprexa Relprev®). Commercially available), prochlorperazine, mirtazapine (available as Commercially available), risperidone (available as Commercially available), quetiapine fumarate (available as Commercially available), doxepin hydrochloride (available as Commercially available) atomoxetine hydrochloride (available as Commercially available), trimipramine maleate (available as Commercially available), olanzapine / fluoxetine hydrochloride (available as Commercially available), imipramine hydrochloride (available as Commercially available), protriptyline hydrochloride (available as Commercially available), bupropion hydrochloride (available as Wellbutrin and Wellbutrin commercially available) and olanzapine (available as commercially available).

[0062] Actives useful herein may also include uric acid lowering therapeutic agents, including allopurinol (available as commercially available); seizure medications, including gabapentin (available as Commercially available), ethotoin (available as Commercially available), vigabatrin (available as commercially available) and topiramate (available as commercially available); therapeutic agents for herpes zoster, such as herpes zoster live vaccine (available as commercially available); skin care products, including calcitriol (available as Commercially available), Ustekinumab (available as Commercially available), telavancin (available as Commercially available), isotretinoin (available as Commercially available), hydrocortisone / iodoquinol (available as Commercially available), sulfacetamide sodium / sulfur (available as Commercially available), azelaic acid (available as Commercially available), benzoyl peroxide (available as Commercially available), Adapalene (available as Commercially available), fluorouracil (available as Commercially available), pimecrolimus (available as Commercially available), topical erythromycin (available as Commercially available), hydrocortisone (available as Commercially available), metronidazole (available as Commercially available), doxycycline (available as Commercially available), retinoic acid (available as and Commercially available), paramethoxyphenol / retinoic acid (available as Commercially available), vitamin A acid (available as Commercially available), calcipotriol hydrate / betamethasone dipropionate (available as Commercially available), tazarotene (available as Commercially available), fluocinonide (available as Commercially available), desonide (available as Commercially available), miconazole nitrate / zinc oxide (available as Commercially available), ketoconazole (available as commercially available) and efalizumab (available as commercially available).

[0063] Other actives useful herein may include sleep disorder medications, including zaleplon (available as Commercially available), eszopiclone (available as Commercially available), Zolpidem tartrate (available as Ambien Commercially available), lorazepam (available as Commercially available), Flurazepam hydrochloride (available as Commercially available), triazolam (available as Commercially available), clonazepam (available as commercially available), barbiturates, e.g. ), Modafinil (can be used as Commercially available), temazepam (available as Commercially available), ramelteon (available as Commercially available), chlorine Potassium phosphate (can be used as Commercially available), diazepam (available as commercially available), quazepam (available as commercially available) and estazolam (available as commercially available); smoking cessation medications, such as varenicline (available as Commercially available), nicotine such as and bupropion hydrochloride (available as commercially available); and steroids, including alclomethasone dipropionate (available as Commercially available), betamethasone dipropionate (available as Commercially available), mometasone furoate (available as Commercially available), fluticasone (available as Flovent Flovent Commercially available), fluocinonide (available as Commercially available), mometasone furoate monohydrate (available as Commercially available), desoxymethasone (available as Commercially available), clotrimazole / betamethasone dipropionate (available as Commercially available), prednisolone acetate (available as Pred Budesonide Rhinocort Commercially available), prednisolone sodium phosphate (available as Commercially available), desonide (available as commercially available) and halobetasol propionate (available as commercially available).

[0064] The film of the present invention may also contain active substances that can be used for the treatment of thyroid diseases, such as hormones TC and TD (which can be used as Armour commercially available); potassium deficiency treatments, including potassium chloride (available as commercially available); triglyceride regulators, including ω-3-acid ethyl esters (available as commercially available); urinary system drugs, such as phenazopyridine hydrochloride (available as commercially available) and methenamine, methylene blue / phenyl salicylate / benzoic acid / atropine sulfate / hyoscyamine (available as commercially available); prenatal vitamins (available as Advanced

[0065] Prenate weight management drugs, including orlistat (available as commercially available).

[0066] Common H2-antagonists contemplated for use herein include cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifentidine, roxatidine, pisatidine, and aceroxatidine.

[0067] Active antacid ingredients include, but are not limited to, the following: aluminum hydroxide, dihydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate, sodium dihydroxyaluminum carbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth subsalicylate, calcium carbonate, calcium phosphate, citric acid (acid or salt), glycine, magnesium aluminum silicate, magaldrate, magnesium aluminate silicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solid, aluminum mono- or di-basic calcium phosphate, tribasic calcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminate silicate, tartaric acid and salts.

[0068] The pharmaceutically active agents used in the present application can include allergens or antigens such as, but not limited to, plant pollens from grasses, trees, or ragweed; animal dander, which are tiny scales of skin and hair that fall from the skin and fur of cats and other furry animals; insects such as house dust mites, bees, and wasps; and pharmaceuticals such as penicillin.

[0069] Examples of specific active agents include, but are not limited to, 16-alpha fluorocstradiol, 16-alpha-gitoxin, 16-epiestriol, 17 alpha dihydroequilenin, 17 alpha estradiol, 17 beta estradiol, 17 hydroxy progesterone, lalpha-hydroxyvitamin D2, 1-dodecpyrrolidinone, 20-epi-1,25 dihydroxyvitamin D3, 22- 22-oxacalcitriol, 2CVV, 2'-anortho-cGMP, 3-isobutyl GABA, 5-ethynyluracil, 6-FUDCA, 7-methoxytacrine, Abamectin, abanoquil, abecarnil, abiraterone, Ablukast, Ablukast Sodium, Acadesine, acamprosate, Acarbose, Acebutolol, Acecainide Hydrochloride, Aceclidine, aceclofenae, Acedapsone, Aceglutamide Aluminum), Acemannan, Acetaminophen, Acetazolamide, Acetohexamide, Acetohydroxamic Acid, Acetomepregenol, Acetophenazine Maleate, Acetosulfone Sodium, Acetylcholine Chloride, Acetylcysteine, Acetyl-L-Carnitine, Acetylmethadol, Acifran, Acipimox, Acitemate, Acitretin, Acivicin, Aclarubicin, Aclatonium, Acodazole Hydrochloride, Aconiazid oniazide), Acrisorcin, Acrivastine, Acronine, Actisomide, Actodigin, Acyclovir, acylfulvene, Adafenoxate, Adapalene, Adapalene, Adatanserin, Adatanserin hydrochlorideHydrochloride), adecypenol, adecypenol, Adefovir, Adelmidrol, Ademetionine, Adenosine, Adinazolam, Adipheinine Hydrochloride, Adiposin, Adozelesin, Adrafinil, Adrenalone, Airbutamine, Alacepril, Alamecin, Alanine, Alaproclate, Alaptide, Albendazole, Albolabrin, Albuterol, Albutoin, Alclofenae, Alclometasone Dipropionate, Alcloxa, aldecalmycin, Aldesleukin, Aldioxa, Alendronate Sodium, Alendronic Acid, Alentemol, Alentemol Hydrobromide, Allylphenethylamine Hydrochloride, Allylphenethylamine Chloride Chloride), Alexidine, Alfacalcidol, Alfentanil Hydrochloride, Alfuzosin, Algestrol, Cerebrosidase, Aliflurane, Alinastine, Alipamide, Allantoin, Allobarbital, Allopurinol, ALL-TK Antagonist, Alogliptin, Alomidone, Alosetron, Alosetron Hydrochloride, Alovudine, Alpertin, Alpha Amylase, Alidosone, Apidem, Alprazolam, Alprenolol Hydrochloride, Alprenoxime Hydrochloride, Alprostadil, Astatin Sodium, Atanserin Tartrate, Alteplase, Althiazide, Hexamethylmelamine, Altromycin B, Alverin Citrate, AlvirceptorSudotox), amadinone acetate, amantadine hydrochloride, amoxicillin, ambomycin, ambutin, ambuphylline, ambuside, amcifar, amcinonide, amdinocillin, amdinocillin pivoxil, ammethadone hydrochloride, alometasone, amoxicillin, amezinium metilsulfate, amfebutamone, amfenac sodium, amifentazole, amifentazole, amifentine, amifentrine mesylate, sulfamethoxazole Amidox, Amifloxacin, Amifostine, Amikacin, Amiloride Hydrochloride, Amilorzine Hydrochloride, Aminobenzoic Acid Potassium, Aminobenzoic Acid Sodium, Amino Caproic Acid, Aminoglutethimide, Aminohippurate Sodium, Aminolevulinic Acid, Aminophylline, Aminorex, Aminosalicylate Sodium, Aminosalicylic Acid, Amiodarone, Amiprilose Hydrochloride, Amiqulugel, Amixetril, Amitriptyline Hydrochloride, Amlexanox, Amlodipine, Amobarbital Sodium, Amoils, Amoils Hydrochloride, Amorolfine, Amoxapine, Amoxicillin, Amphecloral, Amphetamine Sulfate, Amphomycin, Amphotericin B, Ampicillin, Ampiroxicoll, Azamianidine Sulfate, Amquinoline, Amrinone, Amrinone, Amsacrine, Anagrelide, Anakinra, Ananain, Anaritide, Anaritide Acetate, Anastrozole, Anazolene Sodium, Ancrod, Andrographolid, Androstenone, Angiostatin, Angiotensin Amide, Anidoxorubicin, Anileridine, Anisamide Hydrochloride, Aniracetam, Anisotropine Methylbromide, Anistreplase, Anitrazafen, Anordrin, Antagonist D, Antagonist G, Antarelix, Antazoline Phosphate, Anthelmycin, Anthraquinone, Antiandrogen, Acedapsone, Aprlonidex, Antiestrogen, Antineoplaston, Antipyrine, Antisense Oligonucleotide, Apadoline, Apafant, Apalcillin Sodium, Apatadine, Apazone, Aphidicolin Glycinate, Apixifylline, Apomorphine Hydrochloride, Apraclonidine, Apraclonidine Hydrochloride, Apramycin, Aprindine, Aprindine Hydrochloride, Aprousate Sodium, Aprotinin, Artane Maleate, Artila, Apurinic Acid,acid), Alendipine, Alantolactone, Albaspidin, Arbekicin, Arbodol, Abubutamine Hydrochloride, Arclofenin, Ardeparin Sodium, Argatroban, Arginine, Arginine Tannate, Arimoclomol, Aripiprazol, Arotinolol, Arpinocid, Artilafrine, Artilide, Artridol, Aspalatone, Asparaginase, Asparic Acid, Aspartocin, Asperfuran, Aspirin, Aspoxicillin, Asprelin, Astemizole, Astromicin Sulfate, Asulacrine, Atamestane, Atenolol, Atifedine, Atiprosin, Atiprosin Maleate, Atorlide, Atorvastatin Calcium, Atosiban, Atovaquone, Atpenin B, Atracurium Besylate, Altretamine, Atromide, Atropine, Auranofin, Aureobasidin A, Aurothioglucose, Avilamycin, Avoparcin, Axid, Axinastatin 1, Axinastatin 2, Axinastatin 3, Azabuzine, Azacitidine, Azacyclon, Azacovanazole, Azadirachtine, Azalanstat Di-Hydrochloride, Azakerbine Fumarate, Azanator Maleate, Azanomide, Azaperone, Azaridin, Azaridin, Diazomethyl L-Glutamine, Azasetron, Azatoxin, Azatyrosine, Azelaic Acid, Azelastine, Azelnidipine, Azepine Azepine Azepindole, Azaribine, Azelintide, Azithromycin, Azlocillin, Azolamine, Azomide, Ambomycin, Aztreonam, Azumolene, Bacampicillin Hydrochloride, Baccatin III, Bacitracin, Baclofen, Bacoside A, Bacoside B, Bactobolamine, Balanol, Balaplan, Balhimycin, Balofloxacin, Balsalazide, Bambermycins, Bamipyron, Bamethan Sulfate, Bamifylline Hydrochloride, Bamidazole, Baohuoside 1, Barmsultan, Barnidipine, Basigin, Bathafrine Hydrochloride, Batimistat, Batroxobin, Banzitimine, Barium, Basatin, Banzelin, Barmastat, Beauvericin, Benactyzine Hydrochloride, Becaplermin, Becantazole, Beclomethasone Dipropionate, Bedofenazine, Beinserazide, Beloxepin, Belladonna, Belomifene, Belometon, Bemegride, Benazepril Hydrochloride, Benazeprilat, Bendaclofen, Bendazac, Bendroflumethiazide, Benfluorex, Benidipine, Benolone, Benoxacor, Benoxinate Hydrochloride, Benperidol, Benprin, Benreotamine, Ben tropine, Ben tropine, Ben Benzocaine, benzochlorins, benzotamine hydrochloride, benzozotepane, benzoidazoxan, benzonatate, benzoyl peroxide, Benzoylpas Calcium, benzoylstaurosporine, benzquinamide, benzthiazide, benztropine, benztropine mesylate, benzdamine hydrochloride, Benzylpenicilloylpolylysine, Bepridil, Bepridil hydrochloride, Beractant, Beraprost, Berefrin, Beraprostol, Betoprostol, Erythromycin B, Besipiridine, β-alethine, betaclamycin B, Betamethasone, Betamyron, Betaxolol, Betaxolol hydrochloride, Bethanechol Chloride), Bethanidine Sulfate, Betulinic acid, Bevantolol, Bevantolol hydrochloride, Bezafibrate, bFGF inhibitor, Bilamicol hydrochloride, Biapenem, Bicalutamide, Bicifadine hydrochloride, Diclofenac hydrochloride, Bidisomide, Bifemelane, Bifonazole, Bicarin, Bimithil, Bindali, Binimycin, Bispirone, Bioxalomycin α2, Biperidinol hydrochloride, Biperiden, Genisalate hydrochloride, Biriperone, Bisantrene, Bisaremide, Bisaziridinylspermine, Bis-benzimidazole A, Bis-benzimidazole B, Bisnefad, Bisobryn Lactate, Bisoprolol, Bispyrithione Magsulfex, Bistramide D, Bistramide K, Bistratene A, sodium thiochlorophenate, bitolterol mesylate, bivalirudin, biszelesin, bleomycin sulfate, bolanodiol dipropionate, bolastolone, boldestanolone undecylenate, boldine, bolanodiol, bolmandolin, bopindolol, bosentan, boxidin, brefeldin, breflate, brequinar sodium, bretacenil, bretylium p-toluenesulfonic acidTosylate), Brufentanyl Hydrochloride, Brimonidine, Fibrinase, Broclisin, Broclinar, Brofoxine, Bromodolin Maleate, Bromazepam, Broclozolin, Bromelain, Bromelain, Brofenac, Brominidione, Bromocriptine, Bromophenadrine Hydrochloride, Bromoxamide, Bromperidol, Bromperidol Decanoate, Brompheniramine Maleate, Bromperimol, Bropiridone, Brotizolam, Bucamidol Maleate, Bucinolol, Buclizine Hydrochloride, Bucerolone, Budesonide, Budipine, Budotiamine, Buformin, Bumetanide, Bumetamide, Bunalast, Bunazosin, Bunolol Hydrochloride, Bupivacaine Hydrochloride, Bupivacaine Hydrochloride, Buprenorphine Hydrochloride, Bupropion Hydrochloride, Bupropionate, Buserelin Acetate, Buspirone Hydrochloride, Busulfan, Butabarbital, Butacetin, Butalamol Hydrochloride, Butalbital, Butamirate Citrate Citrate), Butapyrazine, Butaprost, Butedronate Tetrasodium, Butenafine, Butirizine, Buthionine sulfoximine, Butikacin, Butyfenamicin, Butirocin Sulfate, Butisir, Buticostat Propionate, Butoconazole Nitrate, Butolate, Butopamine, Butoprolol Hydrochloride, Butorphanol, Butoxamine Hydrochloride, Buttriptyline Hydrochloride, Cactinomycin, Cadexmer Iodine, Caffeine, Calomel A, Calcifediol, Calcipotriene, Calcipotriene, Calcitonin, Calcitriol, Calcium Undecylenate, Calcium Photoreceptor Protein C), Captestosterone, Cambendazole, Camogre, Camptothecin derivatives, Canagliflozin, Canarypox IL-2, Candesartan, Candida albicans, Canxatril, Candoxatrilat, Caniglibose, Canrenoate Potassium, Canrenone, Capecitabine, Capobenate Sodium, Capobenic Acid, Capromycin Sulfate, Capromab, Capsaicin, Captopril, Caprourea, Caracetamide, Carbachol, Carbadox, Carbamazepine, Carbamide Peroxide, Carbantel Lauryl Sulfate, Carbaspirin CalciumCalcium), Carbazeran, Carbazomycin C, Carbenicillin Potassium, Carbenoxolone Sodium, Carbenoxolone, Carbetimer, Carbetocin, Carbidopa, Carbidopa-levodopa, Carbinoxamine Maleate, Carbocromide, Carbocysteine, Carbol- fuchsin, Carboplatin, Carboprost, Carbovir, Carboxamide-amino-azido-le, Carboxamidyl triazole, Carboxamidyl triazole beta-1,3-glucan, Carbuterol Hydrochloride, CaRest M3, Carfentanyl Citrate, Carcainium, Carfimate, Carmustine, CARN 700, Camidazole, Carosazone, Carpeptide, Carphenazine Maleate, Carprofen, Carsamide, Cartazolate, Carteolol, Carteolol Hydrochloride, Cartilage derived inhibitor, Carubicin Hydrochloride, Carumonam Sodium, Carvedilol, Carvotroline, Carvotroline Hydrochloride, Carzelesin, Casein kinase inhibitors (ICOS), Castanospermine, Caurumonam, Cedax, Cecropin B, Cedefingol, Cefaclor, Cefadroxil, Cefamandole, Cefaparole, Cefatrizine, Cefazolin, Cefbuperazone, Cefcapene Pivoxil, Cefdaloxime Pentexil Tosilate, Cefdinir, Cefditoren Pivoxil, Cefepime, Cefetamet, Cefixime, Cefmenoxime, Cefinenoxime Hydrochloride, Cefinetazole, Cefminox, Cefoperazone Sodium, Ceforamide, Cefoselis, Cefotaxime Sodium, Cefotetan, Cefotiam, Cefoxitin, Cefozopran, Cefpimizole, Cefpiramide, Cefpirome, Cefpodoxime Proxetil, Cefprozil, Cefroxime, Cefsulodin, Ceftazidime, Cefteram, Cefbuten, Cefuroxime, Celastrol, Celikalim, Celiprolol, CepacidiineA. Ceftriaxone sodium, cephalexin, cefuroxime, cephaloridine, ceftriaxone sodium, cefpirin sodium, cephradine, cephaloridine, cerivastatin, ciloprolol, certoparin sodium, blue peptide, cetabene sodium, cetablonium chloride, cetalol hydrochloride, cetirizine, acetylchloramphenicol, cetraxate hydrochloride, cetrorelix, cetylpyridinium chloride, chenodeoxycholic acid, clophedanol hydrochloride, chloral betaine, chlorambucil, chloramphenicol, chlordentoin, chlorantoin (Chlordiazepoxide), Chlorhexidine Gluconate, Chlorins, Chlormadinone Acetate, Chloroorienticin A, Chloroprocaine Hydrochloride, Chlorpropamide, Chloroquine, Chloroquinoxaline sulfonamide, Chlorothiazide, Chlorotrianisene, Chloroxine, Chloroxylenol, Chlorphenesin Carbamate, Chlorpheniramine Maleate, Chloφromazine, Chlorpropamide, Chlorthiazox, Chlorthalidone, Chlorthiazolyl, Cholestyramine Resin, Clomazone, Clonidine, Cicaprost, Clonidine, Cyclazodine, Ciclesonide, Cilostazol, Ciproconazole, Ciprofloxacin, Ciprofibrate, Ciproxifan, Cisapride, Cimetidine, Cimetropium Bromide, Cinacalcet, Cinanserin, Cinepazide Maleate, Cinoxolone, Cinoxidine, Cinoxamate, Cinitapride, Cinitapril, Cinmetacine, Cinnarizine, Cinncalumate, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, Ciproxifan, CPhosphate), chlorpromazine acetate, clomacran phosphate, clomezepine acetate, clomethiazole, clomifene analogs, clomiphene citrate, clomipramine hydrochloride, clonazepam, clonidine, clonidine, cloniglyceride, clonisel, clonixin, clopamide, clopenthixol, cloloperidone hydrochloride, clopidogrel, clopimozil, clopiperazine mesylate, clopiracic acid, cloprednisolone, cloprostenol sodium, dipotassium chlordiazepoxide (Clorazepate Dipotassium), clorazepate, clorsulon, chlorpenthixol, clorprenaline hydrochloride, chlorpromazine, chlorquinox, closiramine aceturate, chlorprothixene, clothixamide maleate, clocortolone pivalate, clotrimazole, cloxacillin benzathine, clomocycline, clozapine, cocaine, coccidioidin, codeine, colchicine, colchicine, colchicine, colestimide, colestimide hydrochloride, colestipol, colfosceril palmitate, colistimethate sodium, colistin sulfate, collismycin A, collismycin B, colterol mesylate, combretastatin A4, combretastatin analogs, complestatin, conagenin, conorphone hydrochloride, contignasterol, contortrostatin, cormethasone acetate, corticorelin sheep Triflutate, corticotropin, cortisone acetate, cortivazol, cortolone, cosalane, costatolide, cosyntropin, cotarnine, coumarin (Coumadin), coumermycin, cram bescidin 816, crilvastatin, crisnatol, cromolyn sodium, cromolyn, cryptophycin 8, cucumariosid, cuprimycin, curacinA, curdlan sulfate, curiosin, cyclopentanthraquinone, cyclazosin, cyclo-HPMPC, cycloclindole, cylilamin maleate, cyclizine, cyclobendazole, cyclobenzaprine, cyclobutanecarboxylic acid A, cyclobutanecarboxylic acid G, tranexamic acid (cyclocapron), cycloguanil pamoate, cycloheximide, cyclopentanthraquinones, cyclopenthiazine, hydrochloric acid Cyclopentolate, ciprofen hydrochloride, cyclophosphamide, cycloplatam, cyclopropane, cycloserine, cyclosin, cyclosporine, cyclothialidine, cyclothiazide, cyclothiazomycin, cycloheptamide, cypemycin, phenylcyclopentylamine hydrochloride, ciproazepam, cyproheptadine hydrochloride, cyproterone acetate, cyproterone acetate, cysteamine, cysteine ​​hydrochloride, cystine, cytarabine, cytarabine hydrochloride, cytarabine octadecyl phosphate ocfosfate), cytochalasin B, cytolytic factor, cytostatin, dacarbazine, dacximab, dactimicin, dactinomycin, daidzein, dalfopristin, dalteparin sodium, daltroban, dalvastatin, danaparoid, danazol, dantrolene, dapagliflozin, daphnodorin A, dapoxetine, dapoxetine hydrochloride, dapsone, daptomycin, daglitazone sodium, darifenacin, darlucin A, darodipine, dacxidomine, daunorubicin hydrochloride, dazadrol maleate, nitrogen hydrochloride Dazepinil Hydrochloride, Dazepinil, Dazopril Fumarate, Dazoxan Hydrochloride, Debrisoquin Sulfate, Decitabine, Deferiprone, Deflazacort, Dehydrocholic Acid, dehydrodidemnin B, Dehydroepiandrosterone, Delapril, Delapril Hydrochloride, Delavirdine Mesylate, Dilequat, Dephapiperazine, Delmadinone Acetate, Delmopinol, Delphinidin, Demecarium Bromide, Demeclocycline, Demeclocycline, Demozepam, Denofungin, Deoxypyridinoline, Depakote, Deproton, Deprost, Depsidomycin, Deramciclane, Dermatan Sulfate sulfate), deciclovir, desiframine acetonide, desflurane, desipramine hydrochloride, desirudin, desacetyl lanolin, deserelin, desmopressin, desogestrel, desonide, desoximetasone, desoxoamiodarone, desoxycorticosterone acetate, detajmium bitartrate, detenol hydrochloride, detirol acetate, devacipiridone, dexamethasone, dexbrompheniramine maleate, dexchlorpheniramine maleate, dexclamol hydrochloride Hydrochloride), Dexbenzimide, Dexfenfluramine Hydrochloride, Dexifosfamide, Deximafen, Dexketoprofen, Dexloglitamide, Dexmedetomidine, Dextromaplatin, Dexoxadrol Hydrochloride, Dexpanthenol, Dexpemetrexate, Dexpropranolol Hydrochloride, Dexrazoxane, Dexsotalol, Dextrin 2-Sulfate, Dextroamphetamine, Dextromethorphan, Dextrorphan Hydrochloride, Dextrothyroxine Sodium, Dexverapamil, Dezaguanine, Dezinamide, Dezocine, Diacetolol Hydrochloride, Diacaine Cyclamate, Diapamide, Diatrizoate Meglumine, Diatrizoic AcidAcid), diaminoveratridine, diazepam, diazepam, diazoxide, dibenzothiophene, dibucaine, dichlorvos, chloralphenazone, diclofenac sodium, dicloxacillin, dicranin, dicumarol, dicyclomine hydrochloride, didanosine, didemnin B, didox, dienestrol, dienogest, diethylcarbamazine citrate, diethylhomospermine, diethylnorspermine, amphetamine hydrochloride, diethylstilbestrol, difenoximide hydrochloride, difenoxin, diflorasone diacetate, difloxacin hydrochloride, difluanine hydrochloride Hydrochloride), diflucortolone, diflunisal, difluprednate, diflustatone, digitalis, digitoxin, digoxin, dihexiverine hydrochloride, dihydrexidine, dihydro-5-azacytidine, dihydrocodeine tartrate Bitartrate), dihydroergotamine mesylate, dihydrotestosterone, dihydrostreptomycin sulfate, dihydrotachysterol, dihydropaclitaxel, 9-, Dilantin, dilevolol hydrochloride, diltiazem hydrochloride, dimethylfalden, dimethylflin hydrochloride, dimenhydrinate, dimercaprol, dimethyldione, dimethylindene maleate, dimethindene, dimethyl prostaglandin A1, dimethyl sulfoxide, dimethylhomospermine, dileracetam, dimoxamine hydrochloride, dinoprost, dinoprostone, dioxadrol hydrochloride, dioxadrol dioxamycin, diphenhydramine citrate, diphenidol, diphenoxylate hydrochloride, diphenylspiromustine, dipivefin hydrochloride, dipivefrin, dipliencyprone, dipropylnorspermine, dipyridamole, dipyrithione, analgin, erythromycin, discodermolide, disobutamide, disophenin, disopyramide, di Salicylic acid, disulfiram, Ditekiren, Divalproex Sodium, Diazoxide, Dobutamine, Docain, Docebenone, Docetaxel, Doconazole, Docosanol, Dofetilide, Dolasetron, Ebastine, Ebitide, Etodroxime, Ebutiole, Ecaprostene, Ecaprostene, Ecteinascidin 722, Edaravone, Edatrexate, Edelfosine, Edelfoside, Ebolizumab, Edoxudine, Edrecolomab, Edrophonium chloride, Edroxyprogesteone acetate, Eflomithine, Efloxate, Egualcen, Eflamizole, Eleatonin, Elemene, Eletriptan, Eleron, Elinogrel, Eliprodil, Elsalbalgin, Eltenae, Eiluocaine, Emalkalim, Emedastine, Emetine hydrochloride, Emiglitate, Emilium Tosylate, Emivirine, Emuizumab, Empagliflozin, Enadoline hydrochloride, Enalapril, Enalaprilat, Enalkret, Enasappat, Enecamptine, Enecamphate, Enecarbene, Endrysone, Enflurane, Enigmatuzone, Enilconazole, Eniprost, Enlimomab, Enloplatin, Enpraz, Enprone, Enoxacin, Enoxacin, Enoxaparin sodium, Enoxaparin sodium, Enoxilone, Enprestat, Enprostil, Enpromate, Enprone, Enterostatin, Enveprimone, Enveprimone, Ephedrine, Epicillin, Epimestrol, Epinephrine, Epinephryl borate, Epipropidine, Epirizole, Epirubicin, Epitetracycline hydrochloride, Epithiazide, Epoetin alfa, Epoetin beta, Epostane, Epostane sodium, Epoxymexrenone, Epristeride, Eprosartan, Eptastigmine, Equilenin, Equilin, Erbufoside, Erdosteine, Ergoloid mesylatesMesylates), ergonovine maleate, ergotamine tartrate, essenalide, erthiophene, erythritol, erythrityl tetranitrate, erythromycin, esmolol hydrochloride, esorubicin hydrochloride, esproquin hydrochloride, estazolam, estradiol, estramustine, estramustine analogs, estradiol hydrobromide, estriol, estrafuroxate, estrogen agonists, estrogen antagonists, estrogens, conjugated estrogens Estrogens), Esterified Estrone, Estrone Sulfate Piperazine (Estropipate), Ethiosulfapron, Ethyl Ephedrine Hydrochloride, Etanidazole, Etanterol, Etarotene, Etazolate Hydrochloride, Eterbital, Ethacizin, Ethacrynic Acid Sodium, Ethacrynic Acid, Ethambutol Hydrochloride, Vanillyl Diethylamine, Ethanolamine Oleate, Ethehlorvynol, Ethyl Ether, Ethinyl Estradiol, Ethiodized Oil, Ethionamide, Ethonam Nitrate, Ethopropazine Hydrochloride, Ethosuximide, Ethyltoin, Ethoxazene Hydrochloride, Ethybenztropine, Ethyl Chloride, Ethyl Dibutate Ethylenol, Ethyndiol, Ethynerone, Ethynodiol Diacetate, Ebendazole, Etidocaine, Etidronate Disodium, Etidronic Acid, Etifenin, Etintidine Hydrochloride, Etizolam, Etodolac, Etofenamate, Etoformin Hydrochloride, Etomidate, Etonogestrel, Etoperidone Hydrochloride, Etoposide, Etoprine, Ethylbenzene Hydrochloride Iridium salts, etazoline, eletrobamine, etretinate, ethyltryptamine acetate, eucatropine hydrochloride Hydrochloride), eugenol, euprofen hydrochloride, eveminomicin, examycin, ixarelin, fenpropol hydrochloride, exemestane, fadrozole, faeriefungin, famciclovir, famotidine, fampridine, pantofarone, pantotrexone hydrochloride, faropenem, fasidotril, fasudil, fazabarbine, fedotozin, felbamate, felbinac, felodipine, felypressin, fenalamide, fenamox, fenbendazole, fenbufen, fencibutol, fenclorac, fenclorac, fendosal, fenestralid, fenethylthecium hydrochloride, fenfluramine hydrochloride, phengabine, phenimide, fenilex, fenmetazole hydrochloride leHydrochloride), phenmethorphanone, fenofibrate, fenoxetine sulfate, fenofibrate, fenoldopam, fenoprofen, fenoterol, fenpipalone, fenprolast hydrochloride, fenproline, fenquinazole, fenretinide, fenspiride, fentanyl citrate, fentiazica, fenticol, fenticonazole, phenidinol hydrochloride, fepristinol, ferric pyrophosphate sodium, ferristene, ferrixan, dried ferrous sulfate, ferumoxides, ferumoxsil, fetosilate hydrochloride, fexofenadine, fezolamine fumarate fumarate), fecitabine, fealuridine, fibrinogen 1 125, filgrastim, filipin, finasteride, flavopiridol maleate, flavopiridol, flavopiridol hydrochloride, flavazadone, flecainide, flubuterol, fleroxacin, fluoxetine, flusitol sulfate, fluethazepam, flezelastine, flobufen, flufenicol, fluoxetine, fludipine, florfenicol, flufenicol, fluoxetine, flusacillin, flucloxacillin, fluxuridine, fluasterone, fluzacort, flubanate hydrochloride, flubendazole, flucilindole, fluclosanide, fluconazole, flucytosine, fluorodeuterated alanine, fludarabine phosphate, fludazonium Chloride), fluorodeoxyglucose F18, fludorex, fludrocortisone acetate, flufenamic acidFluoxetine, ... Decanoate), flupirtine, fluprednisolone, fluproquinezone, fluprostenol sodium, fluquinezone, fludoline hydrochloride, flurandrenolide, flurazepam hydrochloride, flurbiprofen, fluretofen, fluerythromycin, flucitabine, flufamide, fluprogesterone acetate, hexafluorodiethyl ester (Flurothyl), fluorovinyl ether, fluspirone, fluspirine, fluticasone propionate, flutrimazole, flutrene, fluvastatin, fluvastatin sodium, fluvoxamine, fluazifop, folic acid, follicle regulatory protein protein), folliculostatin, fomepizole, dimethazine mesylate, forlasartan, forfenirmex, formetane, formocort, formoterol, fosfenidone, fosazepam, foscarnet sodium, fosfomycin, fosfoethanol sodium, fosinopril, fosinoprilat, fosphenyloin, fosquinone, forsidil, fostricin, fotemustine, basic fuchsin, furomocillin, fungimycin, furaprofen, furazolidone, furazolium chloride, furoglulate sodium, furobufen, furodazole, furosemide, fusidate sodium, fusidic acid, gabapentin, gadobenate dimeglumine, gadobenic acid acid), gadobutrol, gadodiamide, gadotesaphyrin, gadopentetate dimeglumine, gadoteric acid, gadoteridol, gadoversetamide, galantamine, gadoteric acid ...acid, ganciclovir, ganirelix, gelatinase inhibitors, Gemcadiol, gemcitabine, gemeprost, gemfibrozil, gentamicin sulfate, gentian violet, gepirone, pregnathiacene, gestodene, pregnenolone caproate, gestrinone, givotrienolone hydrochloride, gilipamate, glaspimod, glaucocalyxin A, gliserine, glyburide, glibenclamide, glitanylate sodium, gliflunomide, glimepiride, glipizide, glomonam, glucagon, glutapyrone, glutathione inhibitors, glutethimide, glyburide, glycopine, glycopril, glycopyrrolate, glyhexamide, glipizide sodium, glipizide, glipizide, gold 198. Gonadoctrinins, Gonadotropins, Goserelin, Gramicidin, Granisetron, Grepafloxacin, Griseofulvin, Piperazine, Guaithylline, Guanabenzyl, Guanabenzyl Acetate, Guanadrenaline Sulfate, Guanacetidine, Guanethidine Monosulfate, Guanfacine Hydrochloride, Guanisoquin Sulfate, Guanocetine Sulfate, Guanoxetine Hydrochloride, Guanoxabenzyl, Guanoxetine Sulfate, Guanoxifene Sulfate, Guperimox Trihydrochloride, Halazepam, Halcinonide, Halichondrin B, Halobetasol Propionate Propionate), halofantrine, halofantrine hydrochloride, halofantrine, halofuginone hydrobromide, halomon, haloperidol, haloprenisolone, haloprenaline, haloprenaline hydrobromide, halomon, haloperidol, haloprenaline, haloprenaline hydrochloride, halothane, halquinol, halomycin, halomepausal gonadotropin, hatomamicin, hatomarubigin A, hatomarubigin B, hatomarubigin C, hatomarubigin D, heparin sodium, hepsulfam, heregulin, hetacillin, heteronium bromide, hexachlorophene, hydrogen peroxide, hexafluorenium bromide, hexamethylenediacetamide, hexidine, hexoprenaline sulfate, hexorabine, histamine phosphate, histidine, histoplasmosis, histrelin, homatropine hydrobromide Hydrobromide), hydralazine hydrochloride, human chorionic gonadotropin, hyaluronan, hydralazine hydrochloride, hydralazine vinylbenzene copolymerPolistirex), hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydroflumethiazide, hydromorphone hydrochloride, hydroxyamphetamine hydrobromide, hydroxychloroquine sulfate, hydroxyphenamate, hydroxyprogesterone caproate, hydroxyurea, hydroxyzine hydrochloride, hydroxymethylcoumarine, hyoscyamine, hypericin, ibafloxacin, ibandronic acid, ibogaine, ibopamide, ibudilate, ibuprofen, ibuprofen fumarate, icatibant acetate, ichthammol, icotidine, idarubicin, idoxifene, idoxuridine, idomethine, iemefloxacin, iesopitron, ifenprodil, ifosfamide, ilepeimide, illimaquinone, ilmofosine, ilomastat, ilomedipine, iloperidone, iloprost, imafen hydrochloride, imazodan hydrochloride, midodrine, imidazenil, imidazoacridones, imidecyl iodine, imidocarb hydrochloride, imidolinium hydrochloride, imidurea, imiloxy hydrochloride, imipenem, imipramine hydrochloride, imiquimod, immunopotentiator polypeptide, impramine hydrochloride, indacrinone, indapamide, indecainide hydrochloride, indenoxazine hydrochloride, indigotindisulfonate, indinavir, indocyanine green, indoramin hydrochloride, indoxamide, indoxole, indoxyl, indoxyl estrate hydrochloride, indoxyl, indoxyl, indoxyl, indoxyl, indoxyl, indoxyl,Acid), Iogulamide, Iohexol, Iomeprol, Iomethin I 125, Iopamidol, Iopanoic Acid, Iopentol, Iophenoxic Acid, Ioprocemic Acid, Iopromide, Iopronic Acid, Ioprodrol, Iopydol, Iopyrol, Iosefamic Acid, Ioseric Acid, Iotasulamide Meglumine, Iosumetic Acid, Iothalamate Sulfur, Iotetric Acid, Iothalamate Sodium, Iothalamic Acid, Iotexol, Iotroxic Acid, Iotyrosine I 131, Ioversol, Ioxagiate Sodium, Ioxaglate Meglumine, Ioxaglic Acid, Ioxilan, Ioxotrizoic Acid, Ipazilide, Ipexazone, Ipidacrine, Ipodate Calcium, Ipomeanol, 4-, Ipratropium Bromide, Ipropal, Iproindol, Iprofenin, Ipronidazole, Iproplatin, Iprozine, Irinotecan, Irofulven, Iroplax, Isoazotil, Isofladene, Isoflotazine, Isofuran, Isomoxole, Iporidone, Isopamycin, isobengazole, Isobutylphenyl Propionate, Isocarboxazid, Isokonazole, Isoetharine, isofloxythepin, Isofluroate, Isoflurane, Isofurophate, isohomohalicondrin B, Isoleucine, Isoxazole Hydrochloride, Isoxsuprine Hydrochloride, Isoniazid, Isonitine, Isopropyl Alcohol, Isopropyl Unoprostone, Isoprenaline Hydrochloride, Isosorbide, Isosorbide Mononitrate, Isoxazopyrimidine, Isotretinoin, Isoxepac, Isoxepac, Isoxsuprine Hydrochloride, Isradipine, Itameline, Itanserin, Itazigrel, Itopride, Itraconazole, Ivvermectin, jasplakinolide, Josamycin, kahalalide F, Kalafungin, Kanamycin Sulfate, Ketamine Hydrochloride, Ketanserin, Ketazocine, Ketazolam, Kethoxal, Ketipramine Fumarate,Fumarate), ketoconazole, ketoprofen, ketophanol, ketorolac, ketotifen fumarate, kitasamycin, labetalol hydrochloride, lacidipine, lactipine, lactitol, lactivicin, laennec, lafutidine, lamellarin-N triacetate, lamivudine, lamotrigine, lanoconazole, Lanoxin, lanpiridone, lanreotide, lansoprazole, latanoprost, lateritin, laurocapram, laurylisoquinoline nitrogen Bromide, Lavoltidine Succinate, Lazabemide, Lecifibrate, Leinamycin, Lemidipine, Leminprazole, Lenacep, Lenquinoxaline, Legrastim, Lenperone, Lentinan sulfate, Leptin, Leptolstatin, Lercanidipine, Ergonitrile, Lelisetron, Letiamide Hydrochloride, Letrazuril, Letrozole, Leucine, Leucomyzin, Leuprolide Acetate, Leuprolide + Estrogen + Progesterone, Leuprolide, Levamfetamine Succinate, Levamisole, Levodobutamine Lactobionate Lactobionate), D-cromakalim, Levetiracetam, Leveycloserine, Levobetaxolol, Levobunolol, Levobupivacaine, Levocabastine, Levocarnitine, Levodopa, Levodropropizine, Levofloxacin, Levofuraltazone, Levoleucovorin Calcium, Levomethadol Acetate Hydrochloride, Levomoprolol, Levandroxyl Hydrochloride, Levonorepinephrine, Levonorgestrel, Levopropoxyphene Napsylate, Levopropylcillin Potassium, Levomeloxifene, Levorphanol Tartrate Tartrate), levosimendan, levosulpride, levothyroxine sodium, levosulpiride hydrochloride, lexipafan, erythromycin, lialazole, lisofenpril, lidaamidine hydrochloride, lidocaine, lidofenine, lidoflazine, lifarazine, lifibrate, lifiberol, linaroten, lincomycin, linear polyamine analogs, linogliflozin, linopridine, linotroban, linsidomide, lintitript, lintopride, liothyronine I 125, liothyronine sodium, compound thyroxine (Liotrix), lisapride, lisinopril, lissoclinamide7、Lisuride, Lobaplatin, Lobenzarit Sodium, Lobucavir, Lodefran, Lodoxamide, Lofemizole Hydrochloride, Lofentan Oxalate, Lofepamine Hydrochloride, Lofexidine Hydrochloride, Lombricine, Lomefloxacin, Lomerizine, Lometraline Hydrochloride, Lometrexol, Lomofungin, Lomoxicam, Lomustine, Lonapalene, Lonazofen, Lonidamide Hydrochloride, Loracarbef, Lorajmine Hydrochloride, Loratadine, Loraazepam, Lormethasone, Lormetazepam Hydrochloride, Lorescinate, Lorexinadol, Loxamide, Loxapacine, Loxapacine, Loxazepam, Loxiglumic Acid, Loxonidine, Loxoribine, Luteinizing Hormone, Lurasidone, Lutetium, Lutropin Acetate, Luzindole, Lyapolate Sodium, Lycetamine, Lydicamycin, Lydimycin, Lyprinol, Lysine, Lysofylline, Lysozyme, Lytic Peptide, Maduramicin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, Mahafungin, MahHydrochloride), mefenamic acid, mefenamic acid, mefenamic acid hydrochloride ... sodium, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, mefenamic acid methyl ester, me Chloride), ammonia mercuric chloride, mercury Hg197 propanol, meropenem, mesalamine, mesilazine, mesoridazine, mesterolone, mestranol, mesulin hydrochloride, metalol hydrochloride, polyphenylene metaproterenol, metaminol bitartrate, metaxalone, methenolone, methadone hydrochloride, levomethadol acetate, methadone, methamphetamine hydrochloride, methaqualone, methazolamide, methicillin, methenamine, methenolone acetate, methexyl acetate, methicillin sodium, methimazole, methioninase, methionine, methixazone, methixol hydrochloride, methocarbamol, methohexital sodium, methoxfline, methotrexate, levomepromazine, toluene Ketone (methoxatone), methoxylflurane, methotrimeprazine, methyclothiazide, Methyl Palmoxirate, methylnitroate, methysergide, methylbenactyzium, methyldopa, methyldopa ethyl ester hydrochloride, methylene blue, methylergonovine maleate, methylhistamine, R-alpha, methylinosine monophosphate, methylphenidate hydrochloride, methylprednisolone, methyltestosterone, methynodiol diacelate, methysergide, methysergide maleate, methimazole, methithymol, metipranolol, metixene hydrochloride, metkephamid acetate, metoclopramide, metocurine iodide, 16, 16-dimethyl nandrolone (metogest), metolazone, metopimazine, metoxalene, metoprolol, metoxzine, meturedepa, metrizamide, metrizoate, metronidazole, meturedepa, metyrapone, methyrosine, mexiletine hydrochloride, meclofenamate sodium, mezlocillin, mfonelic Acid, mianserin hydrochloride, mibefradil, mibefradil dihydrochloride, mibolerone, michellamine B, miconazole, microcolin A, midodrine, midazolam hydrochloride, midodrine, mifepristone, mifobendate, miglitol, miraxamide, mirabegron, miraxapine, mimic, mimetibatin, miminoprine, minaprine, minaxolone, minocycline, minoxidil, minoxynil, miokamycin, mipafox, mirfentanyl, milodysine, miltefosine, mitobronitol, mitocarcin, mitocromin, mitocycin, mitoguazone, mitolactol, mitomycin, mitopodozide, mitopodozol, mitotane, mitoxantrone, mivacurium, mixanpril, mixidine, mizolastine, mizoribine, molindone hydrochloride, molindone, mometasone, monapirol maleate, monensin, monoctanoin, montelukast sodium, montirelin, monohydroxypropylated alcohol, moracizine, morantel tartrate, moracizine, morniflumate, morphine sulfate, sodium morrhuate, mosapride, mosapride citrate, motilide, moveltion, moxalactam disodium, moxazocine, moxifloxacin, moxonidine,Mumps skin test antigen, mustard anticancer agent, muzolomide, mycaperoxide B, mycophenolic acid, myriaporone, cannabinoid, nabilone, cannabinoid hydrochloride, cannabinoid hydrochloride, nabumetone, N-acetylbenzalone, coenzyme I, nadifloxacin, nadolol, nadroparin calcium, nafadotride, nafamostat, nafarelin, nafcillin sodium, naphthopine, nafedralone hydrochloride, nafedralone malate, nafedralone hydrochloride, nafedralone oxalate, naftifine hydrochloride, nafedralone, nafedralone, nagrestip, nalbuphine hydrochloride, naldemedine, nalidixic acid sodium, nalidixic acid, nalmefene, nalmefone hydrochloride, naloxone Pentazocine, Naltrexone, Namoride, Nandrolone phenylpropionate, Nantrodol hydrochloride, Napatadine hydrochloride, Napaldisulfate, Napamazole hydrochloride, Napaviin, Naphazoline hydrochloride, Naphterpin, Naproxen, Naproxen, Nexagatran, Naranol hydrochloride, Narasin, Naratriptan, Natograstim, Nasaplase, Natamycin, Nateplase, Nagolide hydrochloride, Nebivolol, Niramycin, Nedaplatin, Nedocromil, Nefazodone hydrochloride, Nafluazide hydrochloride, Nefopam hydrochloride, Nelazaline maleate, Nemazoline hydrochloride, Nemorubicin, Neomycin palmitate, Neostigmine bromide, Neridronic acid, Netilmicin sulfate, Neutral endopeptidase, Neutramycin, Nevirapine, Hydrochloride Nesiridin, niacin, nibromosan, nicardipine hydrochloride, nicergoline, niclosamide, nicorandil, nicotinamide, nifedipine, nifirmerone, nifluridide, nifuradine, nifuridone, nifuratel, nifuron, nifurdazide, nifuramide, nifuropirox, nifurtimide, nifuroxazole, nifurthiazole, nilutamide, nilvadipine, nimazone, nimodipine, nipetidine, nilavorine, niridazole, nisamycin, nisterol mesylate, nisofopamine, nisolbamate, nisoldipine, nisoxetine, nisterol acetate, niphenylarsonic acid, nitazoxamide, niticapone, nifuran hydrochloride, nitramine hydrochloride, nitrazepam hydrochloride, nitrazepam, nitrin Nitrocycline, nitrodantin, nitrofurantoin, nitrofurazone, nitroglycerin, nitrocresol mercury, nitromethamine, nitrofen citrate, nitrous oxide, nitrogen oxide antioxidant, nitrullyn, nivacolol, nivemidone sodium, nizatidine, nobelastine, nocodazole, noramycin, norlimium bromide, nomifensine maleate, nomethadol hydrochloride, nobolone, norepinephrine bitartrate, norethindrone, norethindrone, norfloxacin, norflurane, norgestimate, norgestrel, norgestrel, nortriptyline hydrochloride, noscapine, novobiocin sodium, N-substituted benzamimides, nufenoxol, nylestriol, nystatin, O6-benzylguanine, bisphosphonate, oxapramidone, ocfentanil hydrochloride,Osipron, octanoic acid, octamide, octenidine hydrochloride, octodrine, octreotide, octotriptyline phosphate, ofloxacin, oformine, okicenone, olanzapine, oligonucleotide, olopatadine, olprinone, olsalazine, olsalazine sodium, ovani, omeprazole, onapristone, ondansetron, onzolast, oocyte maturation inhibitor, opipramol hydrochloride, oracin, oxaconazole nitrate, octoprotein, orlistat, ormaplatin, ormeprin, ornidazole, opanocin, orphenadrine citrate, osatron, oxacillin sodium Sodium), oxygrelate, oxaliplatin, oxacoumarol hydrochloride, oxabiso, oxaniquin, oxandrolone, mefenamic acid pamoate, hydroxyprotriptyline hydrochloride, oxaprozin, oxabazole, oxaamide, oxaunomycin, oxazepam, oxcarbazepine, oxenolone, oxethazone, oxetolone fumarate, oxfendazole, hydroxyphenylglycine, oxibendazole, oxiconazole, hydroxydopamine, oxyphosphodiesterase, oxyfungin hydrochloride, oxymorphan, oximemonam, oximemonam sodium, opimide, oxiracetam, oxylamido, oxixulen, omemetidine hydrochloride, oxodipine, oxomegestrol phenylpropionate, Oxyclosan, oxprenolol hydrochloride, theophylline, oxybutynin chloride, oxyclosan, oxycodone, oxymetazoline hydrochloride, oxymetholone, oxymorphone hydrochloride, oxypertine, oxyphenbutazone, oxypurinol, oxytetracycline, oxytocin, ozagrel, oxazolidinone, paclitaxel, palauamine, padrimycin, palinavir, palmitoylrhizoxin, sodium pamoate, pamaside, pamadolol sulfate, pamigrel, pamidronate disodium , Pamidronate, Panacet, Panaxytriol, Pancopride, Pancuronium, Panipenem, Pannorin, Panomifen, Pantethine, Pantoprazole, Papaverine Hydrochloride, Parabactin, Acetaminophen, Paraldehyde, Paramethasone Acetate, Renitorin Hydrochloride, Parapentyl Bromide, Parasaniline Pamoate Pamoate), Parbendazole, Paconazole Hydrochloride, Paregoric, Paritad Sulfate, Pargyline Hydrochloride, Parparin Sodium, Paromomycin Sulfate, Paroxetine, Paroxetine, Partricin, Paclomycin, Pazeptine, Pazinklon, Pazoxetine, Pazufloxacin, Pefloxacin, Pegaspargase, Pegotin, Pelanserin Hydrochloride, Peldesine, Pelimycin, Pegretinoin Hydrochloride, Perinone, pemetinic acid, pemetrelide nitrate, pemirolast, pemoline, penacillin, penbutolol sulfate, penciclovir, penfluridol, benzathine penicillin G, penicillin G potassium, procaine penicillin, penicillin G sodium, penicillin V, benzathine penicillin V, hybacillin V, penicillin V potassium, pentamidine, pentaerythritol tetranitrate, pentafuside, pentamidine, pentamidine, pentamidine nitrogen mustard, pentafluidol ... Methylsulfate), pentazocine, pentetic acid, pentothiapine maleate, pentigitide, pentamicin, pentobarbital, pentoman, penttopril, pentosan, pentostatin, pentoxifylline, pentonitrol, pentrozole, peplomycin sulfate, pepstatin, perflubron, perfofamide, perfosfamide, pergolide, perhexiline maleate, perillyl alcohol, perindopril, perindoprilat, perrapine, permethrin, perropil Phenylacetamide, phenantheline, phenantheline, phenantheline hydrochloride, phenantheline tartrate, phenelzine sulfate, phenantheline hydrochloride, phenobarbital, phenoxybenzamine hydrochloride, phenprocoumon, phenserine, phensuccinal, phensuximide, phentermine,Phentermine hydrochloride, phentolamine mesylate, phentoxifylline, phenyl para-aminosalicylate, phenyl acetate, phenylalanine, phenylalanyl ketoconazole, phenylbutazone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenylpropanolamine sulfonated divinylbenzene-vinylbenzene copolymer (Phenylpropanolamine Polistirex), pheniradoline hydrochloride, phenyloin, phosphatase inhibitors, physostigmine, piperazine, picibanil, picotriline diethanolamine, picrotoxin, picrotoxin, pikuterol, pidotimod, pifamine, pilocarpine, pilsicainide, pimagilide, pimetin hydrochloride, pimiprost, pimobendan, pimozide, pinacidil, pinadol, pindolol, pinnenol, pinocebrin, piperazine hydrochloride, pioglitazone, pipanilone, pipazolate, pipecuronium, piperacillin sodium, piperazine maleate, piperobroman, piperosulfan, pipethiazide palmitate, piperosolan hydrochloride, piperozoline hydrochloride Piracazone, Piracazone Hydrochloride, Piracetam, Piramide Hydrochloride, Pirarubicin, Piramonam Sodium, Pirazolic Acid, Pirbenicillin Sodium, Pibuterol Acetate, Pirenperone, Pirenzepine Hydrochloride, Piretamide, Pirfenidone, Pirdicillin Sodium, Pirdronate Sodium, Pirprost, Pirtrexine, Pirlimycin Hydrochloride, Pyrindole, Pyroxine, Pirmenol Hydrochloride, Pirnabine, Piroctone, Pirodavir, Pirostear, Pirroglycine Tartrate, Piroxate, Piramide, Piroxantrone Hydrochloride, Piroxicam, Piroxitone, Pirprofen, Piquinolazole, Pirdomine, Prenylamine, Pituitary, Posterior, Piampicillin Hydrochloride, Pivopril, Pizotifen, Placenta Extract A (placetin A), platinum compounds, platinum-triamine complexes, plicamycin, plometane, porbilast ethylenediamine, podafilox, kudzu extract, poldine methylsulfate, glucosamine, sodium lignin sulfonate, polymyxin B sulfate, polythiazide, pornastat, porfimer sodium, porfimycin, potassium chloride, potassium iodide, potassium permanganate, povidone iodine, pralidoxime chloride Chloride), Pramiracetam Hydrochloride, Pramoxetine Hydrochloride, Pramoxetine Chloride, Pradolinium Chloride, Pravastatin / Pravachol, Prazepam, Prazosin, Prazosin Hydrochloride, Prednazate, Prednicarbate, Prednimustine, Prednisolone, Prednisone, Prednival, Pregnenolone Succinate, Prilosec Hydrochloride, Pridifen Hydrochloride, Prifilone, Prilocaine Hydrochloride,Prilosec, primaquine phosphate, primilol, primidone, lisinopril (Prinivil), primidone tromethamine, primisodane, prizidol hydrochloride, prodiphenhydramine hydrochloride, probenecid, anclomid calcium, probucol, procainamide hydrochloride, procaine hydrochloride, procarbazine hydrochloride, Procaterol hydrochloride, prochlorperazine, procinolone acetonide, prochlorperazine, procyclidine hydrochloride, prazole hydrochloride, prodrug, profadol hydrochloride, progabide, progesterone, proglumide, human proinsulin, proline, prolintanol hydrochloride, promazine hydrochloride, promethazine hydrochloride, propafenone hydrochloride, propantheline bromide, proparacaine hydrochloride, propanitride, propentofylline, oxycodone hydrochloride Liping, Propicacin, Propionylmazine, Propionic acid, Propionylcarnitine, Propionyl-L-carnitine, Disopyramide, Disopyramide + Paracetamol, Propiverine, Propofol, Propoxycaine Hydrochloride, Dextropropoxyphene Hydrochloride, Propranolol Hydrochloride, Cisapride (Propulsid), Propyl bis-acridone, Propiodonium, Propiodonium, Propthiouracil, Proquinezone, Potassium Propirate, Proxen Hydrochloride, Scutellarin, Prostaglandin, Tyrosine kinase inhibitor (prostratin), Protamine sulfate, Endogenous antimicrobial peptide (protegrin), Prorelin, Tosufloxacin, Protriptyline Hydrochloride, Proxazole, Proxazole Citrate, Proxylotriptyline, Promorphanol tartrate, Prulifloxacin, Pseudoephedrine Hydrochloride, Puromycin, Purpurin ( purpurins), pyraburone, pyrantel pamoate, pyrazinamide, pyrazofurin, pyrazoloacridine, pyridostigmine bromide, mepyrilamine maleate, pyrimethamine, pyrinoline, pyrithione sodium, pyrithione zinc, pyrovalerone hydrochloride, pyrroloxamine maleate, pyrocaine, pyrrolifene hydrochloride, pyrrolnitrin, enbopirovinium, quadarazocine mesylate, quazepam, quinazidone, quazodine, quinazolidone, quetiapine, quinfrapone, quinagolide, quinapril, quinaprilat, quinazosin hydrochloride, quibolone, Quinctolate, quinacamine acetate, quinodronium bromide, quinolones hydrochloride, ethinylestradiol, quinfamide, acetate Quingestrol, Quingestrol, Quinidine gluconate, Quinolyl hydrochloride, Quinine sulfate, Quinpirole hydrochloride, Quinprenaline sulfate, Quinulonium bromide, Quinupristin, Quinoprazine maleate, Rabeprazole sodium, Racephenicol, Racepinephrine, RAF antagonist, Rafoxamide, Ralitoline, Raloxifene, Raltitrexed, Ramatroban, Ramipril, Ramoplanin, Ramosetron, Ranelic acid, Ranilomycin, Ranitidine, Ranolazine, Rauwolfia Serpentina, Recanam, Recanam hydrochloride, Reclozepam, Regavir, Relastin, Relaxin, Ralomycin, Remifentanil hydrochloride, Remiprostol,Remoprid, repirastat, repremicin, reproterol hydrochloride, reserpine, capsaicin (resferatoxin), resorcinol, demethylated reteptine, reticulon, reviparin sodium, revizinon, rhenium Re 186 etidronate, rhizoxin, ribaminolide, ribavirin, riboadenylate, ribozyme, licarsetron, lidogrel, rifabutin, riformestane, rifaximin, rifatomide, rifampicin, rifapentine, rifaximin, RII retinamide, rilopris, riluzole, rimantadine, lincarazole hydrochloride, rimexolone, rimaterol hydrobromide, rimuronin, riodipine, rioprost, ripazepam, ripisartan, risedronate sodium, risedronic acid, risocaine, risoprenaline hydrochloride, ripentzepine, Risperdal, risperidone, ritanserin, ritopenem, ritodrine, ritonavir, rizatriptan benzoate, rocasidine hydrochloride, rocuronium Bromide, rhodocaine, roflurane, rogletimide, roxitamine, rotamycin, roletamicide, rogamidine, rolicyprine, rolipram, rolicycline, rolodine, clomazaride, romotide, ronidazole, ropinirole, ropitol hydrochloride, ropivacaine, ropizine, roquine, roxamicin, rosiglitazone, rosofloxacin, rotoxamine, roxaitidine , roxarsone, roxithromycin, roxithromycin, rubicinol B1, ruboxyl, rufloxacin, rupatidine, rutamycin, luzadol, sabeloazole, safinol, safilonide, saintopin, salbutamol, R-salbutamol, salicylic acid salicyclic acid, salicyl alcohol, salicylamide, meglumine salicylate, salicylic acid, salmeterol, salnacediin, salsalate, salmeridine, Sanpatra, Sancycline, Sanfepenem, Sanguinarium Chloride, Saproconazole, Saprisartan, Sapropterin, Saquinavir, Sarofloxacin Hydrochloride, Saraphen Acetate, SarCNU, Sarcophytol A, Sargramostim, Samocillin, Sapicillin, Sargrelide, Sarruplasid, Saruplinon, Satigrel, Satumomab Pendetide, Sik Test Control, Secofungin, Scopolamine Hydrobromide, Scrazaipine Hydrochloride, Sdi 1 analogs, secalciferol, secobarbital, Seelzone, seglitide acetate, selegiline, selegiline hydrochloride, selenium sulfide, selenomethionine Se 75, sefortol, semelite, semdomicin, semodil, semustine, sense oligonucleotides, sepazonium chloride, haloperidol hydrochloride, spriose, seroxetine hydrochloride, selacotide acetate, ergoxol maleate, serine, semethicin, sermorelin acetate, sertaconazole, sertindole,Sertraline, setiline, stropirone, sevirumab, sevoflurane, sezolamide, cibotridine, signal transduction inhibitors, silanolone, cilipid, ceteplasm, silver nitrate, simendan, simtrazine, simvastatin, sincalide, sinefungin, cinidrone, sinnabidol, sipatrazine, sirolimus, sisomicin, cimetropium, sizolan, sobuzosine, sodium starch sulfate, sodium iodide 123. Sodium nitroprusside, sodium oxybate, sodium phenylacetate, sodium salicylate, solverol, soripertin tartrate, porcine alanine growth hormone, somantin hydrochloride, somatomedin B, somatomedin C, human methionine growth hormone, somatotropin, porcine norepinephrine, bovine growth hormone, sonarmin, sobinil, sorivudine, sotalol, soterol hydrochloride, sparfloxacin, sodium acetylaspartate, acetylaspartate, sparmycin, spartin sulfate, spectinomycin hydrochloride, spicamycin D, spiperone, spirodolin mesylate, spiramycin, spirapril hydrochloride, spirapril, spirogermanium hydrochloride, spiromustine, spiro Lactone, spiroplatin, spiroxazone, splenopentin, spongistatin 1, dysprosium diamide, squalamine, stamycin hydrochloride, stannous pyrophosphate, stannous sulfur colloid, stanozolol, vestolon, staurosporine, stavudine stamycin, stenbolone acetate, stironine, stipiamid, stipiamid, stiropentin, stipiamid, stiripentol, stobatin, streptomycin sulfate, streptomycin isoniazid, streptozocin, streptozotocin, stromelysin inhibitors, strontium chloride 89, succibun, succimer, succinylcholine chloride, sucralfate, sudoxicam, sufentanil, sufotidine, thiazepam, sulbactam, sulconazole nitrate, sulfabenzene, sulfadiazine, sulfacetamide, sulfaxetine, sulfadiazine, sulfadoxine, sulfamethazine, sulfamethoxazole, sulfamethoxazole, azole, sulfamethoxazole, sulfadiazine Sulfanilide, zinc aminobenzenesulfonate, sulfanitrophenyl, sulfasalazine, sulfisothiazole, sulfapyrazole, sulfoxalol hydrochloride, sulfinosine, sulfinpyrazone, sulfaiso Azole, Azuridin, Balsalazide, Barium Sulfate, Bazedoxifene, Benzamide, Benzocaine, Benzochloride, Benzocycloheptane, Benzodiazepine, Benzofuran, Benzofurazan, Benzopyran, Benzothiazole, Benzothiophene, Benzoxazole, Benzoxazoline, Benzothiepine, Benzothiazepine, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, Benzothiepin, BenzChloride), Thiethylperazine, Sodium thimerosal, Thimerosal, Thiocoraline, Thiofedrine, Thioguanine, Thiomarinol, Thiopental sodium, Thioperamide, Thioridazine, Thiotepa, Thiothixene, Thiphenamide hydrochloride, Thiphencillin Potassium, Cialan, Tozalone, Threonine, Thrombin, Thrombopoietin, Thrombopoietin mimetic, Thymosin, Thymopoietin receptor agonist, Thymotreonam, Thymidone hydrochloride, Thyroxine I 125, Thyroxine I 131. Sulfolosilast, Sulfolosilast sodium, Tiagabine, Tiamenidine, Tianeptine, tiapafant, tiapamil hydrochloride, thiaramide hydrochloride, thiazofurin, thiapalast sodium, tibolone, tifibic acid, ticarbesone propionate, ticarbodine, ticarcillin cresylate sodium, ticlazone, ticlopidine, tinidic acid, tinolol, tifurate sodium, dicholine tigemonam, tinestrol, tiletamine hydrochloride, tilidine hydrochloride, tilirolol, tirofenazate, tilolone hydrochloride, tiludronate disodium, tiludronate, timofuranone, timofuranone acetate, timolol, tin ethyl etiopurpurin, tinidazole, tinzaparin sodium, tioconazole, thiodazosin, iodine chloride, sulpiride hydrochloride, tiopinac, risperidone hydrochloride, tiotidine, tiotropium bromide, thioxolene, thioxate hydrochloride, tiaprofenic acid, tropesin, tropisetron hydrochloride, tropicamide, troxerutin, troxipide, topotecan, topotecan hydrochloride, topsentin, toprimoxone, toquinizine, torasemide, toremifene, torasemide, tosifen, tosufloxacin, total cell factor, tracazolate, treprostinil, trexanox, trexanox hydrochloride, tridihexethyl hydrochloride, tridihexethyl maleate, tridostigmine, trifenatide, triflavin, transcription inhibitor, trifluoperazine hydrochloride, trifluperidol, trifluperidol hydrochloride, trifluridine, triamcinolone, triamcinolone acetonide, triacetate, triacetyluridine, triazafenide, triamcinolone, triamcinolone acetonide, triamterene, triazolam, trilazad, trilazad, triofiban, tripramide, titanium dichloride, trimebutine, trimegestone, trimetazidine hydrochloride, tobramycin, tocainide, tolfenpyrad, tolfenpyrad, tolamolol, tolazamide, tolamolol, toloxitene, tolperisone, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpyrad, tolfenpy131. Trivoxifene mesylate, tripamide, tripelennamine hydrochloride, triprolidine hydrochloride, triptorelin, trisulfuron, troclosan potassium, troglitazone, triethanolamine, troleandomycin, trombodipine, tromethamine, tropaneserin hydrochloride, tropicamide, tropine ester, tropisetron, spectinomycin, trovafloxacin, troviridine, tryptophan, tuberculin, tubocurarine chloride, tobradazole hydrochloride, tucarcsol, tulobuterol, tulostra, tylosamide, tylogenin, tyropan Sodium valproate, tyrosine, gramicidin, tyrphostins, ubenimex, udazepam, undecylenic acid, uramustine, urapidil, urea, uredepa, uridine triphosphate, urofollicle-stimulating hormone, urokinase, ursodiol, valacyclovir, valine, valproate, sodium valproate, valproic acid, valsartan, vamipril, vanadeine, vancomycin, vaninolol, valperprost hydrochloride, vapreotide, variolin B. Vasopressin, vecuronium bromide, velarexol, vesperidone maleate, venlafaxine, veladolin hydrochloride, veramine, verapamil hydrochloride, verdins, virilopam hydrochloride, vilukast, vilofylline, veroxan, verteporfin, vesirinone, vexibinol, adenosine, vigabatrin, viloxazine hydrochloride, vinblastine sulfate, vinbutine citrate, vinfosinate, vincordate, vincristine sulfate, vindesine, vindesine sulfate, vinpoxetine sulfate, vinsodiol sulfate, vinorelbine, vinpocetine, vinpoxetine, vinprostol, virginiamycin, chloroquine, viroxime, vitexin, vitaxin, vinpoxetine Lazocine, Voriconazole, Vorozole, Vogolide, Warfarin Sodium, Xamoterol, Xanomeline, Sodium Isopropyl Anthracene, Xanthinol Niacinate, Zamilofiban, Difenopine, Xylofen, Xiloban, Ximoprofen, Xipamide, Zorphanol Mesylate, Methamidine Tosylate, Xylazine Hydrochloride, Xylometazoline Hydrochloride, Xylose, Yangambin, Zapril, Zacopril, Zafirlukast, Zalcitabine, Zaleplon, Zaspironone, Zaltoprofen Hydrochloride, Zaltoprofen, Zanamivir, Zankiren, Zanotelon, Zantac, Zafirlukast, Zaltibradine, Zaltosetron, Zaltosetron Maleate, Zanamivir, Zankiren, Zanotelon, Zenazocine MesylateMesylate), zeniplatin, zeranol, zidomecin, zidovudine, zilosil, zilantel, benzyl retinol, zileuton, zimeldine hydrochloride, zinc undecylenate, azithromycin, zinoconazole hydrochloride, zindrostatin, zindroconazole hydrochloride, ziprasidone, zobolt, zofenopril calcium, zofenoprilat, zolamin hydrochloride, zolazepam hydrochloride, zoledronic acid, zoletin hydrochloride, zolmitriptan, zolpidem, zomepirate sodium, zomepidate, zolniclozole hydrochloride, zonisamide, zopiclone, zopolrestat, zorbamycin, zorubicin hydrochloride, zotepine, and zucalcycin.

[0070] For example, U.S. Patent Nos. 9745300, 9708322, 7183282, 7071186, 6552017, 8648077, 8598119, 9751883, 9371324, 9315504, 9428506, 8993572, 8309722, 6713471, 8779139, 9168258, RE039680E1, 961606 1, 9586960, and U.S. Patent Publication Nos. 2017114037, 2017183350, 2015072964, 2004034015, 2017189398, 2016310502, and 2015080404, the foregoing contents of which are incorporated herein by reference in their entirety, another pharmaceutical active that can be used herein is lumateperone.

[0071] Other examples of antidiabetic actives include, but are not limited to, JTT-501 (PNU-182716) (Reglitazar), AR-H039242, MCC-555 (Netoglitazone), AR-H049020 (Tesaglitazar), CS-011 (CI-1037), GW-409544×, KRP-297, RG-12525, BM-15.2054, CLX-0940, CLX-0921, DRF-2189, GW-1929, GW-9820, LR-90, LY-510929, NIP-221, NIP-223, JTP-20993, LY 29311Na, FK614, BMS298585, R 483, TAK 559, DRF 2725 (Ragaglitazar), L-686398, L-168049, L-805645, L-054852, desmethylasteriquinone Bl (L-783281), L-363586, KRP-297, P32 / 98, CRE-16336, and EML-16257.

[0072] Erectile dysfunction treatments useful herein include, but are not limited to, agents useful for promoting blood flow to the penis and for achieving autonomic nervous activity (e.g., increasing parasympathetic (cholinergic) activity and decreasing sympathetic (adrenergic) activity). Active useful for treating erectile dysfunction include, for example, but are not limited to, alprostadil, tadalafil, vardenafil, apomorphine, yohimbine hydrochloride, sildenafil citrate, and any combination thereof. In one embodiment, the active is tadalafil.

[0073] Active or drugs useful for treating headaches and / or migraines can also be used herein. Examples of specific actives include, but are not limited to, triptans, such as eletriptan, naratriptan, rizatriptan (benzoate rizatriptan), sumatriptan, and zolmitriptan. In one embodiment, the active is rizatriptan, optionally in combination with an NSAID.

[0074] In one embodiment, the active can be clonazepam, diazepam, tadalafil, riluzole, buprenorphine, naloxone, or a combination of buprenorphine and naloxone.

[0075] The active can be diazepam. When the active is diazepam, each individual unit dose can comprise about 1 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg of diazepam. In certain embodiments, the oral film comprises about 5 mg, about 10 mg, or about 15 mg of diazepam.

[0076] The active can be riluzole. When the active is riluzole, each individual unit dose can comprise about 10 mg, about 20 mg, about 25 mg, about 30 mg, or about 50 mg of riluzole. In one embodiment, the oral film comprises about 50 mg of riluzole.

[0077] The active can be clonazepam. When the active is clonazepam, each individual unit dose can comprise about 1 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg of clonazepam. In certain embodiments, the oral film comprises about 5 mg or about 20 mg of clonazepam.

[0078] Micronization

[0079] The active used in the oral films disclosed herein can be micronized. The active can be micronized by any means known in the art.

[0080] The average particle size D90 of the active can be less than about 160 microns, less than about 120 microns, less than about 100 microns, less than about 80 microns, less than about 50 microns, less than about 20 microns, less than about 10 microns, or about 8 microns. The average particle size D50 of the active can be less than about 30, less than about 20, less than about 10, less than about 5 microns, less than about 4, or D50 is about 3. The average particle size D10 of the active can be less than about 10, less than about 5, less than about 3, less than about 2, or D10 is about 1. The active can have an average particle size D90 of less than about 15 microns, an average particle size D50 of less than about 4 microns, and an average particle size D10 of less than about 2 microns. The active can have an average particle size D90 of about 8 microns, an average particle size D50 of about 3 microns, and an average particle size D10 of about 1 micron.

[0081] Particle sizes of 0.02 pm to 2000 pm / 0.01 pm to 3500 pm are most commonly measured using laser diffraction light scattering. In this technique, particles pass through the path of a laser and diffract light. The angle of the diffracted light is then correlated to particle size using the difference in refractive index between the particle and the medium. The output measured is a volume distribution, and is typically expressed as D x where x is the expression of the distribution. For example, D 90 will reflect the volume distribution of particles analyzed that capture 90% of the observed diffraction; thus 90% of the particles will fall below this size. Other descriptions of particle size are commonly used, such as a "number distribution" that will correlate to the number of particles having that size, as the volume impact of larger particles can not be proportionally weighted. However, these alternative statistical descriptions of particle size based on laser diffraction light scattering are based on mathematical calculations of the volume distribution; thus, unless otherwise noted, D x particle size descriptions are as volume distributions.

[0082] It is known that an average particle size of less than 200 microns is preferred to obtain a smooth oral film. However, further development has shown that having a finer average particle size, i.e., finely divided particles, can improve the aesthetics and dissolution of the film. Further, dissolution test results for lower film dosages (e.g., 5 mg and 10 mg) show that micronized actives perform better than films containing milled actives (e.g., average particle size D90 of about 100 microns).

[0083] Dissolution Profile

[0084] such as a PION Rainbow dynamic dissolution monitor The PION device ("PION Technology") is a powerful analytical instrument that accurately and efficiently measures percent dissolution data in real time. PION Technology utilizes advanced fiber optics to perform in situ kinetic solubility and supersaturation UV monitoring for dissolution testing to determine the rate of drug release and its dissolution over time. PION Technology uses a single diode array spectrophotometer with 6 to 8 acquisition channels, immersion probes, and interchangeable optical pathlength probes. PION Technology features real-time data display, providing fast and reproducible results for testing actives, dosage forms, and drug products. These measurements are accurate, even in small volumes and complex matrices.

[0085] Fiber-optic-based dissolution systems, such as PION technology, have previously been used with dosage forms other than oral films. However, these systems cannot be properly utilized due to the size and density of oral films; for example, the film dissolves and releases the active even before any measurements are taken. To overcome this problem, a custom film introduction system / holder must be designed and developed. The custom film introduction system / holder prevents the film from floating and being agitated in the dissolution vessel. It also allows for the simultaneous introduction of multiple layers of film, which is critical for rapid data collection. In addition, the sample holder, its distance from the paddle, and the distance and angle to the fiber-optic probe all play an important role in ensuring the flow dynamics requirements of the USP while performing consistent and accurate data collection. Figure 1 A non-limiting exemplary configuration of an apparatus for PION technology is shown in FIG. As shown in the figure, the system is configured with multiple systems arranged in parallel to run simultaneous tests on different samples. The system includes a probe, a dissolution paddle, and a custom sample holder. There are options for the placement of the custom sample holder (height and angle relative to the flow). The size of the holder can also be changed to accommodate the size of the membrane. In addition, as one of ordinary skill in the art will readily appreciate, the path length of the probe can be varied. If the path length is too wide, the signal will be overloaded. If the path is too narrow, the signal will be too weak.

[0086] Figure 2 This is another exemplary configuration of paddles, holders, and a device for adjusting the height of the probe and holder used to obtain a dissolution profile using PION technology. With adequate paddle agitation, the probe height is not expected to affect the results, but the orientation of the sample holder may affect the disintegration of the film and affect the dissolution rate of the active. Figure 1 and 2As shown, for example, the sample holder is placed perpendicular to the wall of the dissolution vessel for maximum exposure. The angle of the holder relative to the dissolution vessel can be changed by repositioning the holder orientation (twisting the holder from perpendicular to another desired angle). The size of the holder can be increased to accommodate larger films, but the range of angles allowed can be limited, for example, if the holder for the larger film is larger, it has less freedom to adjust. If the twist is too deep, the holder or film can contact the side wall of the vessel or contact the rotating paddle - negatively impacting the test.

[0087] It was discovered that the PION technology can be used to test the dissolution of the oral films disclosed herein by customizing the sample holder and sampling manifold. By using the PION technology, there are many advantages, for example:

[0088] 1. No off-line analysis is required;

[0089] 2. More sampling points are available;

[0090] 3. Ability to evaluate multiple wavelengths;

[0091] 4. Ability to evaluate rate of change (e.g., inflection point acceptance criteria);

[0092] 5. Spectral comparison shows potential discrimination between strength and storage conditions.

[0093] It was discovered that the active dissolution profiles and rates of the oral films disclosed herein measured by the PION technology are generally comparable to those measured by traditional dissolution methods, except that the former profiles are more accurate and precise, and as a result, the inflection points are determinable. Using a fiber optic UV monitoring system, such as the PION technology, the dissolution profiles of the oral films can be more accurate and precise. The dissolution profile is an average collection of data points showing the time from t=0 until the point at which 100% of the dosage form or active has dissolved over time. The "active dissolution profile" refers to the dissolution profile of the active after it is released from the film. The film itself and the carriers therein have some effect on the dissolution rate of the active when it is dissolved after being released from the oral film dosage form.

[0094] For example, Figure 9 and 10 show the active dissolution profile, in addition Figures 13 to 23 show the improved and more precise data and derivative that can result from the PION technology. Conversely, Figure 8 show the active dissolution profile measured by traditional dissolution methods, which lack any discrimination for fast release dosage forms at key early time points.

[0095] When using PION technology, the first derivative (or "first derivative") of the active's dissolution profile of the oral film can be plotted, for example, as shown in Figures Figure 19 , 21 and 23. The first derivative plot provides an understanding of the rate of release of the active from the film. The strength and width of the first derivative is proportional to the rate of release. For example, by plotting these derivatives, as shown by the height and width of the first derivative curves, it can be understood that the oral films containing 5 mg and 10 mg of active release faster and more completely than the similar oral film containing 20 mg of active in the first minute. In such a performance, the oral film containing 20 mg of active would have a wider curve, indicating slower release. For all curves, when release is complete, the first derivative approaches 0 and the concentration of drug in the reservoir reaches a plateau.

[0096] It would be expected that if the active had the same particle size distribution in different film dosage forms, the active's dissolution profile would be the same. However, this is not always the case. By using PION technology, significant differences between dosage forms can be seen, indicating that the film and carrier affect the dissolution rate of the active.

[0097] The second derivative (or "second derivative") plot provides a qualitative assessment of the curve. Both the first and second derivative curves provide maxima, minima, and inflection points; providing the ability to determine when the curve is rising / falling and the rate.

[0098] After the film is placed in the medium, the average dissolution of the active, optionally measured by the PION technique, can be greater than about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, or greater than about 55% at about 2 minutes. The average dissolution of the active, optionally measured by the PION technique, can be greater than about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, about 65%, or greater than about 70% at about 3 minutes. The average dissolution of the active, optionally measured by the PION technique, can be greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, about 65%, or greater than about 70% at about 5 minutes. The average dissolution of the active, optionally measured by the PION technique, can be greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, or greater than about 90% at about 10 minutes. The average dissolution of the active, optionally measured by the PION technique, can be greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 98% at about 15 minutes. The average dissolution of the active, optionally measured by the PION technique, can be greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 98%, or greater than about 99% at about 20 minutes. The dissolution of the active as measured herein is after the film is placed in the medium. After being placed in the medium, the film dissolves, thereby releasing the active into the medium.

[0099] Dissolution rate is the rate at which an oral film or active dissolves, which is a calculated amount of % released at a certain time point. Dissolution rate is obtained by performing dissolution testing in a selected apparatus and is measured according to certain dissolution parameters. Dissolution parameters include storage conditions (e.g., time, temperature, and relative humidity) and testing parameters (e.g., apparatus, rotation speed, medium, medium temperature, sampling time points, sample volume, sample filter, HPLC column, mobile phase, flow rate, column temperature, injection volume, detection wavelength, and run time).

[0100] “Active dissolution rate” is the rate at which an active dissolves, which is a calculated amount of % released at a certain time point. In the case of oral film dosage forms as disclosed herein, the oral film dissolves and releases the active, and then dissolves at a precise rate (i.e., active dissolution rate). The dissolution of the active can also be expressed as the % (average) of active dissolved at a certain time point.

[0101] Unless otherwise specified, dissolution of the active is measured under the following storage conditions for the oral film: from about 0 months to about 36 months, from more than 0 months to about 36 months, from about 6 months to about 36 months, from about 6 months to about 24 months, from about 9 months to about 18 months, or about 12 months, at about 20 °C to about 60 °C, about 25 °C to about 40 °C, or about 25 °C, and up to about 75% relative humidity (RH), e.g., at about 60% RH.

[0102] Dissolution testing can be performed under “sink” conditions, as defined by USP <1092>, which are “at least three times the volume of the medium required to form a saturated solution of the drug substance. When sink conditions are present, dissolution results are more likely to reflect the characteristics of the dosage form.” Different media can be required for different drug products, based on the characteristics of the active, e.g., solubility and route of administration. As would be readily understood by one of ordinary skill in the art, the above factors can be considered when developing a dissolution method. USP <1092> further defines the scope of medium evaluation: “Typical media for dissolution can include the following (not listed in order of preference): dilute hydrochloric acid, buffers in the physiological pH range of 1.2 to 7.5 (phosphate or acetate), simulated gastric or intestinal fluids (with or without enzymes), water, and surfactants (with or without acid or buffer).” Surfactants can be, but are not limited to, polysorbate 80, sodium lauryl sulfate, and bile salts. For some drugs, incompatibility of the drug with certain buffers or salts can affect the choice of buffer. The molarity of the buffer and acid used can affect the solubilization effect, and this factor can be evaluated. Aqueous solutions (acidic or buffered solutions) can include a percentage of a surfactant, such as sodium dodecyl sulfate (SDS), polysorbate, or lauryl dimethyl amine oxide, to enhance the solubility of the drug.

[0103] In one embodiment, the dissolution of the active is measured in dilute hydrochloric acid, a buffer in the physiological pH range of 1.2 to 7.5 (e.g., phosphate or acetate) including but not limited to 0.05 molar potassium phosphate monobasic buffer pH 6.8, simulated gastric fluid or intestinal fluid (with or without enzymes) (e.g., 0.1 N HC1), water, and surfactants (e.g., polysorbate 80, sodium lauryl sulfate, and bile salts). In another embodiment, the dissolution of the active is measured in dilute hydrochloric acid, 0.05 molar potassium phosphate monobasic buffer pH 6.8, 0.1 N HC1, water, or 0.5% sodium lauryl sulfate.

[0104] For oral films comprising diazepam, more than about 2% of the diazepam can dissolve after about 3 minutes, more than about 10% of the diazepam can dissolve after about 5 minutes, more than about 15% of the diazepam can dissolve after about 5 minutes, or about 20% to about 25% of the diazepam can dissolve after about 5 minutes, optionally measured by PION technology after the film is placed in the medium. More than about 25%, more than about 30%, or about 35% to about 40% of the diazepam can dissolve after about 10 minutes, optionally measured by PION technology. More than about 42%, more than about 48%, or about 50% to about 55% of the diazepam can dissolve after about 15 minutes, optionally measured by PION technology. More than about 55%, more than about 60%, or about 60% to about 70% of the diazepam can dissolve after about 20 minutes, optionally measured by PION technology. More than about 85%, more than about 90%, or about 92% to about 98% of the diazepam can dissolve after about 30 minutes, optionally measured by PION technology. Any combination of dissolution at the different time points described above is within the scope of the present application.

[0105] For oral films comprising about 5 mg of diazepam, more than about 2% of the diazepam can dissolve after about 3 minutes, more than about 15% of the diazepam can dissolve after about 5 minutes, or about 21% of the diazepam can dissolve after about 5 minutes, optionally measured by PION technology. For oral films comprising about 5 mg of diazepam, more than about 30%, less than about 38%, or about 36% of the diazepam can dissolve after about 10 minutes, optionally measured by PION technology. For films comprising about 5 mg of diazepam, less than about 55%, more than about 45%, or about 50% of the diazepam can dissolve after about 15 minutes, optionally measured by PION technology. For films comprising about 5 mg of diazepam, less than about 70%, more than about 60%, or about 64% of the diazepam can dissolve after about 20 minutes, optionally measured by PION technology. Any combination of dissolution at the different time points described above is within the scope of the present application.

[0106] For an oral film comprising about 15 mg of diazepam, optionally measured by PION technology, more than about 2% of the diazepam can be dissolved after about 3 minutes, more than about 20% of the diazepam can be dissolved after about 5 minutes, more than about 25% of the diazepam can be dissolved after about 5 minutes, and / or about 27% of the diazepam can be dissolved after about 5 minutes. For a film comprising about 15 mg of diazepam, optionally measured by PION technology, more than about 35%, less than about 45%, or about 41% of the diazepam can be dissolved after about 10 minutes. For a film comprising about 15 mg of diazepam, optionally measured by PION technology, less than about 60%, more than about 45%, more than about 50%, or about 55% of the diazepam can be dissolved after about 15 minutes. For a film comprising about 15 mg of diazepam, optionally measured by PION technology, less than about 70%, more than about 60%, more than about 65%, or about 68% of the diazepam can be dissolved after about 20 minutes. Any combination of dissolution at the different time points described above is within the scope of the present application.

[0107] For an oral film comprising riluzole, optionally measured by PION technology, more than about 2% of the riluzole can be dissolved after about 3 minutes, more than about 30% of the riluzole can be dissolved after about 5 minutes, and / or more than about 35% of the riluzole can be dissolved after about 5 minutes. For a film comprising riluzole, optionally measured by PION technology, less than about 75%, less than about 73%, more than about 60%, more than about 65%, and / or more than about 68% of the riluzole can be dissolved after about 10 minutes. For a film comprising riluzole, optionally measured by PION technology, less than 98%, less than about 95%, more than 75%, and / or more than about 80% of the riluzole can be dissolved after about 15 minutes. Any combination of dissolution at the different time points described above is within the scope of the present application.

[0108] For an oral film comprising about 50 mg of riluzole, optionally measured by PION technology, more than about 2% of the riluzole can be dissolved after about 3 minutes, more than 10% of the riluzole can be dissolved after about 5 minutes, more than 20% of the riluzole can be dissolved after about 5 minutes, more than 30% of the riluzole can be dissolved after about 5 minutes, less than about 45% of the riluzole can be dissolved after about 5 minutes, or about 40% of the riluzole can be dissolved after about 5 minutes. For a film comprising about 50 mg of riluzole, optionally measured by PION technology, more than 30%, more than 40%, more than 50%, less than about 75%, or about 71% of the riluzole can be dissolved after about 10 minutes. For a film comprising about 50 mg of riluzole, optionally measured by PION technology, more than 85%, less than 93%, less than about 91%, or about 89% to about 90% of the riluzole can be dissolved after about 15 minutes. Any combination of dissolution at the different time points described above is within the scope of the present application.

[0109] For oral films comprising clobazam, more than about 3%, more than about 5%, more than about 10%, or more than about 15% of the clobazam is soluble after about 1 minute, as measured by PION technology. More than about 5%, more than about 10%, more than about 30%, or more than about 40% of the clobazam is soluble after about 1.5 minutes, as measured by PION technology. More than about 15%, more than about 20%, more than about 40%, or more than about 60% of the clobazam is soluble after about 2.5 minutes, as measured by PION technology. More than about 20%, more than about 30%, more than about 35%, more than about 40%, or more than about 45% of the clobazam is soluble after about 3 minutes, as measured by PION technology. Optionally, after about 5 minutes, more than about 55%, more than about 65%, more than about 70%, or more than about 75% of the clobazam is soluble, as measured by PION technology. Optionally, after about 6.5 minutes, more than about 85%, more than about 90%, or more than about 91% of the clobazam is soluble, as measured by PION technology. Optionally, after about 10 minutes, more than about 95%, or more than about 99% of the clobazam is soluble, as measured by PION technology. Any combination of the above dissolution rates at different time points is within the scope of the present invention.

[0110] For an oral film comprising about 5 mg of clobazam, more than about 25%, more than about 30%, or about 38% of the clobazam is dissolved optionally measured by PION technology after about 1 minute, measured after the film is stored at about 25 °C, and more than about 45%, more than about 50%, or about 59% of the clobazam is dissolved optionally measured by PION technology after about 1 minute, measured after the film is stored at about 40 °C. For a film comprising about 5 mg of clobazam, more than about 60%, or more than about 65% of the clobazam is dissolved optionally measured by PION technology after about 1.5 minutes, measured after the film is stored at about 25 °C, and more than about 75%, or more than about 80% of the clobazam is dissolved optionally measured by PION technology after about 1.5 minutes, measured after the film is stored at about 40 °C. For a film comprising 5 mg of clobazam, more than about 80%, or more than about 85% of the clobazam is dissolved optionally measured by PION technology after about 2 minutes, measured after the film is stored at about 25 °C, and more than about 85%, or more than about 90% of the clobazam is dissolved optionally measured by PION technology after about 2 minutes, measured after the film is stored at about 40 °C. For a film comprising about 5 mg of clobazam, more than about 95%, or about 97% of the clobazam is dissolved optionally measured by PION technology after about 2.5 minutes, measured after the film is stored at about 25 °C, and more than about 95%, or more than about 100% of the clobazam is dissolved optionally measured by PION technology after about 2.5 minutes, measured after the film is stored at about 40 °C. Any combination of dissolution at the different time points described above is within the scope of the present application.

[0111] For an oral film comprising about 10 mg of chlorzoxazone, more than about 15%, or more than about 20% of the chlorzoxazone is soluble after the film is stored at about 25 °C, optionally measured by PION technology, after about 1 minute, and more than about 35%, or more than about 40% of the chlorzoxazone is soluble after the film is stored at about 40 °C, optionally measured by PION technology, after about 1 minute. For a film comprising about 10 mg of chlorzoxazone, more than about 50%, or more than about 55% of the chlorzoxazone is soluble after the film is stored at about 25 °C, optionally measured by PION technology, after about 1.5 minutes, and more than about 65%, or more than about 70% of the chlorzoxazone is soluble after the film is stored at about 40 °C, optionally measured by PION technology, after about 1.5 minutes. For a film comprising about 10 mg of chlorzoxazone, more than about 70%, or more than about 75% of the chlorzoxazone is soluble after the film is stored at about 25 °C, optionally measured by PION technology, after about 2 minutes, and more than about 80%, or more than about 85% of the chlorzoxazone is soluble after the film is stored at about 40 °C, optionally measured by PION technology, after about 2 minutes. Any combination of the above dissolution rates at the different time points is within the scope of the present application.

[0112] For an oral film comprising about 20 mg of clobazam, more than about 2%, or about 4% of the clobazam is dissolved after about 1.5 minutes, measured after the film is stored at about 25 °C, optionally measured by PION technology, and more than about 5%, or about 6% of the clobazam is dissolved after about 1.5 minutes, measured after the film is stored at about 40 °C, optionally measured by PION technology. For a film comprising about 20 mg of clobazam, more than about 10%, or more than about 15% of the clobazam is dissolved after about 2.5 minutes, measured after the film is stored at about 25 °C, optionally measured by PION technology, and more than about 25%, or more than about 30% of the clobazam is dissolved after about 2.5 minutes, measured after the film is stored at about 40 °C, optionally measured by PION technology. For a film comprising about 20 mg of clobazam, more than about 40%, or about 46% of the clobazam is dissolved after about 3.5 minutes, measured after the film is stored at about 25 °C, optionally measured by PION technology, and more than about 65%, or about 68% of the clobazam is dissolved after about 3.5 minutes, measured after the film is stored at about 40 °C, optionally measured by PION technology. For a film comprising about 20 mg of clobazam, more than about 80%, or about 83% of the clobazam is dissolved after about 5.5 minutes, measured after the film is stored at about 25 °C, optionally measured by PION technology, and more than about 90%, or about 94% of the clobazam is dissolved after about 5.5 minutes, measured after the film is stored at about 40 °C, optionally measured by PION technology. Any combination of dissolution at the different time points described above is within the scope of the present disclosure.

[0113] The rate of dissolution of the active can contribute to the organoleptic properties of the oral film. There is a balance between the amount of active dispersed in the film and the amount of active dissolved in the film. If too much active is dissolved rather than dispersed in the film, the patient will taste the active after the film is placed in the mouth, which often has a very unpleasant taste. In one embodiment, less than about 10% of the active is dissolved (also referred to as solubilized) by weight and more than about 90% is dispersed in the oral film. In other embodiments, less than about 8%, less than about 5%, less than about 2%, about 0.1% to about 10%, about 0.5% to about 5%, about 0.5% to about 2.5%, about 1.0% to about 2.0%, about 0.5%, about 0.8%, about 1.0%, about 1.2%, about 1.5%, about 1.8%, or about 2.0% of the active is dissolved by weight in the oral film.

[0114] Dissolution Profile Comparison

[0115] For more substantial changes in a drug product, it is recommended that dissolution profiles be compared between the reference product and the changed product under the same conditions. ("Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage Forms," U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 1997, (available at http: / / www.fda.gov / cder / guidance / oldl 1l9.htm)). http: / / www.fda.gov / cder / guidance.htm A dissolution profile can be considered similar by virtue of (1) overall profile similarity and (2) similarity at each dissolution sampling time point.

[0116] One way to perform a dissolution profile comparison is by using a model independent method that utilizes a difference factor (fi) and a similarity factor (f2). A simple model independent method utilizes a difference factor (fi) and a similarity factor (f2) to compare dissolution profiles (Moore, J.W. and H.H. Flanner, 1996, "Mathematical Comparison of Dissolution Profiles," Pharmaceutical Technology, 20(6):64-74). The difference factor (fi) calculates the percent (%) difference between two curves at each time point and is a measure of the relative error between the two curves:

[0117] fi = { [∑ (R - T)2] / [∑ R2]} · 100 t＝1 n t t t＝1 n t

[0118] where n is the number of time points, R is the dissolution value for the reference (pre-change) batch at time t, and T is the dissolution value for the test (post-change) batch at time t. t t

[0119] The similarity factor (f2) is a log inverse square root transformation of the sum of squared errors and is a measure of the percent (%) similarity in dissolution between the two curves.

[0120] f2 = 50 · log{ [1 + (1 / n)∑ (R - T)2] / [∑ (R - T)2]} · 100 t＝1 n t t 2 -0.5

[0121] The specific procedure for determining the difference factor and the similarity factor is as follows:​​​​​​​​​​​​

[0122] a. Determine the dissolution profile of both the test (changed) product and the reference (unchanged) product.

[0123] b. Using the average dissolution value of the two curves at each time interval, calculate the difference factor (f1) and the similarity factor (f2) using the equations above.

[0124] c. When the f1 value is equal to or less than 15 (0 to 15) and the f2 value is greater than 50 (i.e. 50 to 100), the curves are considered to be similar, thus ensuring the identity of the products.

[0125] As precision improves and PION technology is enhanced, active dissolution profiles can be compared with greater accuracy and to variables that were previously understood to not provide any computable difference in dissolution.

[0126] Polymer

[0127] The film and / or components thereof can be water-soluble, water-swellable, water- insoluble, or a combination of one or more of these. The term "water-soluble" can refer to a substance that is at least partially soluble in an aqueous solvent, including but not limited to water. The term "water-soluble" can not necessarily mean that the substance is 100% soluble in the aqueous solvent. The term "water-insoluble" refers to a substance that is not soluble in an aqueous solvent, including but not limited to water. The solvent can include water, or alternatively can include other solvents (preferably polar solvents) either by themselves or in combination with water.

[0128] The film can be produced by a combination of at least one polymer and a solvent, optionally including other components. The solvent can be water, a polar organic solvent, including but not limited to ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent can be a non-polar organic solvent, such as dichloromethane. The film can be prepared by utilizing a selected casting or deposition method and a controlled drying process. For example, the film can be prepared by a controlled drying process that includes applying heat energy and / or radiant energy to a wet film matrix to form a visco-elastic structure, thereby controlling the uniformity of the contents of the film. The controlled drying process can include contacting the top of the film, the bottom of the film, or a substrate supporting the cast, deposited, or extruded film with air alone, heat alone, or heat and air together, or more than one surface at the same time or at different times during the drying process. Some of these processes are described in more detail in U.S. Patent No. 8,765,167 and U.S. Patent No. 8,652,378, which are incorporated herein by reference. Alternatively, the film can be extruded as described in U.S. Patent Publication No. 2005 / 0037055 Al, which is incorporated herein by reference.

[0129] The polymeric matrix included in the film can be water-soluble, water-swellable, or a combination thereof.

[0130] The polymeric matrix includes a polymer. The polymer can be a polyethylene oxide. The polymer can include cellulose, a cellulose derivative, or a gum. The polymer can include a polyethylene oxide, cellulose, a cellulose derivative such as a cellulose ether, or a combination thereof. The polymer can be a cellulose polymer. In certain embodiments, the cellulose polymer can be hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, and / or sodium carboxymethyl cellulose. In certain embodiments, the polymer can include hydroxypropyl methylcellulose. In certain embodiments, the polymer can include a polyethylene oxide and a cellulose ether, such as hydroxypropyl methylcellulose. In certain embodiments, the polymer can include a polyethylene oxide and / or a polyvinylpyrrolidone. In certain embodiments, the polymeric matrix can include a polyethylene oxide and / or a polysaccharide. In certain embodiments, the polymeric matrix can include a polyethylene oxide, hydroxypropyl methylcellulose, and / or a polysaccharide. In certain embodiments, the polymeric matrix can include a polyethylene oxide, a cellulose polymer, a polysaccharide, and / or a polyvinylpyrrolidone. In certain embodiments, the polymeric matrix can include at least one polymer selected from the group consisting of pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide, propylene oxide copolymer, collagen, albumin, polyamino acid, polyphosphazene, polysaccharide, chitin, chitosan, and derivatives thereof. Further examples of useful water-soluble polymers include, but are not limited to, polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, polysaccharide, and combinations thereof.

[0131] As used herein, the phrase "water-soluble polymer" and its variations refer to polymers that are at least partially soluble in water, and desirably completely or overwhelmingly soluble in water, or absorb water. Polymers that absorb water generally refer to water-swellable polymers. The materials useful in the present invention can be water-soluble or water-swellable at room temperature and other temperatures (e.g., temperatures above room temperature). In addition, the material can be water-soluble or water-swellable at a pressure lower than atmospheric pressure. Desirably, the water-soluble polymer is water-soluble or water-swellable, having a water absorption of at least 20% by weight. Water-soluble polymers having a water absorption of 25% or more by weight are also available. In some embodiments, the film formed by such a water-soluble polymer can be sufficiently water-soluble so as to dissolve when in contact with body fluids.

[0132] Other polymers that can be incorporated into the membrane include biodegradable polymers, copolymers, block polymers, or combinations thereof. It is to be understood that the term "biodegradable" is intended to include materials that can undergo chemical degradation, as opposed to materials that physically decompose (i.e., bioerodible materials). The polymers incorporated into the membrane may also include combinations of biodegradable or bioerodible materials. Useful polymers or polymer classes that are known to meet the above criteria are: poly (glycolic acid) (PGA), poly (lactic acid) (PLA), poly (dimethylsiloxane) (DMSO), poly (methylenediamine ...

[0014] The invention also provides a polymer composition comprising a polymeric matrix comprising a plurality of polymers, e.g., polyalkylene, polyoxalate, poly(α-ester), polyanhydride, polyacetate, polycaprolactone, poly(orthoester), polyamino acid, polyamino carbonate, polyurethane, polycarbonate, polyamide, poly(alkyl cyanoacrylate), and mixtures and copolymers thereof. Other useful polymers include stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propionic acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymers, copolymers of polyurethane and poly(lactic acid), copolymers of α-amino acids, copolymers of α-amino acids and caproic acid, copolymers of α-benzyl glutamate and polyethylene glycol, copolymers of succinate and poly(glycol), polyphosphazenes, polyhydroxyalkanoates, or mixtures thereof. Binary and ternary systems are contemplated. The polymer matrix may comprise one, two, three, four, or more components.

[0133] Other specific polymers that can be used include those sold under the Medisorb and Biodel trademarks. The Medisorb materials are sold by the Dupont Company of Wilmington, Del, and are generally referred to as "glycolide / lactide copolymers," and include "dihydroxy polymers of propionic acid and hydroxy polymers of hydroxyacetic acid." Four such polymers include the following: Medisorb 100L, which is believed to be 100% lactide with a melting point in the range of 338°F to 347°F (170°C to 175°C); Medisorb 100L, which is believed to be 100% lactide with a melting point in the range of 437°F to 455°F (225°C to 235°C); Medisorb 85 / 15, which is believed to be 85% lactide and 15% glycolide with a melting point in the range of 338°F to 347°F (170°C to 175°C); and Medisorb 50 / 50, which is believed to be 50% lactide and 50% glycolide with a melting point in the range of 338°F to 347°F (170°C to 175°C). The Biodel materials represent a class of different chemically distinct polyanhydrides.

[0134] While a variety of different polymers can be used, it can be desirable to select a polymer that provides the film with mucoadhesive properties as well as a desired rate of dissolution and / or disintegration. In particular, it can be desirable to maintain the film in contact with the mucosal tissue for a time that depends on the type of pharmaceutically active included in the composition. Some pharmaceutically actives can only need to be delivered via the mucosa for a few minutes, while others can need to be delivered for up to several hours or even longer. Thus, in some embodiments, one or more water-soluble polymers as described above can be used to form the film. However, in other embodiments, it can be desirable to use a combination of a water-soluble polymer with a water-swellable, water-insoluble, and / or biodegradable polymer. The inclusion of one or more water-swellable, water-insoluble, and / or biodegradable polymers can provide the film with a slower rate of dissolution or disintegration than a film formed from a water-soluble polymer alone. Thus, the film can adhere to the mucosa for a longer period of time (e.g., up to several hours), which can be desirable for the delivery of certain pharmaceutically actives.

[0135] The polymeric matrix can include a dendritic polymer, which can include highly branched macromolecules with a variety of architectural scaffolds. The dendritic polymer can include a dendronized polymer, a dendritic polymer (dendritic graft polymer), a linear dendritic hybrid, a multi-arm star polymer, or a hyperbranched polymer.

[0136] The polymeric matrix can include hyperbranched polymers, which are highly branched polymers with defects in their structure. However, they can be synthesized in a single step reaction, which is advantageous over other dendritic structures and thus suitable for large volume applications. The properties of these polymers, in addition to their globular structure, are rich functionality, intramolecular cavities, low viscosity, and high solubility. Dendrimers have been used for several drug delivery applications. See, e.g., Dendrimers as Drug Carriers: Applications in Different Routes of Drug Administration. J Pharm Sci, Vol. 97, 2008, 123-143, which is incorporated herein by reference.

[0137] Dendrimers can have an internal cavity that can encapsulate a drug. The steric hindrance caused by the highly compact polymer chains can prevent drug crystallization. Thus, branched polymers can provide additional advantages when formulating crystallizable drugs in a polymeric matrix.

[0138] Examples of suitable dendrimers include, but are not limited to, poly(ether)-based dendrons, dendrimers, and hyperbranched polymers; poly(ester)-based dendrons, dendrimers, and hyperbranched polymers; poly(thioether)-based dendrons, dendrimers, and hyperbranched polymers; poly(amino acid)-based dendrons, dendrimers, and hyperbranched polymers; poly(arylene ether)-based dendrons, dendrimers, and hyperbranched polymers; poly(alkylene imine)-based dendrons, dendrimers, and hyperbranched polymers; poly(amidoamine)-based dendrons, dendrimers, or hyperbranched polymers.

[0139] Further examples of hyperbranched polymers include poly(amine), polycarbonates, poly(ether ketone), polyurethane, polycarbosilane, polysiloxane, poly(ester amine), poly(sulfone amine), poly(urea urethane), and polyether polyols such as polyglycerol.

[0140] For example, in some embodiments, the self-supporting film can comprise polyethylene oxide alone or in combination with a second polymeric component. The second polymer can be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer, or any combination thereof. Suitable water-soluble polymers include, without limitation, any of the polymers provided above. In one embodiment, the water-soluble polymer can be a hydrophilic cellulosic polymer, such as hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose. In another embodiment, one or more water-swellable, water-insoluble, and / or biodegradable polymers can also be included in the polyethylene oxide-based film. Any of the water-swellable, water-insoluble, or biodegradable polymers provided above can be employed. The second polymer can be employed in an amount of from about 0% to about 80% by weight of the polymeric matrix, more specifically from about 30% to about 70% by weight, even more specifically from about 40% to about 60% by weight, including greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, and greater than about 70%, about 70%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, or less than about 5% by weight.

[0141] The polymer plays an important role in affecting the viscosity of the film. Viscosity is a property of a liquid that controls the stability of the active in an emulsion, colloid, or suspension. Generally, the viscosity of the matrix will vary from about 400 cps to about 100,000 cps, preferably from about 800 cps to about 60,000 cps, and most preferably from about 1,000 cps to about 40,000 cps. Desirably, the viscosity of the film-forming matrix will increase rapidly at the beginning of the drying process.

[0142] The viscosity can be adjusted based on the other components within the matrix depending on the active selected. For example, if a component is not soluble within the solvent selected, an appropriate viscosity can be selected that prevents the component from settling, which would adversely affect the uniformity of the resulting film. The viscosity can be adjusted in different ways. To increase the viscosity of the film matrix, a higher molecular weight polymer can be selected or a cross-linking agent, such as calcium, sodium, and potassium salts, can be added. The viscosity can also be adjusted by adjusting the temperature or by adding a viscosity-increasing component. Components that increase the viscosity or stabilize the emulsion / suspension include higher molecular weight polymers and polysaccharides and gums, including, without limitation, alginates, carrageenan, hydroxypropyl methyl cellulose, locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gum, and combinations thereof.

[0143] It has also been observed that certain polymers that would normally require plasticizers to obtain flexible films when used alone can be combined without plasticizers and also obtain flexible films. For example, when HPMC and HPC are used in combination, a flexible strong film is provided that has plasticity and elasticity suitable for manufacture and storage. No additional plasticizers or polyols are needed for flexibility.

[0144] Additive

[0145] Additives can be added to the films disclosed herein. A variety of additives that can be incorporated into the films of the present application can provide a variety of different functions. Examples of classes of additives include excipients, lubricants, buffering agents, stabilizers, foaming agents, pigments, colorants, fillers, bulking agents, sweeteners, flavoring agents, flavorants, release modifiers, adjuvants, plasticizers, flow promoters, release agents, polyols, granulating agents, diluents, binders, buffering agents, absorbents, glidants, adhesives, anti-adherents, acidulants, emollients, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, and mixtures thereof. These additives can be added prior to or with one or more actives. The amount of additive in the film can be up to about 80%, from about 0.005% to about 50%, from about 1% to about 20%, or from about 3% to about 20%, including greater than about 1%, greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, about 3%, or less than about 1%, based on the weight of the film composition, which is the total weight of all components therein.

[0146] The additives can be selected from sweeteners, flavoring agents, taste enhancers, fillers, plasticizers, colorants (e.g., dyes or pigments), penetration enhancers, buffering agents, preservatives, silicon dioxide, anti-tacking agents, and any combination thereof.

[0147] The flavoring agents can be selected from natural and synthetic flavoring liquids. An illustrative list of such materials includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of examples includes peppermint oil; cocoa; and citrus oils, such as lemon, orange, grapefruit, lime and grapefruit; and fruit essences including apple, pear, peach, grape, strawberry, raspberry, lemon, lime, orange, cherry, plum, pineapple, apricot, or other fruit flavoring agents.

[0148] Useful flavors or flavoring agents include natural and artificial flavors. These flavors can be selected from synthetic flavor oils and flavoring aromatics, and / or oils, oleoresins, and extracts derived from plants, leaves, flowers, fruits, and so forth, and combinations thereof. Non-limiting flavor oils include spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds. Also useful are artificial, natural or synthetic fruit flavors such as vanilla; chocolate; coffee; cocoa; and citrus oils including lemon, orange, grape, lime, and grapefruit; and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and so forth. These flavors can be used individually or in combination. Commonly used flavors include mints such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavors, whether employed individually or in combination. Flavorants such as aldehydes and esters including cinnamyl

[0149] Other useful flavorants include aldehydes and esters such as benzaldehyde (cherry, almond); citral, i.e., alpha citral (lemon, lime); neral, i.e., beta citral (lemon, lime); decanal (orange, lemon); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); tolyl aldehyde (cherry, almond); 2,6-dimethyl octanal (green fruit); and 2-dodecenal (citrus, mandarin); combinations thereof; and so forth.

[0150] The amount of flavoring agent employed is generally preferred in terms of, for example, the type of flavoring agent, individual flavoring agents, and the desired intensity of such factors. The amount can vary in order to achieve the desired result in the final product. Such variations are within the ability of one skilled in the art without undue experimentation. Generally, amounts of about 0.1 wt% to about 30 wt% can be used in the practice of the present application.

[0151] In one embodiment, the film comprises a berry flavoring agent. The berry flavoring agent can be raspberry, strawberry, blueberry, bousenberry, blackberry, or combinations thereof. In another embodiment, the film comprises a raspberry flavoring agent. The berry flavoring agent, raspberry, strawberry, blueberry, bousenberry, or blackberry flavoring agent can be natural or artificial and can be purchased and / or manufactured by any means known in the art. For example, a raspberry flavoring agent comprising a scent can be obtained by incorporating a mixture of volatile compounds disclosed in E. Aprea et al., “Volatile Compounds of Raspberry Fruit: From Analytical Methods to Biological Role and Sensory Impact,” Molecules 2015, 20, 2445-2474, which is incorporated by reference herein in its entirety. When used, the berry flavoring agent can be present at about 0.1% to about 15% by weight of the composition. In certain embodiments thereof, the berry flavoring agent is present at about 0.5% to about 10%, about 1% to about 8%, about 2% to about 7%, about 3%, about 4%, about 5%, about 6%, or about 7% by weight of the composition.

[0152] Suitable sweeteners include both natural and artificial sweeteners. Non-limiting examples of suitable sweeteners include, for example: water-soluble sweeteners such as monosaccharides, disaccharides, and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, and dihydrochalcones; water-soluble artificial sweeteners such as soluble saccharin salts (i.e., sodium or calcium saccharin salts), cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-l,2,3- oxathiazine-4-one-2,2-dioxide, the potassium salt of 3,4-dihydro-6-methyl-l,2,3- oxathiazine-4-one-2,2-dioxide (acesulfame-K), the free acid form of saccharin, and the like; dipeptide-based sweeteners such as those derived from L-aspartic acid such as L- aspartyl-L-phenylalanine methyl ester (aspartame), L-alpha-aspartyl-N-(2,2,4,4- tetramethyl-3-thietanyl)-D-alaninamide hydrate, L-aspartyl-L-phenylglycerine, and L- aspartyl-L-2,5,dihydrophenylglycine, L-aspartyl-2,5-dihydro-L-phenylalanine, the methyl ester of L-aspartyl-L-(l-cyclohexen)-alanine, and the like; water-soluble sweeteners derived from naturally occurring water-soluble sweeteners such as chlorinated derivatives of ordinary sugar (sucrose) known as, for example, chloro-sucrose; and protein-based sweeteners such as thaurnatoccous danielli (Thaurnatin I and II). Naturally occurring high intensity sweeteners such as Lo Han Kuo, Stevia, stevioside, monellin, and glycyrrhizin can also be used.

[0153] Generally, an effective amount of a sweetener is utilized to provide the desired level of sweetness for a particular composition, and this amount will vary with the sweetener selected. The amount will generally be from 0.01% to about 10% by weight of the composition. These amounts can be used to achieve the desired level of sweetness independent of the flavor level obtained from any optional flavoring oil used. In certain embodiments, the sweetener is present from about 0.5% to about 5%, from about 1% to about 5%, from about 1.5% to about 4%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, or about 5% by weight of the composition.

[0154] The sweetener can be selected from the group consisting of sucralose, stevia, acesulfame potassium, saccharin, fructose, aspartame, and any combination thereof, and can be present from about 0.5% to about 5%, from about 1% to about 5%, from about 1.5% to about 4%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, or about 5%, by weight of the composition. In one embodiment, from about 3% to about 4%, about 3%, or about 3.5%, by weight of the composition, of sucralose, saccharin, aspartame, and any combination thereof is present in the film.

[0155] Coloring additives useful in the present application include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (external D&C). These colorants are dyes, their corresponding lakes, and certain natural and derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

[0156] Further examples of colorants include known azo dyes, organic or inorganic pigments, or colorants of natural origin. Inorganic pigments are preferred, such as oxides of iron or titanium, which are added at concentrations of from about 0.001% to about 10%, and preferably from about 0.5% to about 3%, by weight of the total composition. The film can be any color, including but not limited to white, transparent, blue, green, red, pink, purple, orange, or yellow. In one embodiment, the film is transparent and clear.

[0157] The film also desirably includes a buffering agent to control the pH. Any desired level of buffering agent is incorporated into the polymer matrix to provide the desired pH level encountered as the pharmaceutical active is released from the film. The buffering agent is preferably provided in an amount sufficient to control the release and / or absorption of the active from the film into the body. The buffering agent can include sodium citrate, citric acid, hydrogen tartrate, or any combination thereof.

[0158] In certain embodiments, the film can include a plasticizer, which can include polyalkylene oxides, such as polyethylene glycol, polypropylene glycol, polyethylene-polypropylene glycol; organic plasticizers with low molecular weight, such as glycerol, glycerol monoacetate, glycerol diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, the sugar alcohol sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, plant extracts, fatty acid esters, fatty acids, oils; and the like. Plasticizers can be added at concentrations of about 0.1% to about 40%, or about 0.5% to about 20%, based on the weight of the film composition, including greater than about 0.5%, greater than about 1%, greater than about 1.5%, greater than about 2%, greater than about 4%, greater than about 5%, greater than about 10%, greater than about 15%, about 20%, greater than about 20%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 2%, less than about 1%, and less than about 0.5%. Compounds that improve the textural properties of the film material can also be added, such as animal or vegetable fats, desirably in hydrogenated form, especially those that are solid at room temperature. The melting point of these fats desirably is 50°C or higher. Preferred are triglycerides having C 12 -, C 14 -, C 16 -, C 18 -, C 20 -, and C 22 -fatty acids. These fats can be added alone without the addition of extenders or plasticizers, and can advantageously be added alone or with monoglycerides and / or diglycerides or phospholipids, especially lecithin. The monoglycerides and diglycerides desirably are derived from the above types of fats (i.e., having C 12 -, C 14 -, C 16 -, C 18 -, C 20 -, and C 22 -fatty acids). The total amount of fats, monoglycerides, diglycerides, and / or lecithin can be up to about 5% or in the range of about 0.5% to about 2%, based on the weight of the film composition.

[0159] A variety of other components and fillers can also be added to the films disclosed herein. These can include, without limitation, surfactants; additional antifoams; simethicone to promote smoother film surfaces, for example, by releasing oxygen from the film; thermosetting gels to help maintain dispersion of components, such as gelatin, carrageenan, and gelatin; and inclusion compounds to improve solubility and / or stability of certain active components, such as cyclodextrins and clathrate molecules.

[0160] Still other additives can be inorganic fillers, such as oxides of magnesium, aluminum, silicon, titanium, and the like, desirably in a concentration ranging from about 0.02% to about 3%, and desirably from about 0.02% to about 1%, by weight, based on the weight of the film composition.

[0161] Silicon dioxide, calcium silicate, or titanium dioxide can be useful at concentrations ranging from about 0.02% to about 1%, by weight, of the total composition. These compounds are used as texturizing agents.

[0162] These additives are used in amounts sufficient to achieve their intended purpose. Generally, combinations of some of these additives will alter the overall release profile of the active ingredient and can be used to modify, i.e., retard or accelerate, release.

[0163] An anti-tacking agent can be incorporated into the oral films of the present disclosure. The anti-tacking agent can be selected from the group consisting of lubricants, anti-tacking agents, flow aids, and combinations thereof. Anti-tacking agents aid in the flow properties of the material, for example, by reducing the tackiness to the die during the extrusion process and reducing the tackiness to the roof of the mouth during administration of the dosage form. During consumption of the film, the particles tend to adhere to the roof of the mouth. This is undesirable for films containing bitter drugs, such as dextromethorphan, for example, because the adhered particles release the drug, which increases the amount of bitterness perceived by the user. The addition of an anti-tacking agent to the film reduces the adhesion to the roof of the mouth, thereby effectively reducing the bitterness perceived by the user during consumption.

[0164] The anti-tacking agent can also impart a reduced coefficient of friction of the film to film, thereby reducing the problem of the film dosage units, i.e., strips, sticking to each other. More specifically, in many types of film packaging, the strips are stacked on top of each other. Incorporation of an anti-tacking agent can allow the individual strips to slide smoothly with respect to each other when each unit is removed from the packaging.

[0165] Examples of suitable lubricants for use as anti-tacking agents include, but are not limited to: stearates, such as magnesium stearate, calcium stearate, and sodium stearate; stearic acid; vegetable oils (commercially available as sterotex); talc; waxes; a blend of magnesium stearate and sodium lauryl sulfate (commercially available as stearowet); boric acid; sodium benzoate; sodium acetate; sodium chloride; DL-leucine; polyethylene glycol with a molecular weight of 4000 (commercially available as Carbowax 4000); polyethylene glycol with a molecular weight of 6000 (commercially available as Carbowax 6000); sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and combinations thereof.

[0166] Examples of suitable anti-tacking agents include, but are not limited to: talc; corn starch; synthetic amorphous silica; Syloid (commercially available as Cab-O-Sil); DL-leucine; sodium lauryl sulfate; metallic stearates; and combinations thereof. Examples of suitable glidants include, but are not limited to: talc; corn starch; synthetic amorphous silica; Syloid (commercially available as Cab-O-Sil); syloid; aerogel; and combinations thereof.

[0167] Vitamin E is another suitable anti-tacking agent for use in some embodiments of the present application. Vitamin E can be used as both an anti-tacking agent and an active ingredient in the film. Desirably, Vitamin E TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate) is employed. Vitamin E TPGS is a water-soluble form of Vitamin E derived from natural sources. Vitamin E TPGS is readily absorbed as compared to other forms. In addition, Vitamin E TPGS does not substantially impart a taste to the film. Vitamin E TPGS can be used in solution, for example, in a 10% or 20% solution with water. Vitamin E TPGS is particularly useful in reducing the tackiness of the film and the tendency to stick to the roof of the user's mouth. Vitamin E can be present in an amount of about 0.01% to about 20% by weight of the composition.

[0168] When present, the anti-tacking agent can be included in an amount of about 0.01% to about 20% by weight of the film composition. More particularly, the anti-tacking agent can be present in an amount of about 0.01% to about 10% by weight of the film composition, even more particularly about 0.25% to about 5% by weight of the film composition.

[0169] Combinations of anti-tacking agents can also be employed. For example, a combination of stearate (e.g., magnesium stearate) and silica can be used. A silica product, SIPERNAT ABOUT 500 LS (commercially available from Degussa) having a 4.5 μm average particle size is suitable for use herein. The combination of magnesium stearate and silica can provide improved glidant properties, i.e., help the film strips to smoothly slide with respect to one another in the package. Thus, the magnesium stearate can be present in an amount of about 0.1% to about 2.5% by weight of the film composition, and the silica can be present in an amount of about 0.1% to about 1.5% by weight of the film composition. Such combinations of anti-tacking agents can be useful in a variety of films containing different flavorings and / or actives.

[0170] An anti-tack agent can be included in the film composition itself. For example, a single layer or multi-layer film can be formed that includes an anti-tack agent. For example, a multi-layer film can include two, three, or more layers of film that are in substantial contact with each other. The film layers can be laminated to each other. The anti-tack agent can be present in one or more of the layers of the multi-layer film. For example, some embodiments can include a two-layer film in which the anti-tack agent is present in one of the two film layers. Some embodiments can include a three-layer film in which the anti-tack agent is present in each of the outer layers of the three-layer film, but not in the inner or middle layer. In this regard, a variety of different combinations of layers can be formed.

[0171] Alternatively, the anti-tack agent can be included in a composition used to coat the outer surface of the film. For example, the anti-tack agent can be applied to the film in the form of a wet or dry coating, such as a sugar or sugarless coating. The film can be coated with the anti-tack agent in any conventional manner, such as, but not limited to, dip coating, spray coating, dusting, or fluidized bed. One or more surfaces of the film can be coated. In some embodiments, the anti-tack coating can be applied to a substrate, such as a backing for the film, rather than directly to the film itself. The anti-tack coating can adhere to the film when the film is removed from the backing.

[0172] Some embodiments can include a fat and / or a wax as the anti-tack agent.

[0173] As noted above, any other optional components described in commonly-assigned U.S. Patent No. 7,425,292 and U.S. Patent No. 8,765,167 can also be included in the films described herein.

[0174] Permeation Enhancer

[0175] The films disclosed herein can be penetration enhancers. The actives can be combined with the penetration activity enhancer in a single layer of film, each included in a separate layer, or can each be otherwise included in discrete regions of the same dosage form. In certain embodiments, the actives included in the polymeric matrix can be dispersed in the matrix. In certain embodiments, the penetration enhancers included in the polymeric matrix can be dispersed in the matrix.

[0176] Any penetration enhancer known to be used in the art can be incorporated into the films of the present disclosure. The term "penetration enhancer" can be used interchangeably with absorption enhancer and penetration enhancer. A penetration enhancer is a component that can improve the permeability of a pharmaceutical active through a subject's mucosa and into the bloodstream when delivered to the oral cavity via a film.

[0177] The penetration enhancer can be a non-ionic alkyl glycoside having a hydrophobic alkyl group attached through a linkage to a hydrophilic sugar. The penetration enhancer can be selected from a maltoside or maltoside derivative, a sucroside or sucroside derivative, and an essential oil or component of an essential oil. The penetration enhancer can be selected from an alkyl thiomaltoside, a maltoside, a maltotrioside, a maltopyranoside, a dodecyl maltoside, a tridecyl maltoside, a tetradecyl maltoside, a tetradecyl-beta-D-maltoside, a dodecyl-beta-D-maltoside, a tridecyl-beta-D-maltoside, a sucroside, a sucrose mono-dodecanoate, a sucrose mono-tridecanoate, a sucrose mono-tetradecanoate, and combinations thereof.

[0178] The penetration enhancer can increase the rate and amount of absorption of the pharmaceutically active by greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 100%, greater than 150%, about 200% or more, or less than 200%, less than 150%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or a combination of these ranges, depending on the other components in the composition.

[0179] In certain embodiments, the film comprises a pharmaceutically acceptable non-toxic, non-ionic alkyl glucoside having a hydrophobic alkyl group attached by linkage to a hydrophilic sugar in combination with a mucosal delivery enhancer selected from the group consisting of: (a) an aggregation inhibitor; (b) a charge altering agent; (c) a pH controlling agent; (d) a degradative enzyme inhibitor; (e) a mucilage dissolving or mucilage clearing agent; (f) an antistatic agent; (g) a membrane permeation enhancer selected from the group consisting of: (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelles, liposomes or carriers; (iii) an alcohol; (iv) an enamine; (v) a NO donor compound; (vi) a long chain amphipathic molecule; (vii) a small hydrophobic permeation enhancer; (viii) a sodium or salicylic acid derivative; (ix) a glyceryl ester of acetoacetic acid; (x) a cyclodextrin or β-cyclodextrin derivative; (xi) a medium chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or salt thereof; (xiv) an N-acetylated amino acid or salt thereof; (xv) an enzyme that degrades a selected film component; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) any combination of the membrane permeation enhancers described in (i)-(x); (h) a modulator of epithelial junction physiology; (i) a vasodilator; (j) a selective transport enhancer; and (k) a stable delivery vehicle, carrier, mucosal adhesive, support or complex forming substance that is effectively combined with, associated with, contained within, encapsulated by or bound to the compound, resulting in stabilization of the compound for enhanced transmucosal delivery, wherein the formulation of the compound with the transmucosal delivery enhancer provides increased bioavailability of the compound in the plasma of a subject. Permeation enhancers are described in J. Nicolazzo, et al., J. of Controlled Disease, 105 (2005) 1-15, which is incorporated herein by reference.

[0180] Surfactants and bile salts have been shown to enhance the permeability of a variety of compounds across the buccal mucosa, both in vitro and in vivo. Data obtained from these studies strongly suggest that the increase in permeability is due to the effect of the surfactants on the intercellular lipids of the mucosa.

[0181] Fatty acids have been shown to enhance the permeation of many drugs through the skin, and this has been shown to be associated with an increase in the fluidity of the intercellular lipids by differential scanning calorimetry and Fourier transform infrared spectroscopy.

[0182] In addition, pretreatment with ethanol has been shown to enhance the permeability of tritiated water and albumin across the ventral tongue mucosa, and to enhance the permeability of caffeine across the buccal mucosa of pigs. There have also been some reports of the enhancing effect of Azone.RTM. on the permeability of compounds across oral mucosa. In addition, chitosan (a biocompatible and biodegradable polymer) has been shown to enhance the delivery of drugs through a variety of tissues, including the intestinal and nasal mucosa.

[0183] It has been shown that buccal permeation can be improved by using various types of transmucosal and transdermal penetration enhancers, such as bile salts, surfactants, fatty acids and their derivatives, chelating agents, cyclodextrins, and chitosan. Among these chemicals used for drug permeation enhancement, bile salts are the most common.

[0184] In vitro studies of the enhancing effect of bile salts on buccal permeation of compounds are discussed in Sevda Senel, Drug permeation enhancement via buccal route: possibilities and limitations, Journal of Controlled Release 72 (2001) 133-144, which is incorporated herein by reference. This article also discusses recent studies of the effect of dihydroxy bile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC), and trihydroxy bile salts, sodium glycocholate (GC) and sodium taurocholate (TC) on buccal epithelial permeability at a concentration of about 100 mM, including permeability changes associated with histological effects. Fluorescein isothiocyanate (FITC), morphine sulfate were each used as model compounds.

[0185] Chitosan has also been shown to facilitate the absorption of small polar molecules and peptide / protein drugs through the nasal mucosa in animal models and human volunteers. Other studies have shown enhancement of permeation of compounds across intestinal mucosa and cultured Caco-2 cells.

[0186] The penetration enhancer can be a plant extract. The plant extract can be an essential oil or a composition comprising an essential oil extracted by distillation of plant material. In some cases, the plant extract can include synthetic analogs of compounds extracted from plant material (i.e., compounds made by organic synthesis). The plant extract can include a phenylpropanoid, such as phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid esters, cinnamaldehyde, hydrocinnamic acid, piperonyl phenol, or safrole, or combinations thereof. The plant extract can be an essential oil extract of a clove plant, e.g., from the leaves, stems, or flower buds of a clove plant. The clove plant can be Syzygium aromaticum. The plant extract can comprise about 20% to about 95% eugenol, about 40% to about 95% eugenol, about 60% to about 95% eugenol, and, for example, about 80% to 95% eugenol. The extract can also comprise about 5% to about 15% eugenol acetate. The extract can also comprise caryophyllene. The extract can also comprise up to about 2.1% a-humulene. Other volatile compounds included in lower concentrations in clove essential oil can be β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone, or ethyl hexanoate. Other penetration enhancers can be added to the composition to improve absorption of the drug. Suitable penetration enhancers include natural or synthetic bile salts, such as sodium fusidate; glycocholic acid or deoxycholic acid and salts thereof; fatty acids and derivatives, such as sodium laurate, oleic acid, oleyl alcohol, glycerol monooleate, or palmitoyl carnitine; chelating agents, such as disodium EDTA, sodium lauryl sulfate, atone, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glycerol monolaurate, octoxy-nonyl-9, lauryl polyoxyl-9, polysorbates, sterols or glycerides, such as caprylocaproyl polyoxylglycerides, e.g., Labrasol. The penetration enhancer can include plant extract derivatives and / or lignin monomers. The penetration enhancer can also be a fungal extract.

[0187] Some plant-derived natural products are known to have vasodilatory effects. For a review, see McNeill J.R. and Jurgens, T.M., Can. J. Physiol. Pharmacol. 84:803-821 (2006), which is incorporated herein by reference. In particular, the vasodilatory effects of eugenol have been reported in a number of animal studies. See, for example, Lahlou, S., et al., J. Cardiovasc. Pharmacol. 43:250-57 (2004), Damiani, C.E.N., et al., Vascular Pharmacol. 40:59-66 (2003), Nishijima, H., et al., Japanese J. Pharmacol. 79:327-334 (1998), and Hume W.R., J. Dent Res. 62(9):1013-15 (1983), each of which is incorporated herein by reference. Calcium channel blockade is thought to be the cause of vasodilation induced by plant essential oils or their major component, eugenol. See Interaminense L.R.L. et al., Fundamental & Clin. Pharmacol. 21 :497-506 (2007), which is incorporated herein by reference.

[0188] Fatty acids can be used as inactive ingredients or drug carriers in the preparation of pharmaceuticals. Fatty acids can also be used as formulation ingredients due to certain functional roles and their biocompatible properties. Both free fatty acids and fatty acids as part of complex lipids are important components of primary metabolic fuels (storage and transport of energy), all membranes, and regulators of gene expression. For a review, see Rustan A.C. and Drevon, C.A., Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences (2005), which is incorporated herein by reference. There are two families of essential fatty acids that are metabolized in the human body: omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). If the first double bond is established between the third and fourth carbon atom of the omega carbon, it is referred to as an omega-3 fatty acid. If the first double bond is between the sixth and seventh carbon atom, it is referred to as an omega-6 fatty acid. PUFAs are further metabolized in the body by the addition of carbon atoms and by desaturation (hydrogen extraction). As an omega-6 fatty acid, linoleic acid is metabolized to gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, eicosatetraenoic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, and docosapentaenoic acid. As an omega-3 fatty acid, alpha-linolenic acid is metabolized to stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and docosahexaenoic acid (DHA).

[0189] It has been reported that fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid induce relaxation and hyperpolarization of porcine coronary artery smooth muscle cells via a mechanism involving activation of the Na.sup.+K.sup.+-APTase pump, and that fatty acids with increased cis-unsaturation are more potent. See Pomposiello, S.I. et al., Hypertension 31 :615-20 (1998), which is incorporated herein by reference. Interestingly, the response of pulmonary vessels to arachidonic acid (a metabolite of linoleic acid) can be vasoconstriction or vasodilation depending on the dose, the animal species, the manner of arachidonic acid administration, and the tones of the pulmonary circulation. For example, arachidonic acid has been reported to cause both cyclooxygenase-dependent and cyclooxygenase-independent pulmonary vasodilation. See Peddersen, C.O. et al., J. Appl. Physiol. 68(5): 1799-808 (1990); and see Sparwhake, E.W., et al., J. Appl. Physiol. 44:397-495 (1978) and Wicks, T.C. et al., Circ. Res, 38: 167-71 (1976), each of which is incorporated herein by reference.

[0190] Many studies have reported the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on vascular reactivity after administration in ingestible form. Some studies found that EPA-DHA or EPA alone inhibited the vasoconstrictive effects of norepinephrine or increased the vasodilatory response to acetylcholine in the forearm microcirculation. See Chin, J. P. F., et al., Hypertension 21 :22-8 (1993), and Tagawa, H, et al., J Cardiovasc Pharmacol 33:633-40 (1999), each of which is incorporated herein by reference. Another study found that both EPA and DHA increased systemic arterial compliance and tended to decrease pulse pressure and total vascular resistance. See Nestel, P. et al., Am J. Clin. Nutr. 76:326-30 (2002), which is incorporated herein by reference. Meanwhile, a study found that DHA, but not EPA, enhanced vasodilatory mechanisms and attenuated the constrictive response in the forearm microcirculation in hyperlipidemic overweight humans. See Mori, T. A., et al., Circulation 102:1264-69 (2000), which is incorporated herein by reference. Another study found vasodilatory effects of DHA on rhythmic contractions of isolated human coronary arteries in vitro. See Wu, K.-T. et al., Chinese J. Physiol. 50(4): 164-70 (2007), which is incorporated herein by reference.

[0191] Adrenergic receptors (or adrenoreceptors) are a class of G protein-coupled receptors that are targets for catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline). Epinephrine interacts with both alpha- and beta-adrenergic receptors, causing vasoconstriction and vasodilation, respectively. Although alpha receptors are less sensitive to epinephrine, when activated, they override vasodilation mediated by beta adrenergic receptors because there are more peripheral alpha 1 receptors than beta adrenergic receptors. The result is vasoconstriction at high levels of circulating epinephrine. At lower levels of circulating epinephrine, beta-adrenergic receptor stimulation predominates, causing vasodilation and subsequent reduction in peripheral vascular resistance. Alpha 1 adrenergic receptors are known to be involved in smooth muscle contraction, pupil dilation, vasoconstriction of the skin, mucosa, and abdominal viscera, and contraction of the sphincter muscles of the gastrointestinal (GI) tract and urinary bladder. Alpha 1 -adrenergic receptors are members of the G protein-coupled receptor superfamily. Upon activation, the heterotrimeric G protein G q protein-coupled receptor superfamily. Upon activation, the heterotrimeric G protein G qActivate phospholipase C (PLC). Mechanism of action involves interaction with calcium channels and altering the amount of calcium in the cell. For a review, see Smith R.S. et al., Journal of Neurophysiology, 102(2): 1103-14 (2009), which is incorporated herein by reference. Many cells possess these receptors.

[0192] The a1-adrenergic receptor can be a primary receptor for fatty acids. For example, saw palmetto extract (SPE), which is widely used to treat benign prostatic hyperplasia (BPH), has been reported to bind to a1 -adrenergic, muscarinic, and 1,4-dihydropyridine (1,4-DHP) calcium channel antagonist receptors. See Abe M., et al., Biol. Pharm. Bull. 32(4) 646-650 (2009), and Suzuki M. et al., Acta Pharmacologica Sinica 30:271-81 (2009), each of which is incorporated herein by reference. SPE includes a variety of fatty acids, including lauric acid, oleic acid, myristic acid, palmitic acid, and linoleic acid. Lauric acid and oleic acid can noncompetitively bind to a1 -adrenergic, muscarinic, and 1,4-DHP calcium channel antagonist receptors.

[0193] In certain embodiments, the penetration enhancer can be an adrenergic receptor interacting agent. An adrenergic receptor interacting agent refers to a compound or substance that modifies and / or otherwise alters the action of an adrenergic receptor. For example, an adrenergic receptor interacting agent can prevent stimulation of the receptor by increasing or decreasing the binding capacity of the receptor. Such interacting agents can be provided in short-acting or long-acting forms. Certain short-acting interacting agents can act quickly, but their effects only last for a few hours. Certain long-acting interacting agents can take longer to act, but their effects can last longer. The interacting agent can be selected and / or designed based on one or more of, for example, the desired delivery and dosage, the active pharmaceutical ingredient, the penetration modifier, the penetration enhancer, the matrix, and the condition being treated. The adrenergic receptor interacting agent can be an adrenergic receptor blocker. The adrenergic receptor interacting agent can be a terpene (e.g., a volatile unsaturated hydrocarbon derived from isoprene units found in the essential oils of plants) or a C3-C22 alcohol or acid, preferably a C7-C18 alcohol or acid. In certain embodiments, the adrenergic receptor interacting agent can include farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, and / or docosapentaenoic acid. The acid can be a carboxylic acid, a phosphoric acid, a sulfuric acid, a hydroxamic acid, or a derivative thereof. The derivative can be an ester or an amide. For example, the adrenergic receptor interacting agent can be a fatty acid or a fatty alcohol.

[0194] C3-C22alcohol or acid can be an alcohol or acid having a straight chain C3-C22hydrocarbon chain, e.g., a C3-C22hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; said hydrocarbon chain optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, hydroxy, halo, amino, nitro, cyano. C 3-5 cycloalkyl, 3- to 5-membered heterocycloalkyl, monocyclic aryl, 5- to 6-membered heteroaryl, C 1-4 alkylcarbonyloxy, C 1-4 alkylcarbonyloxy, C 1-4 alkylcarbonyloxy, C a )--, --N(R a )--C(O)--O--, a )--, --N(R a )--C(O)--N(R b )--, or --O--C(O)--O--. R a and R b each independently is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, hydroxy, or haloalkyl.

[0195] Fatty acids with higher unsaturation are effective candidates for enhancing drug penetration. Unsaturated fatty acids show higher enhancing properties than saturated fatty acids, and the enhancing properties increase with the number of double bonds. See A. Mittal, et al, Status of Fatty Acids as Skin Penetration Enhancers—A Review, Current Drug Delivery, 2009, 6, pp. 274-279, which is incorporated herein by reference. The position of the double bond also affects the enhancing activity of the fatty acid. Differences in physicochemical properties of fatty acids resulting from differences in double bond position most likely determine the potency of these compounds as skin penetration enhancers. The skin distribution increases as the position of the double bond shifts toward the hydrophilic end. It has also been reported that fatty acids with double bonds in even positions affect the structural perturbation of both stratum corneum and dermis more rapidly than fatty acids with double bonds in odd positions. Cis unsaturation in the chain can tend to increase activity.

[0196] The adrenergic receptor interacting agent can be a terpene. Terpenes have been reported to have a blood pressure lowering activity in essential oils. See Menezes I.A. et al., Z. Naturforsch. 65c:652-66 (2010), which is incorporated herein by reference. In certain embodiments, the permeation enhancer can be a sesquiterpene. Sesquiterpenes are a class of terpenes composed of three isoprene units, and have the empirical formula C 15 H 24 As monoterpenes, sesquiterpenes can be acyclic or contain rings, including many unique combinations. Biochemical modifications, such as oxidation or rearrangement, produce related sesquiterpenes.

[0197] The adrenergic receptor interacting agent can be an unsaturated fatty acid, such as linoleic acid. In certain embodiments, the permeation enhancer can be farnesol. Farnesol is a 15-carbon organic compound that is an acyclic sesquiterpene alcohol, which is the dephosphorylated form of the natural pyrophosphate farnesyl diphosphate. Under standard conditions, it is a colorless liquid. It is hydrophobic, and thus insoluble in water, but miscible with oils. Farnesol can be extracted from the oils of plants such as citronella, orange blossom, cyclamen, and tuberose. It is an intermediate step in the biosynthesis of cholesterol from mevalonic acid in vertebrates. It has a faint floral or weak citrus-lime odor and is used in perfumery and flavoring agents. Farnesol has been reported to selectively kill acute myeloid leukemia blasts and leukemia cell lines preferentially over primary hematopoietic cells, see Rioja A. et al., FEBS Lett 467(2-3):291-5 (2000), which is incorporated herein by reference. Vasodilatory properties of farnesyl analogs have been reported. See Roullet, J.-B., et al., J. Clin. Invest., 1996, 97:2384-2390, which is incorporated herein by reference. Both farnesol and N-acetyl-S-trans, trans-farnesyl-L-cysteine (AFC), a synthetic mimic of the carboxy terminus of farnesylated proteins, inhibited vasoconstriction of rat aortic rings.

[0198] In one embodiment, the film comprises a permeation enhancer comprising one or more of a phenylpropanoid, farnesol, Labrasol, and linoleic acid. In one embodiment, the permeation enhancer is a phenylpropanoid selected from eugenol; eugenol acetate; cinnamic acid; cinnamic acid esters; cinnamaldehyde; hydrogenated cinnamic acid; piperonyl phenol; safrole; or combinations thereof.

[0199] In one embodiment, the film comprises a permeation enhancer that is a plant extract. The plant extract can be an essential oil extract of a clove plant, an essential oil extract of a leaf of a clove plant, an essential oil extract of a flower bud of a clove plant, an essential oil extract of a stem of a clove plant, or a combination thereof. In one embodiment, the plant extract can be synthetic. The plant extract can comprise about 20% to about 95% eugenol, about 40% to about 95% eugenol, about 60% to about 95% eugenol, or about 80% to about 95% eugenol.

[0200] Uniformity and Manufacture

[0201] For purposes of the present application, the term non-self-aggregating uniformity refers to the films of the present application formed from one or more components other than a polar solvent provide the ability, when the film is formed by conventional drying methods such as high temperature air bath using drying ovens, drying tunnels, vacuum dryers or other such drying equipment, that the occurrence of aggregation or coalescence of the components within the film is substantially reduced (i.e., little or none) as the film is normally subjected. The term uniformity, as used in the present application, includes films incorporating a single component (e.g., a polymer) as well as combinations of components (e.g., a polymer and an active). Uniformity includes the substantial absence of aggregates or coalescences, which are common in conventional mixing and heat drying methods used to form films.

[0202] In addition, the films disclosed herein have a substantially uniform thickness, which likewise is not provided by the use of conventional drying methods for drying water-based polymer systems. The lack of uniform thickness can adversely affect the uniformity of component distribution throughout the extent or area of a given film.

[0203] The films disclosed herein are produced by the appropriate selection of combinations of polymers and polar solvents, optionally including active ingredients as well as other fillers known in the art. These films provide non-self-aggregating uniformity of components within the film by the use of selected casting or deposition methods and controlled drying processes. Examples of controlled drying processes include, but are not limited to, the use of the equipment disclosed in U.S. Patent Nos. 7,425,292; 7,357,891; 7,666,337; 8,603,514; 8,017,150; 8,663,667; 8,652,378; 8.900,497; 8,900,498; 9,108,340; 9,855,221; and 9,931,305, all of which are assigned to Aquestive Therapeutics, Inc., and are incorporated herein in their entirety. Another drying technique for obtaining the films is controlled radiation drying, such as infrared and radio frequency radiation (i.e., microwaves), without uncontrolled air flow.

[0204] The purpose of the drying process is to provide a method of drying the film that avoids the complications associated with conventional drying methods, such as the well-known "crazing" and mass transfer effects that first dry the upper surface of the film, trapping moisture inside. In conventional oven drying methods, as the moisture trapped inside subsequently evaporates, the top surface changes by being torn open and then reformed. This surface disruption by continuous skinning and then reopening the skinned surface to allow evaporation results in non-uniformity and thickness non-uniformity of the film. In addition, excessive air flow, such as hot air flow, can cause mass transfer (i.e., crazing) in the flowable matrix before the matrix achieves sufficient solidification during the drying process. This crazing effect, whether caused by surface skinning / breaking / reforming or mass transfer, creates non-uniformity of active content in the film as the particles are subjected to these uncontrolled mechanical and thermal forces and thus move within the film. This movement disrupts the essential uniformity of the active throughout the film that was achieved during the mixing process, which is required to produce dosage units of substantially the same size cut from the cast film, each having an amount of active that varies no more than 10% from the desired amount of active (the labeled amount).

[0205] These complications are avoided by the present invention and a uniform film is provided by preventing skinning / breaking / reforming or mass transfer of the film matrix before sufficient solidification of the flowable film matrix is formed to prevent movement and agglomeration or clumping of the active particles. The present disclosure provides several methods of controlling the drying process, thereby preventing the deleterious effects present in conventional drying methods and maintaining the essential uniformity of the active in the matrix achieved during mixing. It is also desirable to perform the drying quickly to "lock the active inside" by quickly creating stickiness to achieve a sufficient solid matrix to prevent substantial movement.

[0206] The cast and dried film can then be cut into individual dosage units of substantially equal size (length, width, and thickness) and these dosage units will have an active content that varies no more than 10% from the desired amount of active (the labeled amount).

[0207] Methods of controlling the adverse effects of conventional drying include controlling the oven air flow to prevent crazing, prevent mass movement of the chunks, and prevent premature skinning of the surface before the matrix dries under the skin. The air flow is desirably directed from the top at a distance, at an angle, and at a velocity such that the forces created when the air flow hits the film are unable to overcome the yield value of the film matrix, i.e., a force level below any that would move or otherwise cause crazing and non-uniformity of the film-forming composition that forms the matrix.

[0208] Controlled drying can also include first directing heat to the bottom surface of the film to begin drying from the bottom up in the film. This can be accomplished by applying heat to the bottom surface of the film in the substantial absence of top air flow, or by applying heat to both the bottom and top simultaneously without causing a rippling of the film that would result in premature skinning.

[0209] Alternatively, drying can be accomplished by introducing controlled microwaves to evaporate the water or other polar solvent within the film. Care must be taken when applying microwaves to ensure that the temperature of the substrate does not become too high such that the substrate boils, which would result in non-uniformity of the active within.

[0210] Yet another alternative method for controlled drying can include using a balanced fluid flow (e.g., balanced air flow) for drying, wherein the bottom and top air flows are controlled to provide a uniform film and avoid rippling and premature skinning as described herein. In this case, the air flow directed to the top of the film should not create conditions that would result in movement of the particles present in the wet film due to forces created by the air flow. In addition, it would be desirable to control the air flow directed to the bottom of the film such that the film does not lift due to forces from the air. Uncontrolled air flow above or below the film can create non-uniformity in the final film product. The humidity level in the area around the top surface can also be appropriately adjusted to prevent premature closure or skinning of the polymer substrate surface.

[0211] This manner of drying the film provides several advantages. Among these are faster drying times and a more uniform film surface, as well as a uniform distribution of components for any given area in the film. In addition, the faster drying times allow for rapid establishment of viscosity within the film, further promoting uniform distribution of components and reducing aggregation of components in the final film product. Desirably, drying of the film will occur in about ten minutes or less, or more desirably in about five minutes or less.

[0212] The present application results in an exceptionally uniform film product when attention is paid to reducing aggregation of the constituent components. In addition, avoiding the introduction of excess air and eliminating excess air in the mixing process is desirable in promoting uniformity of the film and the dosage units cut therefrom; further, the selection of polymer and solvent to provide controlled viscosity and to dry the film in a rapid manner as discussed above, while avoiding rippling or bulk movement of the film, is desirable in maintaining and providing a film and dosage units cut therefrom that have the desired uniformity of active content when reduced to a labeled amount. This uniformity of active content in the dosage units is thus achieved by attention to these parameters.

[0213] The products and methods of the present disclosure rely on the interplay between multiple production steps of the film to provide a film with substantially reduced self-aggregation of components within the film. Specifically, these steps include the particular method used to form the film, the preparation of the composition mixture to prevent air bubble inclusions, the control of the viscosity of the film-forming composition, and the method of drying the film. More specifically, a larger viscosity of the components in the mixture is particularly useful to prevent the active from precipitating when the active is not soluble in the chosen polar solvent. However, the viscosity cannot be too large so as to hinder or prevent the chosen casting method, which desirably includes reverse roll coating due to its ability to provide a film of substantially uniform thickness.

[0214] In addition to the viscosity of the film or film-forming components or matrix, other considerations are contemplated to achieve the desired film uniformity. For example, a stable suspension is achieved that prevents the settling of solids (e.g., drug particles) in non-colloidal applications. One method provided by the present invention is to balance the density of the particle phase (p p ) and the liquid phase (pi) and to increase the viscosity (μ) of the liquid phase. For a single particle, Stokes law relates the terminal settling velocity (Vo) of a rigid sphere of radius (r) in a viscous fluid as follows: V o = (2gr r )(p p - pi) / 9μ.

[0215] However, at high particle concentrations, the local particle concentration will affect the local viscosity and density. The viscosity of the suspension is a strong function of the solid volume fraction, and particle-particle and particle-liquid interactions will further hinder the settling velocity.

[0216] Stokian analysis has shown, for example, that the incorporation of a third phase (dispersed air or nitrogen) promotes the stability of the suspension. In addition, increasing the number of particles results in a hindering effect on the settling rate based on the solid volume fraction. In a dilute particle suspension, the settling rate v can be expressed as:

[0217]

[0218] where κ = a constant and is the volume fraction of the dispersed phase. The more particles suspended in the liquid phase results in a decrease in the velocity. Particle geometry is also an important factor, as the particle size will affect the particle-particle flow interactions.

[0219] Similarly, the viscosity of the suspension depends on the volume fraction of the dispersed solids. For a dilute suspension of non-interacting spherical particles, the expression for the suspension viscosity can be expressed as:

[0220]

[0221] where μ oviscosity of the continuous phase and is the solid volume fraction. At higher volume fractions, the viscosity of the dispersion can be represented as:

[0222]

[0223] where C is a constant.

[0224] The viscosity of the liquid phase is critical and desirably modified by tailoring the liquid composition to be a viscoelastic non-Newtonian fluid with a low yield stress value. This corresponds to a high viscosity continuous phase at rest. The formation of a viscoelastic or highly structured fluid phase provides additional resistance to particle settling. In addition, flocculation or aggregation can be controlled to minimize particle-particle interactions. The net effect is to maintain a homogeneous dispersed phase.

[0225] The addition of a hydrocolloid to the aqueous phase of the suspension increases the viscosity, can produce viscoelasticity, and can impart stability depending on the type of hydrocolloid, its concentration, and the particle composition, geometry, size, and volume fraction. The average particle size distribution of the dispersed phase needs to be controlled by selecting a minimum practical average particle size in the high viscosity medium (i.e., < 500 μm). A slight yield stress or elasticity at low shear rates can also contribute to permanent stability independent of the apparent viscosity. The critical particle diameter can be calculated from the yield stress value. In the case of isolated spherical particles, the maximum shear stress developed in a settling medium of given viscosity can be given as:

[0226] τ max = 3Vμ / 2r.

[0227] For pseudoplastic fluids, the viscosity at zero shear rate of this shear stress regime is likely to be the Newtonian plateau viscosity.

[0228] A stable suspension is an important property for the preparation of the premix composition to be fed into the membrane casting machine and for maintaining this stability during the wet membrane stage until sufficient drying has occurred to lock the particles and matrix in a form of sufficient solids to maintain homogeneity. For viscoelastic fluid systems, the rheology that produces a stable suspension over long periods of time (e.g., 24 hours) must be balanced with the requirements of high speed membrane casting operations. One desirable property of the membrane is shear thinning or pseudoplasticity whereby the viscosity decreases with increasing shear rate. Time dependent shear effects (e.g., thixotropy) are also advantageous. Structure recovery and shear thinning behavior are important properties such as the ability of the membrane to self-level as it is formed.

[0229] The rheology of the present compositions and membranes is quite demanding. This is due to the need to produce a stable particle suspension in a viscoelastic fluid matrix with acceptable viscosity values over a wide shear rate range, e.g., 30 to 60 weight percent. During mixing, pumping, and membrane casting, the shear rate can range from 10 seconds-1 to 10 5 Second -1 The range of is experienced, and pseudoplasticity is the preferred embodiment.

[0230] In film casting or coating, rheology is also a determining factor in the ability to form a film with the desired uniformity. Shear viscosity, extensional viscosity, viscoelasticity, and structural recovery will affect the quality of the film. As an illustrative example, the leveling properties of a shear-thinning pseudoplastic fluid are obtained as follows:

[0231] α (n-1 / n) =α o (n-1 / n) -((n-1) / (2n-1))(τ / K) 1 / n (2π / λ) (3+n) / n h (2n+1) / n t

[0232] where α is the surface wave amplitude, α o is the initial amplitude, λ is the wavelength of the surface roughness, and both "n" and "K" are viscosity power law exponents. In this example, the rheological behavior is related to the viscosity, increasing as n decreases and decreasing as K increases.

[0233] Desirably, the films or film-forming compositions of the present disclosure have very rapid structural recovery, i.e., their structural and compositional uniformity does not break up or become discontinuous as the film is formed during processing. Such very rapid structural recovery delays particle settling and sedimentation. Furthermore, the films or film-forming compositions desirably are shear-thinning pseudoplastic fluids. Such fluids, taking into account properties such as viscosity and elasticity, promote film formation and uniformity.

[0234] Therefore, the uniformity of the component mixture depends on a number of variables. As described herein, the component viscosities, mixing techniques and rheological properties of the resulting mixed compositions and wet cast films are important aspects of the present invention. In addition, control of the average particle size and particle shape is also a consideration. Desirably, the average particle size can be 200 microns or less, 150 microns or less or 100 microns or less. In addition, such particles can be spherical, substantially spherical or non-spherical, such as irregularly shaped particles or ellipsoidal particles. Elliptical particles or ellipsoids are ideal because they can maintain the uniformity of the film-forming matrix due to their tendency to settle to a lower degree than spherical particles.

[0235] A variety of techniques can be employed during the mixing phase to prevent bubble inclusion in the final film. To provide a mixture of the composition that is substantially free of bubble formation in the final product, a defoaming agent or surface tension reducing agent is employed. Additionally, the speed of the mixture is desirably controlled to prevent cavitation of the mixture in a manner that draws air into the mixture. Finally, bubble reduction can be further achieved by allowing the mixture to sit for a sufficient time to allow bubbles to escape prior to drying the film. Desirably, the method of the present invention first forms a masterbatch of the film forming components without the active ingredients (e.g., drug particles) or volatile materials (e.g., flavor oils). Just prior to casting, the active is added to a smaller mixture of the masterbatch. Thus, the masterbatch premixture can be allowed to sit for a longer period of time without concern for instability of the drug or other ingredients.

[0236] When forming a matrix that includes the film forming polymer and polar solvent in addition to any additives and active ingredients, this can be done in a number of steps. For example, all of the ingredients can be added together or a premix can be prepared. The advantage of a premix is that all of the ingredients except the active can be combined in advance and the active added just prior to film formation. This is particularly important for actives that can degrade upon continued exposure to water, air, or other polar solvents.

[0237] An apparatus for preparing the films of the present invention is disclosed, for example, in U.S. Patent No. 8,765,167, the entire contents of which are incorporated herein in their entirety.

[0238] Additionally, the films disclosed herein can include particles that are sensitive to temperature, for example, flavorants that can be volatile or drugs that can have a low degradation temperature. In this case, the drying temperature can be reduced while the drying time is increased to sufficiently dry the uniform film of the present invention. Additionally, bottom drying also tends to result in lower internal film temperatures as compared to top drying. In bottom drying, the evaporative vapor more easily carries heat away from the film as compared to top drying, which reduces the temperature of the internal film. This lower internal film temperature generally results in reduced drug degradation and a decrease in loss of certain volatile ingredients, such as flavorants.

[0239] Additionally, particles or microparticles can be added to the film forming composition or matrix after the composition or matrix is cast into a film. For example, particles can be added to the film prior to drying the film. The particles can be metered to the film in a controlled manner and disposed on the film by suitable techniques, for example, by using a doctor blade (not shown), which is a device that lightly or gently contacts the surface of the film and controls the disposition of the particles onto the surface of the film. Other suitable, but non-limiting techniques include using an additional roller to dispose the particles on the surface of the film, spraying the particles onto the surface of the film, and the like. The particles can be disposed on one or both of the opposing film surfaces, i.e., the top and / or bottom film surfaces. Desirably, the particles are disposed firmly on the film, for example, embedded into the film. Additionally, it is desirable that such particles are not completely encapsulated or embedded into the film, but rather remain exposed to the surface of the film, for example, in instances where the particles are partially embedded or partially encapsulated.

[0240] The particles can be any available sensory agent, cosmetic agent, pharmaceutical agent, or combinations thereof. Desirably, the pharmaceutical agent is a taste-masked or controlled release pharmaceutical agent. Available sensory agents include flavoring agents and sweetening agents. Available cosmetic agents include breath freshening agents or decongesting agents, for example menthol, including menthol crystals.

[0241] By providing a film of uniform thickness, monitoring and controlling the thickness of the film also aids in the production of a uniform film. The thickness of the film can be monitored with a gauge, for example, a Beta Gauge. The gauge can be connected to another gauge at the end of the drying apparatus, i.e., the drying oven or tunnel, to communicate through a feedback loop to control and adjust the opening in the coating apparatus, resulting in control of the uniform film thickness.

[0242] The film product is generally formed by combining a suitably selected polymer and a polar solvent, along with any active ingredients or fillers as desired. Desirably, the solvent content of the combination is at least about 30% by weight of the total combination. Desirably, the matrix formed by the combination is formed into a film by roll coating, and then desirably dried by a rapid and controlled drying process to maintain the uniformity of the film, more particularly, the consistent non-self-aggregating uniformity. The resulting film will desirably contain less than about 10% by weight of solvent, more desirably less than about 8% by weight of solvent, even more desirably less than about 6% by weight of solvent and most desirably less than about 2%. The solvent can be water, a polar organic solvent, including but not limited to ethanol, isopropanol, acetone, dichloromethane, or any combination thereof.

[0243] The above discussed parameters, such as, but not limited to, rheological properties, viscosity, mixing methods, casting methods, and drying methods, also influence the material selection of the different components of the present invention, in view of the above. Moreover, such considerations with proper material selection provide the compositions of the present invention, including pharmaceutical and / or cosmetic dosage forms or film products, with a substantially uniform distribution of the active(s) within the cast wet film and which maintains such substantially uniform distribution during the drying process, such that identical size dosage units can be cut from the continuously cast and dried film, which have a substantially uniform amount of the active present when compared to the desired amount of the active (i.e., the labeled amount of the active for each dosage unit). Desirably, the uniformity of the continuously cast self-supporting film is measured by cutting individual unit doses of substantially equal size from the self-supporting continuously cast film, which vary no more than 10% of the desired amount of the at least one active. For the sake of clarity, it is assumed that the desired amount of the unit dose of the film can be, for example, 10 mg of one or more given pharmaceuticals. The film of the present invention requires uniformity such that the substantially equal unit doses of the film cut from the continuously cast and dried film will vary no more than 10% of the desired amount, i.e., the unit dose will vary no more than + / - 1 mg or in other words 9 mg to 11 mg.

[0244] Forming a Film

[0245] The films disclosed herein must be formed into a continuously cast wet film or wet sheet prior to drying. The term "continuously cast" is intended to refer to a relatively high speed manufacturing process that uses a conveyor belt substrate onto which the wet film matrix is cast and formed, which is then continuously passed into a drying apparatus, such as an oven, and then further continuously passed onto a wound mandrel for storage or directly into a cutting and packaging station. The term continuous is intended to distinguish such a process from those performed, for example, in a laboratory setting, such as where the wet film matrix is cast onto a tray.

[0246] After the desired components are combined to form a multi-component substantially uniform matrix comprising a polymer, water, and an active or other desired component, the combination is formed into a wet sheet or film by any method known in the art, such as extrusion, coating, spreading, casting, or drawing the multi-component matrix. If a multi-layer film is desired, this can be achieved by co-extruding more than one combination of components, which can be of the same or different composition. A multi-layer film can also be achieved by continuously coating, continuously spreading, or continuously casting the wet film matrix onto a film layer that has already been formed and desirably dried.

[0247] While a variety of different continuous film forming techniques can be used, it is desirable to select a method that will provide a flexible film, such as reverse roll coating. The flexibility of the film allows the web to be rolled and transported for storage or prior to being cut into individual dosage forms. Desirably, the film can also be self-supporting, or in other words, capable of maintaining its integrity and structure in the absence of a separate support. In addition, the film of the present application can be selected from edible or ingestible materials.

[0248] Continuous coating or continuous casting methods are particularly useful for the purpose of forming the film of the present application. Specific examples include reverse roll coating, gravure coating, dip or immersion coating, metering bar or mayer bar coating, slot die or extrusion coating, gap or knife over roll coating, air knife coating, curtain coating, or combinations thereof, especially when a multi-layer film is desired.

[0249] When forming a film according to the present application, continuous roll coating, or more specifically, reverse roll coating is particularly desirable. This step provides excellent control and uniformity of the resulting film, which is desirable in the present application. In this method, the coating material is measured on an applicator roll by precisely setting the gap between the upper metering roll and the applicator roll below it. The coating is transferred from the applicator roll to the substrate as it passes around a support roll adjacent to the applicator roll. Both three-roll and four-roll methods are common.

[0250] Gravure coating methods rely on an engraved roll running in a coating bath, which fills the engraved dots or lines of the roll with coating material. Excess coating is wiped off the roll by a doctor blade, and then the coating is deposited onto the substrate as it passes between the engraved roll and a pressure roll.

[0251] Offset gravure is common, in which the coating is deposited on an intermediate roll before being transferred to the substrate.

[0252] In a simple dip or immersion coating method, the substrate is dipped into a bath of coating, which is usually low in viscosity so that the coating can flow back into the bath as the substrate emerges.

[0253] In a metering bar coating method, excess coating is deposited on the substrate as it passes through a bath roll. A wire metering bar, sometimes called a Meyer bar, allows a desired amount of coating to be retained on the substrate. This amount is determined by the diameter of the wire used on the bar.

[0254] In a slot die method, the coating is extruded through a slot by gravity or under pressure onto the substrate. If the coating is 100% solid, the method is called "extrusion", and in this case, the line speed is usually much faster than the extrusion speed. This results in a coating that is considerably thinner than the width of the slot.

[0255] Gap or roll-liner blade methods rely on the coating applied to the substrate which then passes through a "gap" between a "blade" and a backing roll. Excess is scraped off as the coating and substrate pass through.

[0256] Air knife coating is where the coating is applied to the substrate and excess is "blown away" by a powerful jet from an air knife. This method can be used for water-based coatings.

[0257] In curtain coating methods, a bath with a slot at the bottom allows a continuous curtain of coating to fall into the gap between two conveyors. The object to be coated is passed along the conveyors at a controlled speed and thus receives the coating on its upper surface.

[0258] The substrate can be any material known to be used in the art. For example, it can be a polyester film, such as optionally coated polyethylene terephthalate, a plastic sheet, glass, or a cellulose-based paper. The substrate can be polyethylene terephthalate (e.g., mylar) or parchment paper. When the substrate is polyethylene terephthalate, it can be biaxially oriented polyethylene terephthalate, which is optionally corona treated on its bottom or top surface.

[0259] Drying the Film

[0260] The drying step is also a factor with respect to maintaining the uniformity of the film composition. A controlled drying process is particularly important when the components in the film can have a tendency to increase aggregation or coalescence when in the absence of a viscosity-increasing composition or where the viscosity is controlled, such as by selection of the polymer. Alternative methods of forming the film with a precise dose would not require a controlled drying process, either by casting the film on a predetermined cavity on the production line, or by applying the desired amount of active onto the individual dose unit after the dose unit is cut from a continuous cast film that does not contain the active. Both of these alternative methods do not have the same challenges with respect to maintaining the uniformity of the active content from the mixing process through the drying process as with a continuous cast film where the active is incorporated into the film matrix prior to casting. With these alternative methods, it is not possible to have migration of the active to adjacent dose forms. When a controlled or rapid drying process is needed, this can be accomplished by a variety of methods. A variety of methods that can be used include those that require the application of heat. The liquid carrier is removed from the film in a manner that maintains the uniformity, or more specifically, the consistent non-heterogeneity, of the non-aggregation achieved in the wet film.

[0261] As discussed above, the use of a hot air stream to dry the wet continuous cast film does not produce the corrugation of the wet, flowable cast film substrate, the mass transfer of the wet, flowable cast film substrate, or the premature surface skinning as discussed above. Parameters selected to achieve this include ensuring that the air stream is directed from the top at a distance, angle, and velocity such that the force created when the air stream hits the film does not overcome the yield value of the film substrate, i.e., any level of force that would move or otherwise cause corrugation and non-uniformity of the film-forming composition forming the substrate. Desirably, but not necessarily, the film is exposed to a high temperature differential as it enters the oven such that the water content is rapidly removed to quickly solidify the flowable substrate and lock the actives into a more solid structure. In doing so, and as long as care is taken to ensure that the uniformity of the film is maintained throughout the drying process, the continuous cast film substrate can be dried using air emanating only from the top or above the transfer substrate, using air emanating only from the bottom of the transfer substrate, or by using air from both above and below the transfer substrate (the top and bottom of the film).

[0262] Thus, in one aspect of the drying process, the film can be dried from the bottom of the film to the top of the film. Desirably, any top air flow present must not cause the non-uniformity conditions discussed above. Once the initial solidification period has passed and a sufficiently solid visco-elastic structure has formed, the potential for corrugation and premature skinning is greatly reduced, if not eliminated. This can occur within the first few minutes of the drying process, e.g., from about 0.5 minutes to about 4.0 minutes. Controlling the drying in this manner prevents the destruction and reformation of the top surface of the film that results from conventional drying methods. Drying the continuous cast wet film in a manufacturing environment includes casting the wet flowable film substrate onto a transfer substrate.

[0263] In some cases, it can be preferable to begin the drying process by supplying an air stream to the bottom surface of the film and thereby below the transfer substrate. In this case, the heat from the air stream is first applied to the bottom side of the film to provide the necessary energy to evaporate or otherwise remove the liquid carrier. The film dried in this manner dries faster and more uniformly than air-dried films (dried in the open air) or films dried by conventional drying methods. The film dried by applying heat to the bottom dries simultaneously in the center and at the edges as compared to air-dried films that first dry at the top and edges. This also prevents the settling of the ingredients that occurs with films dried by conventional methods. The outer air temperature at which the film is dried can be about 130°C or less, provided that the film substrate itself does not reach a temperature high enough to reach the boiling point (e.g., 100°C) or to destroy its uniformity. Desirably, the outer air temperature can be about 100°C or less or about 80°C or less.

[0264] Another method of controlling the drying process, which can be used alone or in combination with the other controlled methods disclosed above, includes controlling and varying the humidity within the drying apparatus of the drying film. In this way, premature drying of the top surface of the film can be avoided.

[0265] Furthermore, it has been found that the length of the drying time can be appropriately controlled, i.e., balanced with the heat sensitivity and volatility of the ingredients (and particularly the flavor oils and medicaments). The amount of energy, temperature, and length and speed of the conveyor can be balanced to accommodate such active materials and to minimize loss, degradation, or inactivation in the final film.

[0266] One particular example of a suitable drying method is disclosed by U.S. Patent No. 4,631,837 to Magoon ("Magoon"), incorporated herein by reference, which is directed to a method of drying fruit pulp. In one embodiment of the present application, the present inventors have adapted this method to the preparation of thin films.

[0267] The method and apparatus of Magoon is based on the interesting property of water. While water transfers energy both within and to its surroundings by conduction and convection, water can only radiate energy into and to water. Thus, the Magoon device includes a surface on which the fruit pulp is placed, which is permeable to infrared radiation. The underside of the surface is in contact with a temperature-controlled water bath. The water bath temperature is desirably controlled at a temperature slightly below the boiling temperature of water. This creates a "refraction window" when wet fruit pulp is placed on the surface of the device. This means that infrared energy is allowed to radiate through the surface only to the area of the surface occupied by the fruit pulp until the fruit pulp is dried. The Magoon device provides the films of the present application with an efficient drying time, reducing the instances of film component aggregation.

[0268] The thickness of the final dried, self-supporting film disclosed herein and the dosage units made therefrom can vary depending on the thickness of each layer and the number of layers. Both the thickness and the number of layers (i.e., one or more layers, e.g., two, three, four, or more) can be adjusted to vary the erosion kinetics. The film can initially have a thickness of about 500 μm to about 1,500 μm, or about 20 mils to about 60 mils, and when dried, a thickness of about 3 μm to about 250 μm, or about 0.1 mils to about 10 mils. Desirably, the dried film will have a thickness of about 2 mils to about 8 mils, and more desirably, about 3 mils to about 6 mils.

[0269] If the final self-supporting film product (or dosage unit made therefrom) has two layers, the total film thickness can be from about 0.005 mm to about 2 mm, from about 0.01 mm to about 1 mm, or from about 0.1 mm to about 0.5 mm. The total film thickness can be greater than about 0.1 mm, greater than about 0.2 mm, about 0.5 mm, greater than about 0.5 mm, less than about 0.5 mm, less than about 0.2 mm, or less than about 0.1 mm. The thickness of each layer can vary from about 10% to about 90%, or from about 30% to about 60% of the total thickness of the layered self-supporting film. Any one layer can be greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 70%, greater than 90%, about 90%, less than 90%, less than 70%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the total thickness of the layered self-supporting film. The preferred thickness of each layer can vary from about 0.01 mm to about 0.9 mm, or from about 0.03 mm to about 0.5 mm.

[0270] The final film products and dosage units disclosed herein can dissolve (which includes dispersion and dissolution) in from about 30 seconds to about 24 hours, from about 30 seconds to about 30 minutes, from about 1 minute to about 24 hours, from about 1 minute to about 30 minutes, from about 1 minute to about 20 minutes, from about 3 minutes to about 40 minutes, or from about 5 minutes to about 30 minutes. The final self-supporting film products and dosage units disclosed herein can dissolve in greater than about 1 minute, greater than about 5 minutes, greater than about 7 minutes, greater than about 10 minutes, greater than about 12 minutes, greater than about 15 minutes, greater than about 20 minutes, greater than about 30 minutes, about 30 minutes, or less than about 30 minutes, less than about 20 minutes, less than about 15 minutes, less than about 12 minutes, less than about 10 minutes, less than about 7 minutes, less than about 5 minutes, or less than about 1 minute. The sublingual dissolution rate can be shorter than the buccal dissolution rate.

[0271] More specifically, the orally dissolving film dosage units (also referred to as "unit doses") can be divided into three main categories: fast dissolving, moderate dissolving, and slow dissolving. The orally dissolving film dosage units can also include a combination of any of the above categories. Fast dissolving film dosage units can dissolve in the oral cavity in about 1 second to about 30 seconds, including greater than about 1 second, greater than about 5 seconds, greater than about 10 seconds, greater than about 20 seconds, and less than about 30 seconds. Moderate dissolving film dosage units can dissolve in the oral cavity in about 1 minute to about 30 minutes, including greater than about 1 minute, greater than about 5 minutes, greater than about 10 minutes, greater than about 20 minutes, and less than about 30 minutes. Slow dissolving film dosage units can dissolve in the oral cavity in greater than about 30 minutes, including about 30 minutes to about 24 hours, about 30 minutes to about 12 hours, about 30 minutes to about 10 hours, and about 1 hour to about 10 hours. Fast dissolving film dosage units can comprise (or consist of) low molecular weight hydrophilic polymers (e.g., polymers having a molecular weight of about 1,000 to about 9,000 Daltons, or polymers having a molecular weight up to about 200,000 Daltons). In contrast, slow dissolving film dosage units can comprise high molecular weight polymers (e.g., having a molecular weight of millions).

[0272] Certain advantages can reside in moderate dissolving film dosage units in that they can dissolve fairly quickly, while having good levels of mucoadhesion. Moderate dissolving film dosage units can also be flexible, quickly wettable, and generally non-irritating to patients. Such moderate dissolving film dosage units can provide a fast enough rate of dissolution, for example between about 1 minute to about 20 minutes, while providing acceptable levels of mucoadhesion such that the film is not easily removed once placed in the oral cavity of a patient. This can ensure that the pharmaceutical active is delivered completely to the patient.

[0273] Self-supporting means that the film maintains its integrity and structure without any separate support. The films of the present disclosure are formulated to be absorbed in the oral mucosa, i.e., buccal or sublingual. While a variety of different film forming techniques can be used, it is desirable to select a method that will provide a flexible film, such as reverse roll coating. The flexibility of the film allows the sheet of film to be rolled up and shipped for storage or prior to being cut into individual dosage forms.

[0274] Use of the Film

[0275] The films disclosed herein are well suited for a number of uses. The highly uniform nature of the film composition makes it particularly well suited for incorporation into pharmaceuticals. In addition, the polymers used in constructing the film can be selected to allow for a range of film disintegration times. Variations or extensions in the time at which the film will disintegrate can allow for control over the rate of release of the active, which can allow for a sustained release delivery system. In addition, the films can be used to administer an active to any of a number of body surfaces, particularly those including mucosal membranes (e.g., oral, anal, vaginal, ophthalmic mucosal membranes), surfaces on the skin surface, or surfaces within the body, e.g., wounds during surgery, and the like.

[0276] The films can be used to orally administer an active. This is accomplished by preparing a film as described above and introducing it into the oral cavity of a mammal. The film can be prepared and adhered to a second layer or support layer, removed therefrom prior to use (i.e., introduction into the oral cavity). The film can be adhered to a support or backing material of any kind that can be known in the art and is preferably not water soluble. If an adhesive is used, it is desirable to be a food grade adhesive that is edible and does not alter the properties of the active. Mucosal adhesive compositions are particularly useful. In many cases, the film composition itself acts as a mucosal adhesive.

[0277] The films can be administered under the tongue or to the tongue of a mammal. When desired, a particular film shape corresponding to the shape of the tongue can be preferred. Thus, the film can be cut into a shape where one side of the film corresponding to the back of the tongue will be longer than the side corresponding to the front of the tongue. Specifically, the desired shape can be a triangular or trapezoidal shape. Ideally, the film will adhere to the oral cavity, prevent it from being ejected from the oral cavity, and allow more active to be introduced into the oral cavity as the film dissolves.

[0278] Another use of the films disclosed herein is to take advantage of the tendency of the films to dissolve quickly when introduced into a liquid. By preparing a film according to the present application, introducing it into a liquid, and allowing it to dissolve, an active can be introduced into a liquid. This can be used to prepare a liquid dosage form of an active or to flavor a beverage.

[0279] The films of the present application are ideally packaged in a sealed, air and moisture resistant package to protect the active from exposure to oxidation, hydrolysis, volatilization, and interaction with the environment. In addition, the films of the present application dissolve immediately upon contact with saliva or mucosal areas, which eliminates the need to rinse the dose with water.

[0280] Desirably, a series of such unit doses are packaged together according to a prescribed regimen or treatment, e.g., 10 days to 90 days supply (depending on the particular treatment). Individual self-supporting films can be packaged individually without a backing, or on a backing and peeled off for use.

[0281] Method of Use

[0282] Also disclosed herein are methods of treating epilepsy, seizures, and other forms of seizure in a human comprising administering to the human an oral film for delivery of a desired amount of active in a single unit dose. The film comprises: a) a water-soluble, water-swellable, or both water-soluble and water-swellable polymer matrix; b) an active having a mean particle size D90 of less than about 160 microns; and c) an additive selected from the group consisting of a sweetener, a flavorant, a flavor enhancer, a filler, a plasticizer, a dye, a pigment, a permeation enhancer, a buffer, a preservative, a silicon dioxide, an anti-tacking agent, and any combination thereof. The active in the oral film can have any dissolution profile and rate discussed above.

[0283] The active can be any active described herein. In certain embodiments, the active can be clobazam, diazepam, riluzole, or any combination thereof.

[0284] Another embodiment relates to a method of treating Lennox-Gastaut syndrome in a human comprising administering to the human an oral film disclosed herein.

[0285] The terms used in connection with these embodiments (methods of use) have the same meaning and definition as discussed above.

[0286] The features and advantages of the present application are more fully shown by the following examples, which are provided for purposes of illustration and should not be construed as limiting the application.

[0287] Examples

[0288] Example 1 - Clobazam

[0289] Oral films having the following compositions shown in Table 1 were prepared to compare milled and micronized actives.

[0290] Table 1: Formulations of oral films comprising milled or micronized clobazam

[0291]

[0292] Figure 3 The average active dissolution profiles of films comprising 5 mg of clobazam milled (D90 = 106 microns) and micronized (D90 = 8.3 microns) (N = 3) and RLD Onfi tablets are shown. Table 2 presents some of the data points described in the figures shown in Figure 3

[0293] Table 2: Dissolution testing for oral films comprising milled or micronized clobazam

[0294]

[0295] ​Thus, oral films comprising micronized clonazepam perform better (i.e., dissolve significantly faster) than oral films comprising milled clonazepam.

[0296] Example 2 - Dissolution Study of Oral Films Comprising Diazepam

[0297] Oral thin films comprising diazepam (DBSF) containing 5 mg and 15 mg of active were prepared. Dissolution of 5 mg and 15 mg DBSF was tested using both traditional dissolution method and PION technology under storage conditions of 25 °C for 12 months. The traditional dissolution method used herein is a common method to test the dissolution characteristics of solid oral dosage forms such as tablets and capsules. The traditional dissolution method utilizes a modified USP apparatus 5 setup, and a modified sample holder necessary to hold the film in place. All other aspects of the traditional dissolution method are similar to those of other solid oral dosage forms, including manual sampling and collection of samples at specific time points, followed by offline analysis of samples using HPLC. The traditional dissolution method is practically limited by the frequency and consistency of manual sampling and sample aliquot removal. The PION technology utilizes a traditional dissolution bath with a non-traditional setup. The bath is set up with apparatus 2 (paddle) with a modified sample holder mounted above the paddle. An in-line optical fiber probe is located inside the vessel. Samples are tested in situ at predetermined intervals. Sampling is done automatically, and analyzed in-line, without the need for sample removal, manual sampling, or offline HPLC testing. Table 3 demonstrates a comparison of system parameters between the traditional dissolution method and PION technology used to test DBSF.

[0298] Table 3: Exemplary System Parameters for Traditional Dissolution Method vs. PION Technology

[0299]

[0300] Figure 4 Figure 1 is a graph showing the active dissolution profile of DBSF as measured by the traditional dissolution method. Figure 5 Figure 2 is a graph showing the active dissolution profile of DBSF as measured by the PION technology. Many data points are shown in Tables 4 and 5, as well as a comparison of results obtained by the traditional dissolution method versus those obtained using the PION technology.

[0301] Table 4: Active Dissolution Rate and Comparison for DBSF Containing 5 mg Diazepam

[0302]

[0303] Table 5: Active Dissolution Rate and Comparison for DBSF Containing 15 mg Diazepam

[0304]

[0305]

[0306] According to the calculations shown above in Tables 4 and 5, the active dissolution profile of the 5 mg oral film was similar, while the active dissolution profile of the 15 mg oral film was different. However, by using the PION technology, the active dissolution profile was much more accurate and enhanced with much more time intervals available. In the case of the traditional dissolution method, the active dissolution profile contained only 7 data points, while the active dissolution profile obtained using the PION technology had more than five times that amount. Furthermore, the data was immediately available when using the PION technology, while the first data point using the traditional dissolution method was at 5 minutes. In the case of these fast dissolving dosage forms, the activity prior to the 5 minute mark can be an important and distinguishing factor.

[0307] Example 3 - Dissolution Study of Oral Films Containing Riluzole

[0308] Oral thin films (ROSF) containing 50 mg of riluzole were prepared. The dissolution of the 50 mg ROSF after about 6 months of storage at 25 °C was tested in 0.1 N HC1 (a medium that simulates the conditions in the stomach) using the traditional dissolution method and the PION technology. Table 3 above shows the parameters used for the traditional dissolution method and the PION technology for the tested ROSF.

[0309] Figure 6 is a graph of the active dissolution profile of the ROSF as measured by the traditional dissolution test. Figure 7 is a graph of the active dissolution profile of the ROSF as measured by the PION technology. Table 6 shows the number of data points as well as a comparison of the results obtained by the traditional dissolution method and the results obtained using the PION technology.

[0310] Table 6: Active Dissolution Rate and Comparison for ROSF

[0311]

[0312] According to the calculations shown above in Table 6, the active dissolution profile of the 50 mg oral film containing riluzole was similar. However, by using the PION technology, the active dissolution profile was much more accurate and enhanced with much more time intervals available. In the case of the traditional dissolution method, the active dissolution profile contained only 6 data points, while the active dissolution profile obtained using the PION technology had more than five times that amount. Furthermore, the data was immediately available when using the PION technology, while the first data point using the traditional dissolution method was at 5 minutes. In the case of these fast dissolving dosage forms, the activity prior to the 5 minute mark can be an important and distinguishing factor.

[0313] Example 4 - Dissolution Study of Oral Films Containing Clobazam

[0314] Oral thin films (COSF) containing clopidogrel were prepared comprising 5 mg, 10 mg and 20 mg of active with the composition as shown in Table 7.

[0315] Table 7: Composition of COSF formulations

[0316]

[0317] The COSF used in the examples herein contained clopidogrel with an average particle size D90 of 6 to 8 microns.

[0318] Dissolution of 5 mg and 20 mg COSF was tested using both traditional dissolution method and PION technology. Table 3 above shows the parameters used for testing COSF using traditional dissolution method and PION technology.

[0319] Figure 8 Figure 1 is a graph showing the active dissolution profile of 5 mg COSF measured by traditional dissolution method after about 24 months of storage under shelf life and accelerated conditions at 25 °C and 40 °C and 60 RH respectively. As shown therein, the film is almost completely released at the first sampling point. There is no information about the active dissolution profile during the very critical time period of 0 to 10 minutes (when most of the dissolution occurs). Also, the lack of precision of the traditional dissolution method is clearly visible in this graph, where there is no detectable difference between the active dissolution profiles of the two samples from 0 to 10 minutes.

[0320] In contrast, Figure 9 and 10 Figures 2 and 3 show the active dissolution profiles of COSF samples measured by PION technology. As shown in these figures, there are clear detectable differences between the samples at different storage conditions and at different dosage amounts. Figure 9 Figure 2 is a graph of the active dissolution profiles of COSF measured by PION technology at different dosages and temperatures; Figure 10 Figure 3 is the enhanced and smoothed curves of the same study as in Figure 9 Figure 2. Figure 10 Figures 4 and 5 depict the active dissolution profiles of these COSF dosages from 0 to 10 minutes after about 12 months of storage at about 25 °C and about 40 °C under different storage conditions. A comparison of many data points and results obtained using PION technology at different temperatures is shown in Tables 8 and 9.

[0321] Table 8: Active dissolution rates and comparison of 5 mg COSF

[0322]

[0323] Table 9: Active dissolution rates and comparison of 20 mg COSF

[0324]

[0325] Figure 9 and 10 And the calculations shown in Tables 8 and 9 demonstrate the possible precision through the use of PION technology, including measuring data points in fractions of a minute. This creates identifiable measurable differences between the dosage forms containing different amounts of active and under different storage conditions.

[0326] Figure 11 and Figure 12 depicts the second derivative of the active dissolution profile measured by PION technology in Figure 9 and 10 From this, the calculation of the exact inflection point (identified on the graph) can be achieved.

[0327] Example 5: COSF Dose Comparison

[0328] Oral thin films containing clopidogrel (COSF) containing 5 mg, 10 mg, and 20 mg of active with the composition shown in Table 7 were prepared. The films were stored at about 25 °C and 60 RH for about 24 months and then tested using PION technology to determine how the active dissolution profile varied between the COSF containing different amounts of active. Table 3 above shows the parameters used for the PION technology.

[0329] Figure 13 The actual data points obtained are plotted, while Figure 14 is a smoothed curve of the points shown in Figure 13 As shown in these graphs, there is a detectable difference between the active dissolution profiles of each film. The 5 mg COSF has the fastest release (steepest curve, reaching 100% at 2.5 minutes), followed by the 10 mg COSF (reaching 100% release at 3.0 minutes), and finally, the 20 mg COSF has the slowest release profile, approaching 100% after 7.0 minutes.

[0330] Figure 15 is a first derivative plot of the active dissolution profile of Figure 13 This graph provides information about the rate of release. The strength and width of the first derivative is proportional to the rate of release. As shown by the height and width of the first derivative curve in the graph, the 5 mg and 10 mg COSF release faster and more fully in the first minute, while the 20 mg COSF releases more slowly, i.e., the curve is shorter and wider (lower strength). For all curves, the first derivative approaches 0 as release is completed, and the drug concentration in the blood vessel reaches a plateau. The 5 mg and 10 mg COSF first derivative curves are essentially identical and reach the plateau earlier than the 20 mg COSF curve.

[0331] Again, as noted above with respect to Figure 8 the differences shown in Figures 14, Figure 13 , 14 and 15 would not be apparent using traditional dissolution methods. Only with the enhanced discriminatory power of the PION technology can these differences be detected and documented.

[0332] Example 6: Comparison of COSF under different storage conditions

[0333] The 5 mg, 10 mg, and 20 mg COSF prepared above were tested using the PION technology after 1) storage at about 25 °C and 60 RH for about 24 months; 2) storage at about 40 °C and 60 RH for about 24 months; or 3) after the final product was completed (no storage time, T = about 0 months). Table 3 above shows the parameters used for the PION technology. The active dissolution profiles were compared to determine how the different storage conditions affected the dissolution rate.

[0334] Figure 16 The active dissolution profiles for 5 mg, 10 mg, and 20 mg COSF after storage at about 25 °C and 60 RH for about 24 months, and after storage at about 40 °C and 60 RH for about 24 months are shown. For all film strengths, the active in the samples stored at 40 °C dissolved faster than the active in the same dosage form stored at 25 °C. The active in the 5 mg COSF stored at 40 °C dissolved the fastest, followed by the 10 mg COSF stored at 40 °C, while the 20 mg COSF sample had the slowest dissolution profile. The enhanced discriminatory power of the PION system is seen here. The active dissolution profiles obtained using the PION technology were precise enough to show differences based on film strength and storage condition, both of which unexpectedly affected the dissolution rate of the active.

[0335] Statistical analysis based on FDA guidelines further demonstrated the similarity or lack of similarity between the different samples (strength / storage condition / age / etc.). Using the PION technology, the similarity or lack of similarity was more apparent than with traditional dissolution methods due to the increase in precision and the first derivative calculations. For example, as shown in Table 10, the 5 mg to 10 mg at 25 °C demonstrated statistical similarity, while the 5 mg to 10 mg at 25 °C versus 40 °C did not demonstrate statistical similarity. For similarity, f2 (similarity factor) must not be less than 50 and f 1 (difference factor) must not be greater than 15.

[0336] Table 10: Statistical Similarity Comparison

[0337]

[0338] Figure 18The active substance dissolution profiles are shown for 5 mg, 10 mg, and 20 mg COSF after about 24 months of storage at about 25 °C and 60 RH, as well as for un-stored (T = about 0 months). For both 5 mg and 10 mg COSF, the samples tested after storage dissolved faster than the final product samples of the same strength (T = 0).

[0339] With respect to statistical similarity, the active substance dissolution profiles of the final product 5 mg and 10 mg COSF were not statistically similar to the identically stored samples. The active substance dissolution profiles of the final product 20 mg COSF samples were statistically similar to the stored 20 mg COSF samples.

[0340] Table 11: Statistical similarity comparison of final product and stored product

[0341]

[0342] Figure 17 and 19 are the first derivative curves of the plots of Figure 16 and 18 As shown by the height and width of the first derivative curves in the plots, 5 mg and 10 mg COSF dissolved faster and more completely in the first minute, while 20 mg COSF dissolved more slowly, i.e., the curve was shorter and wider (lower strength). For all curves, the first derivative approached 0 when dissolution was complete, and the drug concentration in the blood vessel reached a plateau. The first derivative curves for 5 mg and 10 mg COSF reached the plateau earlier than the curve for 20 mg COSF.

[0343] Example 7: Comparison of media

[0344] 5 mg, 10 mg, and 20 mg COSF were prepared and tested (no storage phase) using PION technology to determine how the choice of media affected the dissolution rate. The parameters used for PION technology are shown in Table 3 above. Thus, the dissolution of the active substance in each film was tested in the following baths: 0.1 N HC1, 0.05 molar solution of potassium dihydrogen phosphate adjusted to pH 6.8 with sodium hydroxide, or water.

[0345] Figure 20 The active substance dissolution profiles are shown for 5 mg, 10 mg, and 20 mg COSF in different media. Figure 21 are the first derivative curves of the plots of Figure 20 Even with the increased resolution of the PION technology, the choice of media did not affect the dissolution; samples of the same strength dissolved in different media were statistically similar. In the case of traditional dissolution methods, the active substance dissolution profile will typically not provide this enhanced information unless there are significant solubility issues.

[0346] Example 8: Comparison of Release of Liquid Mixture and Film

[0347] An experiment was designed to evaluate the effect of additional excipients on active release. Specificity is an aspect of method development to ensure that any excipients contained within the drug product do not interfere with the quantitation of the active. Therefore, the active dissolution profile of the following samples was measured by PION technology and is shown in Figure 22

[0348] • 5 mg COSF final product (referred to in Figure 22 as "5 mg nominal") ;

[0349] • liquid mixture of the film composition prior to drying;

[0350] • placebo, which is a film with all excipients except the active; and

[0351] • 5 mg COSF final product, but with twice the amount of excipients (referred to in Figure 22 as "5 mg w / 2 placebo").

[0352] As shown in Figure 22 , the placebo, which is a film without the active, shows some interference - about 20% of the response. Therefore, the excipients alone and the film dosage form have an effect on the active dissolution profile. Figure 23 Figure 22 is the first derivative curve of

[0353] It was hypothesized that the active in the liquid mixture dissolves faster than the active in the film, which needs to hydrate, swell and then release the active. However, it was unexpectedly found that the film has a faster dissolution profile than the liquid mixture. Based on these results, it is believed that the dry film, which absorbs water into the matrix, promotes the release and dissolution of the active.

[0354] Example 9: Evaluation of Substrate Performance

[0355] An experiment was performed in which the substrate used during the manufacture of an oral film containing 20 mg of clozapine, particularly in the drying step, was varied. In particular, the COSF 20 mg formulation was used to coat a variety of substrates for comparative evaluation using a 40 mil gap. The coated substrates were dried at 80 °C for 15 minutes. The dried coated substrates were evaluated and the results are shown in Table 12.

[0356] Table 12: Properties and Comparison of Coated Substrates

[0357]

[0358] ​​After drying, all dried film samples were able to be removed from the substrate. However, the edges of the films had strong adhesion to the glass substrate, and moderate adhesion to the polyethylene terephthalate substrate that was treated with a corona. The best performing substrate was polyethylene terephthalate (untreated).

[0359] Example 10: Evaluation of solubility of clobazam in COSF intermediates and final product

[0360] Experiments were performed to evaluate the solubility of clobazam in the liquid mixture (pre-dry) and the oral film (COSF). Oral thin films containing 10 mg and 20 mg of clobazam were prepared and then dissolved in 1.5 ml of water. Two additional samples were evaluated - one was the active in water (without adding excipients to the composition used for the oral film); and the second was the liquid mixture used for the film, but tested prior to film formation (i.e. drying). Table 13 demonstrates the results of the evaluation.

[0361] Table 13: Solubility of clobazam

[0362]

[0363] As shown in the table above, between about 1% and about 2% of the clobazam was dissolved in each of the test samples, while over 98% remained dispersed. The wet bulk sample of the liquid mixture composition of the film, where the active dissolved was lower than the film sample that was subsequently hydrated with 1.5 ml of water. This is because the drying process in the film formation process increased the solubility of the active in the formulation. The solubility is a function of the drying process and the size of the film (e.g. thickness). For example, the 10 mg film had a higher percent dissolution than the 20 mg film because the 10 mg film was thinner, and therefore had greater exposure to heat per unit area during the drying process. The solubility was also proportional to the mouth feel characteristics of the oral film.

[0364] While there have been described herein certain desired embodiments of the present application, it is understood that various modifications can be made to the described embodiments and the generic principles of the application and such modifications are intended to fall within the purview of the present application. Accordingly, it is intended that the present application not be limited to the described embodiments but will include all embodiments falling within the true scope of the application.

[0365] The present application is also directed to the following embodiments:

[0366] 1. An oral film for delivering a desired amount of an active in a single unit dose, the film comprising:

[0367] a) a water-soluble, water-swellable, or water-soluble and water-swellable polymer matrix;

[0368] b) the active having an average particle size D90 of less than about 160 microns; and

[0369] c) an additive selected from the group consisting of sweeteners, flavorants, taste enhancers, fillers, plasticizers, dyes, pigments, penetration enhancers, buffering agents, preservatives, silicon dioxide, anti-tack agents, and any combination thereof;

[0370] wherein, after the film is placed in a medium, more than about 2% of the active dissolves in the medium after about 3 minutes.

[0371] 2. The film of embodiment 1, wherein the average particle size D90 of the active is less than about 120 microns.

[0372] 3. The film of embodiment 2, wherein the average particle size D90 of the active is less than about 100 microns.

[0373] 4. The film of embodiment 2, wherein the average particle size D50 of the active is less than about 30 microns.

[0374] 5. The film of embodiment 4, wherein the average particle size D50 of the active is less than about 20 microns.

[0375] 6. The film of embodiment 2, wherein the average particle size D10 of the active is less than about 10 microns.

[0376] 7. The film of embodiment 6, wherein the average particle size D10 of the active is less than about 5 microns.

[0377] 8. The film of embodiment 1, wherein the individual unit dose comprises about 0.5 mg to about 100 mg of the active.

[0378] 9. The film of embodiment 8, wherein the active is chlorzoxazone.

[0379] 10. The film of embodiment 1, wherein more than about 10% of the active dissolves after about 3 minutes after the film is placed in the medium.

[0380] 11. The film of embodiment 1, wherein more than about 40% of the active dissolves after about 5 minutes after the film is placed in the medium.

[0381] 12. The film of embodiment 1, wherein more than about 50% of the active dissolves after about 5 minutes after the film is placed in the medium.

[0382] 13. An oral film for delivering a desired amount of an active in an individual unit dose, the film comprising:

[0383] d) a water-soluble, water-swellable, or both water-soluble and water-swellable polymer matrix;

[0384] e) said active is clobazam and has an average particle size D90 of less than about 160 microns; and

[0385] f) an additive selected from the group consisting of sweeteners, flavoring agents, taste enhancers, fillers, plasticizers, dyes, pigments, penetration enhancers, buffering agents, preservatives, silicon dioxide, anti-tacking agents, and any combination thereof;

[0386] wherein more than about 20% of said active dissolves in the medium after about 3 minutes after the film is placed in the medium.

[0387] 14. The film of embodiment 13, wherein said active has an average particle size D90 of less than about 120 microns.

[0388] 15. The film of embodiment 14, wherein said active has an average particle size D90 of less than about 100 microns.

[0389] 16. The film of embodiment 13, wherein said active has an average particle size D50 of less than about 30 microns.

[0390] 17. The film of embodiment 16, wherein said active has an average particle size D50 of less than about 20 microns.

[0391] 18. The film of embodiment 14, wherein said active has an average particle size D10 of less than about 10 microns.

[0392] 19. The film of embodiment 18, wherein said active has an average particle size D10 of less than about 5 microns. [0...

Claims

1. A self-supporting oral film for delivering a desired amount of active in individual unit doses, the film comprising: a) a water-soluble polymer matrix, a water-swellable polymer matrix, or a water-soluble and water-swellable polymer matrix; b) said active being clobazam and having a mean particle size D90 of less than about 160 microns; and c) additives selected from the group consisting of sweeteners, flavoring agents, flavor enhancers, fillers, plasticizers, dyes, pigments, penetration enhancers, buffers, preservatives, silicon dioxide, anti-sticking agents, and any combination thereof; in, After placing the film in the medium, about 40% or more of the active is dissolved in the medium after about 5 minutes.

2. The film according to claim 1, wherein After placing the film in the medium, more than about 20% of the active was dissolved in the medium after about 3 minutes.

3. The film of claim 1 wherein the active has an average particle size D90 of less than about 120 microns.

4. The film of claim 1 wherein the active has an average particle size D50 of less than about 30 microns.

5. The film of claim 3, wherein the active has an average particle size D10 of less than about 10 microns.

6. The film of claim 1, wherein after placing the film in the medium, greater than about 55% of the active is dissolved after about 5 minutes.

7. The film of claim 1, wherein after placing the film in the medium, more than about 5% of the active dissolves after about 1.5 minutes.

8. The film of claim 1, wherein the individual unit doses comprise from about 2 mg to about 20 mg of clobazam.

9. The film of claim 8, wherein the individual unit dose comprises about 5 mg of clobazam.

10. The film of claim 9, wherein after placing the film in the medium, greater than about 30% of the active is dissolved after about 1 minute.

11. The film of claim 9, wherein after placing the film in the medium, greater than about 80% of the active is dissolved after about 2 minutes.

12. The film of claim 9, wherein after placing the film in the medium, greater than about 95% of the active is dissolved after about 2.5 minutes.

13. The film of claim 8, wherein the individual unit dose comprises about 10 mg of clobazam.

14. The film of claim 13, wherein after placing the film in the medium, greater than about 50% of the active is dissolved after about 1.5 minutes.

15. The film of claim 13, wherein after placing the film in the medium, greater than about 70% of the active is dissolved after about 2.5 minutes.

16. The film of claim 8, wherein the individual unit dose comprises about 20 mg of clobazam.

17. The film of claim 16, wherein after placing the film in the medium, more than about 2% of the active is dissolved after about 1.5 minutes.

18. The film of claim 16, wherein after placing the film in the medium, greater than about 40% of the active is dissolved after about 3.5 minutes.

19. Use of the single unit dose oral film of claim 1 in the manufacture of a medicament for treating epilepsy and / or epileptic seizures in humans.

20. The film of claim 1, wherein the water-soluble polymer matrix, the water-swellable polymer matrix, or the water-soluble and water-swellable polymer matrix comprises a polymer selected from the group consisting of polyethylene oxide (PEO), pullulan, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HPC), hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, and combinations thereof.

21. The film of claim 20, wherein the polymer is polyethylene oxide (PEO).

22. The film of claim 1 wherein the active has an average particle size D90 of about 8 microns to no greater than about 160 microns.

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