Oral film compositions and dosage forms having precise active agent dissolution profiles

Abstract

Disclosed herein are oral films with individual unit doses for delivery of one or more active agents, which have a precisely calculated and controlled dissolution profile for the active agent. A variety of active agents can be used, including, for example, clobazam, diazepam, or riluzole. Also disclosed are methods for treating various diseases and conditions, such as epilepsy and seizures, by administering the oral films disclosed herein. [Selection diagram] None

Description

[Technical field]

[0001] Field of Disclosure The present disclosure relates to unit dose oral films for the delivery of one or more active agents, such as clobazam, having a mean particle size D90 of less than about 160 microns, which have a precisely controlled dissolution rate of the active agents, and methods of administering the same to patients in need thereof to treat various disorders, including epilepsy and seizures. [Background technology]

[0002] background Active ingredients such as drugs or medicines can be prepared in tablet form to allow accurate and consistent administration. However, preparing and dispensing this form of drug has many disadvantages, such as the need to add a large proportion of adjuvants to make it a manageable size, the larger drug form requires additional storage space, and dispensing involves counting the tablets, which tends to be inaccurate. In addition, swallowing is difficult for many, estimated to be 28% of the population. Tablets may be broken into smaller pieces or even crushed as a means to overcome swallowing difficulties, but this is not a suitable solution for many tablet or pill forms. For example, crushing or destroying tablet or pill forms, alone or mixed with food, to aid in oral intake also compromises the controlled release properties. Films are sometimes used in place of tablets and pills to deliver active ingredients such as drugs, medicines, etc. Historically, however, films and methods for making drug delivery systems using this dosage form have presented several unique challenges in both formulation, processing, and pharmacokinetics. In particular, films and oral dosage units cut from films have suffered from several adverse characteristics that have not allowed their practical use until recent years, when advances have made films a highly desirable dosage form. Similar to traditional tablets and pills, the absorption of drugs administered in oral film form depends on several factors, including the release of the drug substance from the film, and the dissolution and solubilization of the drug under physiological conditions. In one mode, in vitro dissolution is a good predictor of in vivo performance. In vitro dissolution testing of immediate release oral dosage forms is used to assess drug product quality from lot to lot; to guide the development of new formulations; and to ensure product quality, bioequivalence, and performance as product changes occur. Summary of the Invention [Problem to be solved by the invention]

[0003] Because oral films dissolve rapidly, these fast dissolving products require improved dissolution testing that allows for accurate measurements almost instantly upon placement in liquid and at very short time intervals. [Means for solving the problem]

[0004] overview Disclosed is an oral film for delivering a desired amount of active agent, with each unit dose having an average particle size D90 of less than about 160 microns.The film comprises a water-soluble polymeric substrate, a water-swellable polymeric substrate, or a water-soluble and water-swellable polymeric substrate; and an additive.The active agent can be selected from a variety of active agents, such as those disclosed herein, including clobazam, riluzole, diazepam, or any combination thereof.The additive can be selected from the group consisting of sweeteners, flavorings, flavor enhancers, fillers, plasticizers, dyes, pigments, permeation enhancers, buffers, preservatives, silicon dioxide, anti-tack agents, and any combination thereof.When the film is placed in a medium, more than about 2% of the active agent dissolves in the medium after about 3 minutes.

[0005] The active agent has an average particle size D90 of 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 a D90 of about 8 microns. Optionally, the active agent also has an average particle size D50 of less than about 30, less than about 20, less than about 10, less than about 4, or a D50 of about 3, and / or an average particle size D10 of less than about 10, less than about 5, less than about 2, or a D10 of about 1.

[0006] When the active agent is clobazam, each unit dose may contain about 2 mg to about 20 mg, about 5 mg, or about 20 mg of clobazam. Optionally, less than about 10% of the active agent in the oral film dissolves. In certain embodiments, when the film is placed in a medium, more than about 20% of the active agent dissolves after about 3 minutes, about 30% of the active agent dissolves after about 3 minutes, about 30% of the active agent dissolves after about 1 minute, about 50% of the active agent dissolves after about 1 minute, about 95% of the active agent dissolves after about 2.5 minutes, about 40% of the active agent dissolves after about 3.5 minutes, about 55% of the active agent dissolves after about 5 minutes, about 75% of the active agent dissolves after about 5 minutes, about 85% of the active agent dissolves after about 6.5 minutes, or about 95% of the active agent dissolves in the medium after about 10 minutes. Thus, in certain embodiments, dissolution of the active agent is measured after storage of the film for greater than 0 months to about 36 months, at about 20° C. to about 60° C., and / or at a relative humidity (RH) of up to about 75%, or at about 60% RH.

[0007] The oral film may optionally contain a sweetener selected from the group consisting of sucralose, stevia, acesulfame potassium, saccharin, fructose, aspartame, and any combination thereof, present at about 0.5 to about 5% by weight of the composition. The oral film may optionally contain a berry flavor, present at about 0.1 to about 15% by weight of the composition. Also disclosed is a method of treating epilepsy and seizures by administering to a person in need thereof an oral film containing an active agent in each unit dose. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 is an exemplary configuration of a system for use in PION technology. [Diagram 2] FIG. 2 is an exemplary configuration of a system for use in PION technology. [Diagram 3] FIG. 3 is a graph showing the dissolution of active agent in oral films containing 5 mg milled clobazam (D90=106 microns) and 5 mg clobazam (D90=8.3 microns), and oral tablets containing clobazam. [Figure 4] FIG. 4 is a graph of the average active agent dissolution profile of buccal films containing 5 mg and 15 mg of diazepam as measured by conventional dissolution. [Diagram 5] FIG. 5 is a graph of the average active agent dissolution profile of buccal films containing 5 mg and 15 mg diazepam as measured by PION technology. [Figure 6] FIG. 6 is a graph of the average active agent dissolution profile of oral films containing 50 mg of riluzole as measured by conventional dissolution. [Figure 7] FIG. 7 is a graph of the average active agent dissolution profile of oral films containing 50 mg of riluzole as measured by PION technology. [Figure 8] FIG. 8 is a graph showing the average active agent dissolution profile of oral films containing 5 mg of clobazam after about 24 months of storage at RH60, about 25° C. and about 40° C. as measured by conventional dissolution. [Figure 9] FIG. 9 is a graph of the average active agent dissolution profiles of oral films containing 5 mg and 20 mg of clobazam after storage at about 25° C. and about 40° C. as measured by PION technology. [Figure 10] FIG. 10 is an expanded view of the graph from FIG. 9 showing active agent dissolution profile curves from 1 to 10 minutes for oral films containing 5 mg and 20 mg of clobazam after storage at about 25° C. and about 40° C. [Figure 11]FIG. 11 is a graph of the second derivative and inflection point of the results in FIG. 9 for an oral film containing 5 mg of clobazam. [Figure 12] FIG. 12 is a graph of the second derivative and inflection points of the results in FIG. 9 for oral films containing 5 mg and 20 mg clobazam. [Figure 13] FIG. 13 is a graph of the average active agent dissolution profiles for oral films containing 5 mg, 10 mg, and 20 mg of clobazam after storage for about 24 months at RH60, about 25° C., and about 40° C. [Figure 14] FIG. 14 is a graph of the average active agent dissolution profiles for oral films containing 5 mg, 10 mg, and 20 mg of clobazam after storage for about 24 months at RH60, about 25° C., and about 40° C. [Figure 15] FIG. 15 is a first derivative graph of the active agent dissolution profile of FIG. [Figure 16] FIG. 16 is a graph of the active agent dissolution profile of oral films containing 5 mg, 10 mg, and 20 mg of clobazam after about 24 months of storage at RH 60 and about 25° C., and after about 24 months of storage at RH 60 and about 40° C., as measured by PION technology. [Figure 17] FIG. 17 is a first derivative graph of the active agent dissolution profile of FIG. [Figure 18] FIG. 18 is a graph of the active agent dissolution profile of oral films containing 5 mg, 10 mg, and 20 mg of clobazam after about 24 months of storage at RH60 and about 25° C., and as-manufactured, i.e., without storage, as measured by PION technology. [Figure 19] FIG. 19 is a first derivative graph of the active agent dissolution profile of FIG. [Figure 20] FIG. 20 is a graph of the active agent dissolution profiles of oral films containing 5 mg, 10 mg, and 20 mg of clobazam in various media as measured by PION technology. [Figure 21] FIG. 21 is a first derivative graph of the active agent dissolution profile of FIG. [Figure 22] FIG. 22 is a graph of the active agent dissolution profiles of a liquid mixture containing clobazam, oral films containing 5 mg of clobazam, and placebo as measured by PION technology. [Diagram 23] FIG. 23 is a first derivative graph of the active agent dissolution profile of FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description To ensure batch-to-batch consistency and to identify potential issues with the bioavailability of the pharma- ceutical active agent, the dissolution profile, more specifically, the dissolution rate, of the oral film and the pharmaceutical product containing the active agent is established. A surprising new means to test the dissolution profile more accurately and precisely has been developed using PION technology, a fiber optic UV monitoring system. Disclosed herein are oral films for delivering a desired amount of an active agent having a mean particle size D90 of less than about 160 microns in each unit dose, the films having an active agent dissolution profile with improved accuracy, more sampling points, and more rapid change assessment compared to conventional dissolution tests and profiles currently known for film dosage forms.

[0010] Each unit dose oral film (i.e., dosage unit) disclosed herein contains a water-soluble polymeric base, a water-swellable polymeric base, or a water-soluble and water-swellable polymeric base; optionally, a micronized active agent; and one or more additives. The film is self-supporting, and the active agent is substantially uniformly distributed within the film. Substantially uniform distribution is evaluated by each unit dose being substantially the same size and having no more than 10% variation in the desired amount of active agent. The film containing the active agent can be made by casting, for example, as described in U.S. Patent Nos. 7,666,337; 8,603,514; 8,765,167; 9,855,221; and 9,931,305 (all of which are incorporated herein by reference in their entirety), and then cut into each unit dose (dosage unit). Alternatively, each unit dose can be prepared as an individual well or strip, such as those disclosed in U.S. Pat. Nos. 8,956,685; 8,936,825; and U.S. Patent Application No. 2012 / 0263865, all of which are incorporated herein by reference in their entirety.

[0011] The term "film" may include films and sheets of any shape, including rectangular, square, or other desired shapes. The film may be of any desired thickness and size. In some embodiments, the film may be of a thickness and size such that it can be administered to a patient, for example, by placement in the oral cavity. The film may be relatively thin, from about 0.0025 mm to about 0.250 mm, or the film may be somewhat thicker, from about 0.250 mm to about 1.0 mm. Some films may be thicker, for example, greater than about 1.0 mm, or thinner, for example, less than about 0.0025 mm. The film may be a single layer, or the film may be multi-layered, including laminated or multi-layer cast films. If multi-layered, the active agent may be present in one layer, in more than one layer (but not all layers), or in all layers. The active agent may be present in a mucosal contact layer. The active agent may be combined with one or more additives in a single layer, or may be included in separate layers, or each may be included in separate regions of the same dosage form.

[0012] Activator Film can be processed so that active agent is distributed substantially uniformly throughout.For example, when film, such as cast film, is cut into each unit dose of substantially the same size, the amount of active agent in unit dose is known to be quite accurate.This accuracy in dosage is particularly advantageous, and is actually required by government regulatory agencies such as the US FDA when active agent is a drug, i.e., a drug. Active agents that can be incorporated into the films of the present invention include, but are not limited to, pharmaceutical and cosmetic active agents, drugs, medications, antigens or allergens such as ragweed pollen, spores, microorganisms including bacteria, seeds, mouthwash ingredients such as chlorates or chlorites, flavors, fragrances, enzymes, preservatives, sweeteners, colorants, spices, vitamins, and combinations thereof.

[0013] The amount of active agent in the film will vary depending on several factors, including, for example, the active agent selected, the treatment strength desired, the number of layers of the film, and the formulation selected, as will be readily understood by one of ordinary skill in the art. The pharma- ceutical active agent comprises from about 0.001 to about 99% by weight, from about 0.003 to about 75% by weight, or from about 0.005 to about 50% by weight, e.g., greater than about 0.005% by weight, greater than about 0.05% by weight, greater than about 0.5% by weight, greater than about 1% by weight, greater than about 5% by weight, greater than about 10% by weight, greater than about 15% by weight, greater than about 20% by weight, greater than about 30% by weight, greater than about 50% by weight, greater than about 50% by weight, less than about 30% by weight, less than about 20% by weight, less than about 15% by weight, less than about 10% by weight, less than about 5% by weight, less than about 1% by weight, less than about 0.5% by weight, less than about 0.05% by weight, or less than about 0.005% by weight of the film composition. The amounts of other ingredients can vary depending on the active agent and other ingredients, but generally these ingredients are not greater than about 50%, not greater than about 30%, or not greater than about 15% of the total weight of the film composition.

[0014] Suitable active agents for use in the films herein include, but are not limited to, the following therapeutic classes: ACE inhibitors; adrenergic agents; corticosteroids; adrenal cortex suppressants; aldosterone antagonists; alkaloids; amino acids; anabolic agents; central nervous system stimulants; analgesics; anesthetics; appetite suppressants; anti-acne agents; anti-adrenergic agents; anti-allergy agents; anti-amebic agents; anti-anemic agents; anti-angina pectoris agents; anti-anxiety agents; anti-arthritic agents; anti-arrhythmic agents; anti-asthmatic agents; anti-atherosclerotic agents; anticholesterolemic agents; antibacterial agents; antibiotics; anticholinergic agents; anticoagulants; antispasmodics; antidepressants; antidiabetic agents; antidiarrheal agents; antidiuretics. ;Antidotites;Antiemetics;Anticonvulsants;Antifibrinolytics;Antifungals;Hemostatics;Antihistamines;Antilipidemics;Antihypertensives;Antihypotensives;Anti-infectives (both systemic and non-systemic);Antiinflammatory agents;Antilipids;Antimanic agents;Antimicrobials;Antimigraine;Antimitotics;Antifungals;Antidepressants;Antineoplastics;Antineutropenic agents;Antiobesity agents;Antiparasitic agents;Antiparkinsonian agents;Antiproliferatives;Antipsychotics;Antipyretics;Antirheumatics;Antisepyrrhic agents;Antisecretory agents;Antispasmodics;Antistroke agents;Antithrombotic agents;Antithyroid agents;Antineoplastics;Antitussives;Antiulcer agents;Antiuricemic agents;Antiviral agents;Appetite suppressants;Appetite stimulants;Biological response modifiers;Blood glucose regulators;Blood regulators modifier);blood metabolism regulators;bone resorption inhibitors;bronchodilators;cardiovascular agents;central nervous system stimulants;cerebrodilators;contraceptives;coronary artery dilators;cholinergic agents;tussives;decongestants;depressants;diagnostic aids;dietary supplements;diuretics;dopamine agonists;enzymes;estrogen receptor agonists;endometriosis management agents;expectorants;erectile dysfunction treatment agents;erythropoiesis agents;fibrinolytic agents;ovulation inducers;fluorescent agents;free oxygen radical scavengers;gastric acid suppressants;gastrointestinal motility enhancers;genetic modifiers ;Glucocorticoids;Hair growth stimulants;Hemostatic agents;Histamine H2 receptor antagonists;Homeopathic remedies;Hormones;Hypercalcemia control agents;Hypocalcemia control agents;Cholesterol-lowering agents;Hypoglycemic agents;Lipid-lowering agents;Antihypertensive agents;Ion exchange resins;Contrast media;Immunologic agents;Immunomodulators;Immunostimulants;Immunosuppressants;Keratolytic agents;Laxatives;LHRH agonists;Mood regulators;Motion sickness preparations;Mucinolytic agents;Muscle relaxants;Mydriatics;Nasal decongestants;Neuromuscular blocking agents;Neuroprotectants;NMDA antagonists;Non-hormonal sterol derivatives;osteoporosis treatments;uterotonics;parasympatholytics;parasympathomimetics;plasminogen activators;platelet activating factor antagonists;platelet aggregation inhibitors;prostaglandins;psychiatric treatments;psychotropic agents;radioactive agents;respiratory agents;scabicides;sclerosing agents;sedatives;hypnotics;selective adenosine A1 antagonists;serotonin antagonists;serotonin inhibitors;serotonin receptor antagonists;smoking cessation treatments;steroids;stimulants;sympatholytics;uterine relaxants;thyroid hormones;thyroid inhibitors;thyromimetics;tranquilizers;tremor treatments;amyotrophic lateral sclerosis treatments;cerebral ischemia treatments;Paget's disease treatments;unstable angina treatments;vasoconstrictors;vasodilators;weight management agents;wound healing agents;xanthine oxidase inhibitors;and combinations thereof.;

[0015] Examples of active agents suitable for use herein include antacids, H2 antagonists, and analgesics. For example, antacid dosage forms can be prepared using calcium carbonate components alone or in combination with magnesium hydroxide and / or aluminum hydroxide. Additionally, antacids can be used in combination with H2 antagonists.

[0016] Painkillers include opiates and opiate derivatives, such as oxycodone (commercially available as Oxycontin®); ibuprofen (commercially available as Motrin®, Advil®, Motrin Children's®, Motrin IB®, Advil Children's®, Motrin Infants'®, Motrin Junior®, Ibu-2®, Proprinal®, Ibu-200®, Midol Cramp Formula®, Bufen®, Motrin Migraine Pain®, Addaprin®, and Haltran®), aspirin (Empirin®, Ecotrin®, Genuine Bayer®, and Halfprin®), acetaminophen (Silapap Infant's®, Silapap Children's®, Tylenol®, Tylenol®), and acetaminophen (Silapap Infant's®, Silapap Children's®, Tylenol®, Tylenol®). Children's®, Tylenol Extra Strength®, Tylenol Infants' Original®, Tylenol Infants'®, Tylenol Arthritis®, T-Painol®, Q-Pap®, Cetafen®, Dolono®, Tycolene®, APAP®, and Aminofen®), and combinations thereof which may optionally contain caffeine.meperidine hydrochloride (commercially available as Demerol®), capsaicin (commercially available as Qutenza®), morphine sulfate and naltrexone hydrochloride (commercially available as Embeda®), hydromorphone hydrochloride (commercially available as Dilaudid®), propoxyphene napsylate and acetaminophen (commercially available as Darvocet-N®), fentanyl (Duragesic®, Onsolis®, and Fentora®), ®), sodium hyaluronate (commercially available as Euflexxa®), adalimumab (commercially available as Humira®), sumatriptan succinate (commercially available as Imitrex®), fentanyl iontophoresis (commercially available as Ionsys®), orphenadine citrate (commercially available as Norgesic®), magnesium salicylate tetrahydrate (commercially available as Novasal®), oxymorphone hydrochloride (Opana®), Other pain relief agents may also be used in the present invention, including ER®), methocarbamol (commercially available as Robaxin®), carisoprodol (commercially available as Soma®), tramadol hydrochloride (commercially available as Ultracet® and Ultram®), morphine sulfate (commercially available as MS Contin®), metaxalone (commercially available as Skelaxin®), oxycodone hydrochloride (commercially available as OxyContin®), acetaminophen / oxycodone hydrochloride (commercially available as Percocet®), oxycodone / aspirin (commercially available as Percodan®), hydrocodone bitartrate / acetaminophen (commercially available as Vicodin®), hydrocodone bitartrate / ibuprofen (commercially available as Vicoprofen®), nepafenac (commercially available as Nevanac®), and pregabalin (commercially available as Lyrica®).

[0017] The films disclosed herein further comprise any of the following: etodolac (commercially available as Lodine®), ketorolac tromethamine (commercially available as Acular® or Acuvail®), naproxen sodium (commercially available as Anaprox®, Naprosyn®), flurbiprofen (commercially available as Ansaid®), diclofenac sodium / misoprostol (commercially available as Arthrotec®), celecoxib (commercially available as Celebrex®), sulindac (commercially available as Clinoril®), Oxaprozin (commercially available as Daypro®), piroxicam ( They may also include such agents as NSAIDs, including Feldene®, indomethacin (commercially available as Indocin®), meloxicam (commercially available as Mobic®), mefenamic acid (commercially available as Ponstel®), tolmetin sodium (commercially available as Tolectin®), choline magnesium trisalicylate (commercially available as Trilisate®), diclofenac sodium (commercially available as Voltaren®), diclofenac potassium (commercially available as Cambia® or Zipsor®), and misoprostol (commercially available as Cytotec®). Opiate agonists and antagonists, such as buprenorphine and naloxone, are examples of drugs for use in the present invention.

[0018] Other drugs as other active agents for use herein include antidiarrheals such as loperamide (commercially available as Imodium AD®, Imotil®, Kaodene®, Imperim®, Diamode®, QC Anti-Diarrheal®, Health Care America Anti-Diarrheal®, Leader AD®, and Imogen®), nitazoxanide (commercially available as Alinia®) and diphenoxylate hydrochloride / atropine sulfate (commercially available as Lomotil®), antihistamines, cough suppressants, decongestants, vitamins, and mouth fresheners. Common medications used alone or in combination for colds, aches, fevers, coughs, congestion, runny noses, and allergies, such as acetaminophen, ibuprofen, chloropheniramine maleate, dextromethorphan, dextromethorphan HBr, phenylephrine HCl, pseudoephedrine HCl, diphenhydramine, and combinations thereof, such as dextromethorphan HBr and phenylephrine HCl (available as Triaminic®), may be included in the film compositions of the present invention.

[0019] Other active agents useful herein include, but are not limited to, alcoholism treatments such as acamprosate calcium (commercially available as Campral®); allergy treatments such as promethazine hydrochloride (commercially available as Phenergan®), bepotastine besylate (commercially available as Bepreve®), hydrocodone polistirex / chlorpheniramine polistirex (commercially available as Tussionex®), cetirizine hydrochloride (commercially available as Zyrtec®), and naphthalene hydrochloride (commercially available as Naphthalene®). (commercially available as Zyrtec-D®), cetirizine hydrochloride / pseudoephedrine hydrochloride (commercially available as Zyrtec-D®), promethazine hydrochloride / codeine phosphate (commercially available as Phenergan® with codeine), pemirolast (commercially available as Alamast®), fexofenadine hydrochloride (commercially available as Allegra®), meclizine hydrochloride (commercially available as Antivert®), azelastine hydrochloride (commercially available as Astelin®), nizatidine (commercially available as Axid®), desmopressin (commercially available as Acetolide®), cyclosporine ... Loratadine (commercially available as Clarinex®), cromolyn sodium (commercially available as Crorom®), epinastine hydrochloride (commercially available as Elestat®), azelastine hydrochloride (commercially available as Optivar®), prednisolone sodium phosphate (commercially available as Olapred ODT®), olopatadine hydrochloride (commercially available as Patanol®), ketotifen fumarate (commercially available as Zaditor®), and montelukast sodium (Singula ir®); and antihistamines, such as diphenhydramine HCl (available as Benadryl®), loratadine (available as Claritin®), astemizole (available as Hismanal®), nabumetone (available as Relafen®), diphenydramine HCL (available as TheraFlu®), and clemastine (available as Tavist®).

[0020] The films of the present disclosure may further comprise a composition that is capable of administering to the patient an effective amount of an anti-Alzheimer's disease treatment, such as tacrine hydrochloride (commercially available as Cognex®), galantamine (commercially available as Razadyne®), donepezil hydrochloride (commercially available as Aricept®), rivastigmine tartrate (commercially available as Exelon®), caprylidene (commercially available as Axona®), and memantine (commercially available as Namenda®); anemia agents, such as cyanocobalamin (commercially available as Nascobal®) and ferumoxytol (commercially available as Feraheme®); anesthetics, such as antipyrine and benzocaine (Aur algan®, Aurodex®, and Auroto®; antianginal agents such as amlodipine besylate (commercially available as Norvasc®), nitroglycerin (commercially available as Nitro-Bid®, Nitro-Dur®, Nitrolingual®, Nitrostat®, Transderm-Nitro®), isosorbide mononitrate (commercially available as Imdur®), and isosorbide dinitrate (commercially available as Isordil®); cough suppressants such as guaifenesin; anti-Alzheimer's drugs such as nicergoline; and Ca H Antagonists such as nifedipine (commercially available as Procardia® and Adalat®) may also be included.

[0021] Active agents useful in the present disclosure also include anti-asthma agents, such as albuterol sulfate (commercially available as Proventil®), ipratropium bromide (commercially available as Atrovent®), salmeterol xinafoate (commercially available as Serevent®), zafirlukast (commercially available as Accolate®), flunisolide (commercially available as AeroBid®), metaproterenol sulfate (commercially available as Alupent®), albuterol inhalant (commercially available as Ventolin®), terbutaline sulfate (commercially available as Brethine®), formoterol (commercially available as Foradil®), cromolyn sodium (commercially available as Intal®), levalbuterol, and the like. methylprednisolone hydrochloride (commercially available as Xopenex®), zileuton (commercially available as Zyflo®), fluticasone propionate / salmeterol (commercially available as Advair®), albuterol sulfate / triamcinolone acetonide (commercially available as Azmacort®), dimethylxanthine (commercially available as Theophylline®), and beclomethasone (commercially available as Beclovent®, Beconase®, Qvar®, Vancenase®, Vanceril®); angioedema agents such as C1 esterase inhibitors (human) (commercially available as Berinert®) and ecallantide (commercially available as Kalbitor®);and antibacterial agents such as trimethoprim / sulfamethoxazole (commercially available as Bactrim®), mupirocin (commercially available as Bactroban®), metronidazole (commercially available as Flagyl®), sulfisoxazole acetyl (commercially available as Gantrisin®), bismuth subsalicylate and metronidazole / tetracycline hydrochloride (commercially available as Helidac Therapy®), nitrofurantoin (commercially available as Macrodantin®), norfloxacin (commercially available as Noroxin®), erythromycin ethylsuccinate / sulfisoxazole acetyl (commercially available as Pediazole®), and levofloxacin (commercially available as Levaquin®);

[0022] The films of the present disclosure may further comprise one or more antibiotics, such as amoxicillin (commercially available as Amoxil®), ampicillin (commercially available as Omnipen®, Polycillin®, and Principen®), amoxicillin / clavulanate potassium (commercially available as Augmentin®), moxifloxacin hydrochloride (commercially available as Avelox®), besifloxacin (commercially available as Besivance®), clarithromycin (commercially available as Biaxin®), ceftibuten (commercially available as Cedax®), cefuroxime axetil (commercially available as Ceftin®), cefprozil (commercially available as Cefzil®), ciprofloxacin hydrochloride (commercially available as Ciloxan® and Cipro®), clindamycin phosphate (commercially available as Cleocin®), and the like. T®), doxycycline hydrochloride (commercially available as Doryx®), dirithromycin (commercially available as Dynabac®), erythromycin (EES®, E-Mycin®, Eryc®, Ery-Tab®, Erythrocin®, and PCE®), topical erythromycin (commercially known as A / T / S®, Erycette®, T-Stat®), gemifloxacin (commercially known as Factive®), ofloxacin (commercially known as Ocuflox®, Floxin®), telithromycin (commercially known as Ketek®), lomefloxacin hydrochloride (commercially known as Maxaquin®), minocycline hydrochloride (commercially known as Minocin®), fosfomycin tromethamine (commercially known as Monurol®), penicillin and potassium (Penicillin VK®, Veetids®), trimethoprim (commercially known as Primsol®), ciprofloxacin hydrochloride (commercially known as Proquin®), cyclosporine ...XR®), rifampin, isoniazid and pyrazinamide (commercially available as Rifater®), cefditoren (commercially available as Spectracef®), cefixime (commercially available as Suprax®), tetracycline (Achromycin V® and Sumycin®), tobramycin (commercially available as Tobrex®), rifaximin (commercially available as Xifaxan®), azithromycin (commercially available as Zithromax®), azithromycin suspension (commercially available as Zmax®), linezolid (commercially available as Zyvox®), benzoyl peroxide and clindamycin (commercially available as BenzaClin®), erythromycin and benzoyl peroxide (commercially available as Benzamycin®), dexamethasone (commercially available as Ozurdex®), ciprofloxacin and dexamethasone (commercially available as Ciprodex®), polymyxin B sulfate / neomycin sulfate / hydrocortisone (commercially available as Cortisporin®), colistin sulfate / neomycin sulfate / hydrocortisone acetate / thonzonium bromide (Cortisporin-TC They may also include cephalexin hydrochloride (commercially available as Keflex®), cefdinir (commercially available as Omnicef®), and gatifloxacin (commercially available as Zymar®).

[0023] Other useful active agents include cancer therapeutics such as cyclophosphamide (commercially available as Cytoxan®), methotrexate (commercially available as Rheumatrex® and Trexal®), tamoxifen citrate (commercially available as Nolvadex®), bevacizumab (commercially available as Avastin®), everolimus (commercially available as Afinitor®), pazopanib (commercially available as Votrient®), and anastrozole (commercially available as Arimidex®); leukemia therapeutics such as ofatumumab (commercially available as Arzerra®); antithrombotic agents anticoagulants, such as, for example, antithrombin recombinant lyophilized powder (commercially available as Atryn®), prasugrel (commercially available as Efient®); anticoagulants, such as, for example, aspirin and extended release dipyridamole (commercially available as Aggrenox®), warfarin sodium (commercially available as Coumadin®), dipyridamole (commercially available as Persantine®), dalteparin (commercially available as Fragmin®), danaparoid (commercially available as Orgaran®), enoxaparin (commercially available as Lovenox®), heparin (Hep-Lock, Hep-Pak, Hep-Pak CVC, commercially available as Heparin Lock Flush), tinzaparin (commercially available as Innohep®), and clopidogrel bisulfate (commercially available as Plavix®); antiemetics such as granisetron hydrochloride (commercially available as Kytril®) and nabilone (commercially available as Cesamet®), trimethobenzamide hydrochloride (commercially available as Tigan®), and ondansetron hydrochloride (commercially available as Zofran®);Antifungal therapeutics include, for example, ketoconazole (commercially available as Nizoral®), posaconazole (commercially available as Noxafil®), ciclopirox (commercially available as Penlac®), griseofulvin (commercially available as Gris-PEG®), oxiconazole nitrate (commercially available as Oxistat®), fluconazole (commercially available as Diflucan®), sertaconazole nitrate (commercially available as Ertaczo®), terbinafine hydrochloride (commercially available as Lamisil®), ciclopirox (commercially available as Loprox®), nystatin / triamcinolone acetonide (commercially available as Mycolog-II®), econazole nitrate (commercially available as Spectazole®), itraconazole (commercially available as Sporanox®), and terconazole (commercially available as Terazol®);

[0024] Active agents further include anti-inflammatory agents, such as hydroxychloroquine sulfate (commercially available as Plaquenil®), fluticasone propionate (commercially available as Cutivate®), canakinumab (commercially available as Llaris®), amcinonide (commercially available as Cyclocort®), methylprednisolone (commercially available as Medrol®), budesonide (Entocort®), and the like. antispasmodics, such as phenobarbital / hyoscyamine sulfate / atropine sulfate / scopolamine hydrobromide (commercially available as Donnatal®); antiviral therapeutics, such as oseltamivir phosphate (commercially available as Tamiflu®); antiparasitic agents, such as tinidazole (commercially available as Tindamax®); appetite treatments, such as megestrol acetate (Megace®); ES®), phentermine hydrochloride (commercially available as Adipex-P®), and diethylpropion hydrochloride (commercially available as Tenuate®); arthritis agents such as leflunomide (commercially available as Arava®), certolizumab pegol (commercially available as Cimzia®), diclofenac sodium (commercially available as Pennsaid®), golimumab (commercially available as Simponi®), and tocilizumab (commercially available as Actemra®); bladder control agents such as trospium chloride (commercially available as Sanctura®), desmopressin acetate (commercially available as DDAVP®), tolterodine tartrate (commercially available as Detrol®), oxybutynin chloride (commercially available as Ditropan® or Gelnique®), darifenacin (commercially available as Enablex®), and solifenacin succinate (commercially available as VESIcare®); vasoconstrictors, such as methylergonovine maleate (commercially available as Methergine®);plasma uric acid control agents, such as rasburicase (commercially available as Elitek®); iron deficiency anemia agents, such as ferumoxytol (commercially available as Feraheme®); lymphoma agents, such as pralatrexate (commercially available as Folotyn®), romidepsin (commercially available as Isodax®); malaria agents, such as artemether / lumefantrine (commercially available as Coartem®); hyponatremia agents, such as tolvaptan (commercially available as Samsca®); agents for the treatment of von Willebrand's disease (commercially available as Wilate®); antihypertensive agents, such as treprostinil (commercially available as Tyvaso®), tadalafil (commercially available as Adcirca®);Cholesterol-lowering agents such as paricalcitol (commercially available as Altocor®), pitavastatin (commercially available as Livalo®), lovastatin, niacin (commercially available as Advicor®), colestipol hydrochloride (commercially available as Colestid®), rosuvastatin calcium (commercially available as Crestor®), fluvastatin sodium (commercially available as Lescol®), atorvastatin calcium (commercially available as Lipitor®), lovastatin (commercially available as Mevacor®), niacin (commercially available as Niaspan®), pravastatin sodium (commercially available as Pravachol®), pavastatin sodium, and buffered aspirin (Pravigard®); PAC®), cholestyramine (commercially available as Questran®), simvastatin and niacin (commercially available as Simcor®), atenolol, chlorthalidone (commercially available as Tenoretic®), atenolol (commercially available as Tenormin®), fenofibrate (commercially available as Tricor®), fenofibrate (commercially available as Triglide®), ezetimibe / simvastatin (commercially available as Vytorin®), colesevelam (commercially available as WelChol®), bisoprolol fumarate (commercially available as Zebeta®), ezetimibe (commercially available as Zetia®), bisoprolol fumarate / hydrochlorothiazide (commercially available as Ziac®), and simvastatin (commercially available as Zocor®);

[0025] Active agents included herein also include chronic kidney disease medications, such as paricalcitol (commercially available as Zemplar®); contraceptives, such as etonogestrel (commercially available as Implanon®), norethindrone acetate, ethinyl estradiol (commercially available as Loestrin 24 FE®), ethinyl estradiol, norelgestromin (commercially available as Ortho Evra®), levonorgestrel (Plan B®), levonorgestrel and ethinyl estradiol (commercially available as Preven®), levonorgestrel, ethinyl estradiol (commercially available as Seasonique®), and medroxyprogesterone acetate (commercially available as Depo-Provera®); COPD agents such as arformoterol tartrate (commercially available as Brovana®) and ipratropium bromide, albuterol sulfate (commercially available as Combivent®); cough suppressants such as benzonatate (commercially available as Tessalon®), guaifenesin, codeine phosphate (commercially available as Tussi-Organidin NR®), and acetaminophen, codeine phosphate (commercially available as Tylenol with Codeine®); agents for the treatment of diabetes such as pioglitazone hydrochloride, metformin hydrochloride (ACTOplus®); met®), bromocriptine mesylate (commercially available as Cyclote®), liraglutide (commercially available as Victoza®), saxagliptin (commercially available as Onglyza®), pioglitazone hydrochloride (commercially available as Actos®), glimepiride (commercially available as Amaryl®), rosiglitazone maleate, metformin hydrochloride (commercially available as Avandamet®), rosiglitazone maleate (commercially available as Avandaryl®), rosiglitazone maleate (commercially available as Avandia®), exenatide (commercially available as Byetta®), exenatide (commercially available as Bydureon®), chlorpropamide (commercially available as Diabinese®),Pioglitazone hydrochloride, glimepiride (commercially available as Duetact®), metformin hydrochloride (commercially available as Glucophage®), glipizide (commercially available as Glucotrol®), glyburide, metformin (commercially available as Glucovance® and Fortamet®), metformin hydrochloride (commercially available as Glumetza®), sitagliptin (commercially available as Januvia®), detemir (commercially available as Levemir®), glipizide, metformin hydrochloride (commercially available as Metaglip®), glyburide (commercially available as Micronase®), repaglinide (commercially available as Prandin®), These may also include insulin glargine (commercially available as Lantus® or Toujeo®), insulin aspart (commercially available as Novolog®), insulin lispro, empagliflozin (commercially available as Jardiance®), and tolazamide (commercially available as Tolinase®).

[0026] Other useful active agents include digestive aids, such as sulfasalazine (commercially available as Azulfidine®), rabeprazole sodium (commercially available as AcipHex®), lubiprostone (commercially available as Amitiza®), dicyclomine hydrochloride (commercially available as Bentyl®), sucralfate (commercially available as Carafate®), lactulose (commercially available as Chronulac®), docusate (commercially available as Colace®), balsalazide disodium, and the like. methadone (commercially available as Colazal®), losartan potassium (commercially available as Cozaar®), olsalazine sodium (commercially available as Dipentum®), chlordiazepoxide hydrochloride, clidinium bromide (commercially available as Librax®), esomeprazole magnesium (commercially available as Nexium®), famotidine (commercially available as Pepcid®), lansoprazole (commercially available as Prevacid®), lansoprazole and naproxen (commercially available as Prevacid®), NapraPAC®), amoxicillin / clarithromycin / lansoprazole (commercially available as Prevpac®), omeprazole (commercially available as Prilosec®), pantoprazole sodium (commercially available as Protonix®), metoclopramide hydrochloride (commercially available as Reglan® or Metozolv®), cimetidine (commercially available as Tagamet®), ranitidine hydrochloride (commercially available as Zantac®), and omeprazole, sodium bicarbonate (commercially available as Zegerid®);Diuretics may also be included, such as spironolactone, hydrochlorothiazide (commercially available as Aldactazide®), spironolactone (commercially available as Aldactone®), bumetanide (commercially available as Bumex®), torsemide (commercially available as Demadex®), chlorothiazide (commercially available as Diuril®), furosemide (commercially available as Lasix®), metolazone (commercially available as Zaroxolyn®), and hydrochlorothiazide, triamterene (commercially available as Dyazide®);

[0027] Active agents useful herein also include agents for the treatment of emphysema, such as tiotropium bromide (commercially available as Spiriva®); fibromyalgia medications, such as milnacipran hydrochloride (commercially available as Savella®); agents for the treatment of gout, such as colchicine (commercially available as Colcrys®), and febuxostat (commercially available as Uloric®); enema treatments, such as aminosalicylic acid (commercially available as Mesalamine® and Rowasa®); epilepsy medications, such as They may also include valproic acid (commercially available as Depakene®), felbamate (commercially available as Felbatol®), lamotrigine (commercially available as Lamictal®), primidone (commercially available as Mysoline®), oxcarbazepine (commercially available as Trileptal®), zonisamide (commercially available as Zonegran®), levetiracetam (commercially available as Keppra®), and phenytoin sodium (commercially available as Dilantin®).

[0028] Active agents useful herein further include ophthalmic medications and therapeutic agents, such as dipivefrin hydrochloride (commercially available as Propine®), valganciclovir (commercially available as Valcyte®), ganciclovir eye gel (commercially available as Zirgan®); bepotastine besilate (commercially available as Bepreve®), besifloxacin (commercially available as Besivance®), bromfenac (commercially available as Xibrom®), fluorometholone (commercially available as FML®), pilocarpine hydrochloride (commercially available as Pilocar®), cyclosporine (commercially available as Restasis®), brimonidine tartrate (Alphagan®), and the like. P®), dorzolamide hydrochloride / timolol maleate (commercially available as Cosopt®), bimatoprost (commercially available as Lumigan®), timolol maleate (available as Timoptic®), travoprost (commercially available as Travatan®), latanoprost (commercially available as Xalatan®), echothiophate iodide (commercially available as Phospholine Iodide®), and ranibizumab (commercially available as Lucentis®); tear modulating agents such as acetazolamide (commercially available as Diamox®); gallstone agents such as ursodiol (commercially available as Actigall®); agents for the treatment of gingivitis such as chlorhexidine gluconate (commercially available as Peridex®);headache medications, such as butalbital / codeine phosphate / aspirin / caffeine (commercially available as Fiornal® with codeine), naratriptan hydrochloride (commercially available as Amerge®), almotriptan (commercially available as Axert®), ergotamine tartrate / caffeine (commercially available as Cafergot®), butalbital / acetaminophen / caffeine (commercially available as Fioricet®), butalbital / aspirin / caffeine (commercially available as Fiorinal®), frovatriptan succinate (commercially available as Frova®), rizatriptan benzoate (commercially available as Maxalt®), isometheptene mucate / dichlorphenazone / acetaminophen (commercially available as Midrin®), dihydroergotamine mesylate (Migranal®), flu medications such as Haemophilus b conjugate vaccine; tetanus toxoid conjugates (commercially available as Hiberix); and cardiac medications such as quinidine sulfate, isosorbide dinitrate / hydralazine hydrochloride (commercially available as BiDil), digoxin (commercially available as Lanoxin), flecainidine acetate (commercially available as Tambocor), mexiletine hydrochloride (commercially available as Mexitil), disopyramide phosphate (commercially available as Norpace), procainamide hydrochloride (commercially available as Procanbid), and propafenone (commercially available as Rythmol);

[0029] Other useful active agents include hepatitis treatments such as entecavir (commercially available as Baraclude®), Hepatitis B Immunoglobulin (commercially available as HepaGam B®), and Copegus / Rebetol / Rivasphere / Vilona / Virazol (commercially available as Ribavirin®); herpes treatments such as valacyclovir hydrochloride (commercially available as Valtrex®), penciclovir (commercially available as Denavir®), acyclovir (commercially available as Zovirax®), and famciclovir (commercially available as Famvir®); high blood pressure treatments such as enalaprilat (available as Vasotec®), captopril (available as Capoten®), and lisinopril (available as Zestril®), verapamil hydrochloride (commercially available as Calan®), and lisinopril (available as Zestril®). available as Altace®), olmesartan medoxomil (commercially available as Benicar®), amlodipine / atorvastatin (commercially available as Caduet®), nicardipine hydrochloride (commercially available as Cardene®), diltiazem hydrochloride (commercially available as Cardizem®), quinapril hydrochloride (commercially available as Accupril®), quinapril hydrochloride / hydrochlorothiazide (commercially available as Accuretic®), perindopril erbumine (commercially available as Aceon®), candesartan cilexetil (commercially available as Atacand®), candesartan cilexetil / hydrochlorothiazide (commercially available as Atacand®),HCT®), irbesartan / hydrochlorothiazide (commercially available as Avalide®), irbesartan (commercially available as Avapro®), amlodipine besylate / olmesartan medoxomil (commercially available as Azor®), levobunolol hydrochloride (commercially available as Betagan®), betaxolol hydrochloride (commercially available as Betoptic®), nebivolol (commercially available as Bystolic®), captopril / hydrochlorothiazide (commercially available as Capozide®), doxazosin mesylate (commercially available as Cardura®), clonidine hydrochloride (commercially available as Catapres®), carvedilol (commercially available as Coreg®), nadolol (commercially available as Corgard®), nadolol / bendroflumethiazide (commercially available as Corzide®), valsartan (Diovan®), (commercially available as DynaCirc®), guanabenzacetate (commercially available as Wytensin®), guanfacine hydrochloride (commercially available as Tenex® or Intuniv®), losartan potassium / hydrochlorothiazide (commercially available as Hyzaar®), propranolol hydrochloride (commercially available as Indera®), propranolol hydrochloride / hydrochlorothiazide (commercially available as Inderide®), eplerenone (commercially available as Inspra®), ambrisentan (commercially available as Letairis®), enalapril maleate / felodipine (commercially available as Lexxel®), metoprolol tartrate (commercially available as Lopressor®), benazepril hydrochloride (commercially available as Lotensin®), benazepril hydrochloride / hydrochlorothiazide (LotensinHCT®), amlodipine / benazepril hydrochloride (commercially available as Lotrel®), indapamide (commercially available as Lozol®), trandolapril (commercially available as Mavik®), telmisartan (commercially available as Micardis®), telmisartan / hydrochlorothiazide (commercially available as Micardis HCT®), prazosin hydrochloride (commercially available as Minipress®), amiloride, hydrochlorothiazide (commercially available as Moduretic®), fosinopril sodium (ZZXT fosinopril sodium / hydrochlorothiazide (commercially available as Monopril-HCT), pindolol (commercially available as Visken), felodipine (commercially available as Plendil), sildenafil citrate (commercially available as Revatio), nisoldipine (commercially available as Sular), trandolapril / verapamil hydrochloride (commercially available as Tarka), aliskiren (commercially available as Tekturna), eprosartan mesylate (commercially available as Teveten), eprosartan mesylate / hydrochlorothiazide (commercially available as Teveten), HCT®), moexipril hydrochloride / hydrochlorothiazide (commercially available as Uniretic®), moexipril hydrochloride (commercially available as Univasc®), enalapril maleate / hydrochlorothiazide (commercially available as Vaseretic®), and lisinopril / hydrochlorothiazide (commercially available as Zestoretic®).

[0030] The films of the present disclosure may be used to inhibit the release of active agents useful in medications for the treatment of HIV / AIDS, such as amprenavir (commercially available as Agenerase®), tipranavir (commercially available as Aptivus®), efavirenz / emtricitabine / tenofovir (commercially available as Atripla®), lamivudine / zidovudine (commercially available as Combivir®), indinavir sulfate (commercially available as Crixivan®), lamivudine (commercially available as Epivir®), saquinavir (commercially available as Fortovase®), zalcitabine (commercially available as Hivid®), lopinavir / ritonavir (commercially available as Kaletra®), fosamprenavir calcium (commercially available as Lexiva®), ritonavir / ritonavir ... navir (commercially available as Norvir®), zidovudine (commercially available as Retrovir®), atazanavir sulfate (commercially available as Reyataz®), efavirenz (commercially available as Sustiva®), abacavir / lamivudine / zidovudine (commercially available as Trizivir®), didanosine (commercially available as Videx®), nelfinavir mesylate (commercially available as Viracept®), nevirapine (commercially available as Viramune®), tenofovir disoproxil fumarate (commercially available as Viread®), stavudine (commercially available as Zerit®), and abacavir sulfate (commercially available as Ziagen®); homocysteine ​​remover removers), such as betaine anhydrous (commercially available as Cystadane®); medications such as insulin (commercially available as Apidra®, Humalog®, Humulin®, Iletin®, Tresiba®, and Novolin®); and HPV treatments, such as the human papilloma virus vaccine (commercially available as Gardasil®) or bivalent human papilloma virus (commercially available as Cervarix®);Immunosuppressants may include, for example, cyclosporine (commercially available as Gengraf®, Neoral®, Sandimmune®, and Apo-Cyclosporine®);

[0031] Active agents useful in the present disclosure further include prolactin inhibitors such as bromocriptine mesylate (commercially available as Parlodel®); agents for adding to stress tests such as regadenoson (commercially available as Lexiscan®); hair loss medications such as finasteride (commercially available as Propecia® and Proscar®); pancreatitis treatments such as gemfibrozil (commercially available as Lopid®); hormonal agents such as norethindrone acetate / ethinyl estradiol (commercially available as femHRT®), goserelin acetate (Zoladex®), (commercially available as Prometrium®), progesterone gel (commercially available as Prochieve®), progesterone (commercially available as Prometrium®), salmon calcitonin (commercially available as Miacalcin®), calcitriol (commercially available as Rocaltrol®), Synthroid (commercially available as Levothroid®, Levoxyl®, Unithroid®), testosterone (commercially available as Testopel®, Androderm®, Testoderm®, and AndroGel®);Menopausal medications, such as estradiol / norethindrone acetate (commercially available as Activella®), drospirenone / estradiol (commercially available as Angeliq®), estradiol / levonorgestrel (Climara®), Pro®), estradiol / norethindrone acetate (commercially available as CombiPatch®), estradiol (commercially available as Estrasorb®, Vagifem®, and EstroGel®), esterified estrogens and methyltestosterone (commercially available as Estratest®), estrogens (commercially available as Alora®, Climara®, Esclim®, Estraderm®, Vivelle®, Vivelle-Dot®), etropipate (commercially available as Ogen®), conjugated estrogens (commercially available as Premarin®), and medroxyprogesterone acetate (commercially available as Provera®); menstrual medications, such as leuprolide acetate (Lupron®); Depot), tranexamic acid (commercially available as Lysteda®), and noresindrone acetate (commercially available as Aygestin®); and muscle relaxants such as cyclobenzaprine hydrochloride (commercially available as Flexeril®), tizanidine (commercially available as Zanaflex®), and hyoscyamine sulfate (commercially available as Levsin®);

[0032] Active agents useful herein also include osteoporosis drugs, such as ibandronate sodium. sodium) (commercially available as Boniva®), risedronate (commercially available as Actonel®), raloxifene hydrochloride (commercially available as Evista®, Fortical®), and alendronate sodium (commercially available as Fosamax®); ovulation enhancers such as clomiphene citrate (commercially available as Serophene®, Clomid®, Serophene®); agents for treating Paget's disease such as etidronate disodium (commercially available as Didronel®); pancreatic enzyme deficiency medications such as pancrelipase (commercially available as Pancrease® or Zenpep®); agents for the treatment of Parkinson's disease such as pramipexole dihydrochloride (commercially available as Mirapex®), ropinirole hydrochloride (commercially available as Requip®), carbidopa / levodopa (Sinemet®), CR®), carbidopa / levodopa / entacapone (commercially available as Stalevo®), selegiline hydrochloride (commercially available as Zelapar®), rasagiline (commercially available as Azilect®), entacapone (commercially available as Comtan®), and selegiline hydrochloride (commercially available as Eldepryl®); multiple sclerosis drugs, such as dalfampridine (commercially available as Ampyra®) and interferon; prostate medications such as flutamide (commercially available as Eulexin®), nilutamide (commercially available as Nilandron®), dutasteride (commercially available as Avodart®), tamsulosin hydrochloride (commercially available as Flomax®), terazosin hydrochloride (commercially available as Hytrin®), and alfuzosin hydrochloride (commercially available as UroXatral®).

[0033] The films of the present invention may further comprise antipsychotics such as alprazolam (available as Niravam®, Xanax®), clozopin (available as Clozaril®), haloperidol (available as Haldol®), fluoxetine hydrochloride (available as Prozac®), sertraline hydrochloride (available as Zoloft®), asenapine (commercially available as Saphris®), iloperidone (commercially available as Fanapt®), paroxtine hydrochloride (available as Paxil®), aripiprazole (marketed as Abilify®), guanfacine (marketed as Intuniv®), amphetamines and methamphetamines (marketed as Adderall® and Desoxyn®), clomipramine hydrochloride (marketed as Anafranil®), buspirone hydrochloride (marketed as BuSpar®), citalopram hydrobromide (marketed as Celexa®), duroflurane hydrochloride (marketed as Diazepam®), rifampicin ... Xetine hydrochloride (commercially available as Cymbalta®), methylphenidate (Ritalin, commercially available as Daytrana®), divalproex sodium (valproic acid) (commercially available as Depakote®), dextroamphetamine sulfate (commercially available as Dexedrine®), venlafaxine hydrochloride (commercially available as Effexor®), selegiline (commercially available as Emsam®), carbamazepine (commercially available as Equetro®), lithium carbonate (Eskalit h®), fluvoxamine maleate / dexmethylphenidate hydrochloride (commercially available as Focalin®), ziprasidone hydrochloride (commercially available as Geodon®), ergoloid mesylates (commercially available as Hydergine®), escitapram oxalate (commercially available as Lexapro®), chlordiazepoxide (commercially available as Librium®), molindone hydrochloride (commercially available as Moban®), phenelzine sulfate (commercially available as Nardil®),Thiothixene (commercially available as Navane®), desipramine hydrochloride (commercially available as Norpramin®), benzodiazepines (such as those available as Oxazepam®), nortriptyline hydrochloride (commercially available as Pamelor®), tranylcypramine sulfate (commercially available as Parnate®), prochlorperazine, mirtazapine (commercially available as Remeron®), risperidone (commercially available as Risperdal®), quetiapine fumarate (Seroquel®), ®), doxepin hydrochloride (commercially available as Sinequan®), atomoxetine hydrochloride (commercially available as Strattera®), trimipramine maleate (commercially available as Surmontil®), olanzapine / fluoxetine hydrochloride (commercially available as Symbyax®), imipramine hydrochloride (commercially available as Tofranil®), protriptyline hydrochloride (commercially available as Vivactil®), bupropion hydrochloride (commercially available as Wellbutrin®, Wellbutrin SR®, and Wellbutrin XR®), and olanzapine (commercially available as Zyprexa®).

[0034] Active agents useful herein also include uric acid lowering agents, such as allopurinol (commercially available as Zyloprim®); seizure medications, such as gabapentin (commercially available as Neurontin®), ethotoin (commercially available as Peganone®), vigabatrin (commercially available as Sabril®), and topiramate (commercially available as Topamax®); treatments for shingles, such as live shingles vaccine (commercially available as Zostavax®);skin care agents, such as calcipotriene (commercially available as Dovonex®), ustekinumab (commercially available as Stelara®), telavancin (commercially available as Vibativ®), isotretinoin (commercially available as Accutane®), hydrocortisone / iodoquinol (commercially available as Alcortin®), sodium sulfacetamide / sulfur (commercially available as Avar®), azelaic acid (commercially available as Azelex®, Finacea®), benzoyl peroxide (commercially available as Desquam-E®), adapalene (commercially available as Differin®), fluorouracil (commercially available as Efudex®), pimecrolimus (commercially available as Elidel®), topical erythromycin (commercially available as A / T / S®, Erycette®, T-Stat®), hydrocortisone (Cetacort®), (commercially available as Hytone®, Nutracort®), metronidazole (commercially available as MetroGel®), doxycycline (commercially available as Oracea®), tretinoin (commercially available as Retin-A® and Renova®), mequinol / tretinoin (commercially available as Solag®), acitretin (commercially available as Soriatane®), calcipotriene hydrate / They may also include betamethasone dipropionate (commercially available as Taclonex®), tazarotene (commercially available as Tazorac®), fluocinonide (commercially available as Vanos®), desonide (commercially available as Verdeso®), miconazole nitrate / zinc oxide (commercially available as Vusion®), ketoconazole (commercially available as Xolegel®), and efalizumab (commercially available as Raptiva®);

[0035] Other active agents useful herein include sleep disorder medications such as zaleplon (available as Sonata®), eszopiclone (available as Lunesta®), zolpidem tartrate (commercially available as Ambien®, Ambien CR®, Edluar®), lorazepam (commercially available as Ativan®), flurazepam hydrochloride (commercially available as Dalmane®), triazolam (commercially available as Halcion®), clonazepam (commercially available as Klonopin®), barbiturates such as Phenobarbital®, modafinil (commercially available as Provigil®), temazepam (commercially available as Restoril®). , ramelteon (commercially available as Rozerem®), clorazepate dipotassium (commercially available as Tranxene®), diazepam (commercially available as Valium®), quazepam (commercially available as Doral®), and estazolam (commercially available as ProSom®); smoking cessation agents, such as varenicline (commercially available as Chantix®), nicotine, such as Nicotrol®, and bupropion hydrochloride (commercially available as Zyban®);as well as steroids such as alclometasone dipropionate (commercially available as Aclovate®), betamethasone dipropionate (commercially available as Diprolene®), mometasone furoate (commercially available as Elocon®), fluticasone (commercially available as Flonase®, Flovent®, Flovent Diskus®, Flovent Rotadisk®), fluocinonide (commercially available as Lidex®), mometasone furoate monohydrate (commercially available as Nasonex®), desoximetasone (commercially available as Topicort®), clotrimazole / betamethasone dipropionate (commercially available as Lotrisone®), prednisolone acetate (Pred Forte®, Prednisone®, Budesonide Pulmicort®, Rhinocort®), Aqua®), prednisolone sodium phosphate (commercially available as Pediapred®), desonide (commercially available as Tridesilon®), and halobetasol propionate (commercially available as Ultravate®);

[0036] The films of the present invention may further include active agents useful in the treatment of thyroid disorders, such as the hormones TC and TD (commercially available as Armour Thyroid®); potassium deficiency treatments, such as potassium chloride (commercially available as Micro-K®); triglyceride regulators, such as omega-3-acid ethyl esters (commercially available as Omacor®); urological agents, such as phenazopyridine hydrochloride (commercially available as Pyridium®) and methenamine, methylene blue / phenyl salicylate / benzoic acid / atropine sulfate / hyoscyamine (commercially available as Urised®); prenatal vitamins (commercially available as Advanced Natalcare®, Materna®, Natalins®, Prenate Advance®); weight control agents, such as orlistat (commercially available as Xenical®) and sibutramine hydrochloride (commercially available as Meridia®).

[0037] Well-known H2 antagonists contemplated for use herein include cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifentidine, roxatidine, pisatidine and aceroxatidine.

[0038] 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, citrate ion (acid or salt), aminoacetic acid, magnesium aluminate sulfate hydrate, magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, aluminum calcium phosphate monobasic or dibasic, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminosilicate, tartaric acid and salts.

[0039] Active agents for use in the present invention may include allergens or antigens, such as, but not limited to, plant pollen from grasses, trees, or ragweed; animal dander, i.e., the fine flakes from the skin and hair of cats and other furry animals; insects such as dust mites, bees and wasps; and drugs such as penicillin.

[0040] Examples of specific active agents include, but are not limited to, the following: 16-alpha fluoroxtradiol (16-alpha fluorocstradiol), 16-α-gitoxin, 16-epiestradiol, 17α-dihydroequilenin, 17α-estradiol, 17β-estradiol, 17-hydroxyprogesterone, lα-hydroxyvitamin D2, 1-dodecapyrrolidinone, 20-epi-1,25-dihydroxyvitamin D3, 22-oxacalcitriol, 2CVV, 2'-nor-cGMP, 3-isobutyl GABA, 5-ethynyluracil, 6-FUDCA, 7-methoxytacrine, abamectin, abanoquil, abecarnil, abiraterone, abulkast, abulkast sodium, acadesine, acamprosate, acarbose, acebutolol, acecainide hydrochloride, aceclidine, aceclofenac, acedapsone, aceglutamide aluminum, acemannan, ace Toaminophen, Acetazolamide, Acetohexamide, Acetohydroxamic Acid, Acetomepregenol, Acetophenazine Maleate, Sodium Acetosulfonate, Acetylcholine Chloride, Acetylcysteine, Acetyl-L-Carnitine, Acetylmethadol, Acifran, Acipimox, Acitemate, Acitretin, Acivicin, Aclarubicin, Aclatonium, Acodazole Hydrochloride, Aconiazid, Acrizorcine, Acrivastine, Acronine, Actisomide, Actodigin, Acyclovir, Acylfulvene, Adafenoxate, Adapalene, Adapalene, Adatanserin, Adatanserin Hydrochloride, Adecipenol, Adecipenol, Adefovir, Adelmidrol, Ademethionine, Adenosine, Adinazolam, Adipheinine Hydrochloride Hydrochloride), Adiposin, Adzelesin, Adrafinil, Adrenalone, Albutamine, Alacepril, Alamecin, Alanine, Alaproclate, Araptide, Albendazole, Albolabrin, Albuterol, Albutoin, Alclofenac, Alclometasone Dipropionate, Alcloxa, Aldecarmycin, Aldesleukin, Aldioxa,Alendronate sodium, Alendronate, Alentamol, Alentamol hydrobromide, Alethamine hydrochloride, Aleuronium chloride, Alexidine, Alfacalcidol, Alfentanil hydrochloride, Alfuzosin, Algestone acetonide, Alglucerase, Aliflurane, Alinastine, Alipamid, Allantoin, Allobarbital, Allopurinol, ALL-TK antagonists, Alogliptin, Alonimide, Alosetron, Alosetron hydrochloride, Alovudine, Alpertin, α amylase, α idosone, Alpidem, Alprazolam, Alprenolol hydrochloride, Alprenoxime hydrochloride, Alprostadil, Alrestatin sodium, Altanserin tartrate, Alteplase, Althiazide, Altretamine, Althromycin B, Alverin citrate Citrate), Alvirceptosudotox, Amadinone acetate, Amantadine hydrochloride, Ambamustine, Ambomycin, Ambruticin, Ambufilin, Ambuside, Amcinafal, Amcinonide, Amdinocillin, Amdinocillin pivoxil, Amedalin hydrochloride, Ameromethasone, Amertolide, Amesergide, Amethanethrone acetate, Amezinium methylsulfate, Amphebutamone, Amfenac sodium, Amflutisol, Amicycline, Amidefrin mesylate, Amidox, Amifloxacin, Amifostine, Amikacin, Amiloride hydrochloride, Aminacrine hydrochloride, Potassium aminobenzoate, Sodium aminobenzoate, Aminocaproic acid , aminoglutethimide, sodium aminohippurate, aminolevulinic acid, aminophylline, aminorex, sodium aminosalicylate, aminosalicylic acid, amiodarone, amiprilose hydrochloride, amiquincin hydrochloride, amisulpride, amitraz, amitriptyline hydrochloride, amlexanox, amlodipine, amobarbital sodium, amodiaquine, amodiaquine hydrochloride, amorolfine, amoxapine, amoxicillin, amfechloral, amphetamine sulfate, amphomycin, amphotericin B, ampicillin, ampiroxicam, ampiidine sulfate, amquinate, amrinone, amrinone, amrubicin, amsacrine, amylin, amythiamicin,anagestone acetate, anagrelide, anakinra, ananain, anaritide, anaritide acetate, anastrozole, anazolene sodium, ancrod, andrographolide, androstenedione, angiogenesis inhibitors, angiotensin amide, anidoxime, anileridine, anilopam hydrochloride, aniracetam, anilolac, anisotropine methylbromide, anistreplase, anitrazafen, anordrin, antagonist D, antagonist G G), antarelix, antazoline phosphate, anthermycin, anthralin, anthramycin, antiandrogenic agents, acedapsone, felbamate, antiestrogenic agents, antineoplastons, antipyrine, antisense oligonucleotides, apadrine, apafant, apalcillin sodium, apaxifylline, apazone, aphidicolin glycinate, apixifylline, apomorphine hydrochloride, apraclonidine, apraclonidine hydrochloride, apramycin, aprindine, aprindine hydrochloride, ap Roslate Sodium, Aprotinin, Aptazapine Maleate, Aptiganel, Apurinic Acid, Aranidipine, Aranotin, Arbaprostil, Arbekicin, Arbidol, Arbutamine Hydrochloride, Alclofenin, Ardeparin Sodium, Argatroban, Arginine, Argipressin Tannate, Arildone, Aripiprazole, Arotinolol, Arpinocid, Artefren, Altilide Fumarate, Asimadoline, Aspartone, Asparaginase, Asparic Acid Acid), aspartocin, asperfuran, aspirin, aspoxicillin, asprelin, astemizole, astromycin sulfate, asraculin, atamestane, atenolol, atevirdine, atipamezole, atipromycin maleate, atolid, atorvastatin calcium, atosiban, atovaquone, atopenine B, atracurium besylate, atrimustine, atrinositol, atropine, auranofin, aureobasidin A, gold thioglucose, avilamycin, avoparcin, avridin, axid, axinastatin 1,Axinastatin 2, Axinastatin 3, Azabon, Azacitidine, Azaclorzine hydrochloride, Azaconazole, Azadirachtine, Azalanstat dihydrochloride, Azaroxan fumarate, Azanator maleate, Azanidazole, Azaperone, Azaribine, Azaserine, Azasetron, Azatadine maleate, Azathioprine, Azathioprine sodium, Azatoxin, Azatyrosine, Azelaic acid, Azelastine, Azelnidipine, Azepindole, Azetepa, Azimilide, Azithromycin Isin, Azlocillin, Azolimine, Azosemide, Azotomycin, Aztreonam, Azumolene Sodium, Bacampicillin Hydrochloride, Baccatin III, Bacitracin, Baclofen, Bacoside A, Bacoside B, Bactoboramine, Balanol, Balagipon, Balhimycin, Balofloxacin, Balsalazide, Bambelmycin, Bambuterol, Bamethan Sulfate, Bamifilin Hydrochloride, Bamidazole, Baofosside 1, Balmastine, Barnidipine, Basifungin, Batanopride Hydrochloride, Batebra st, baterapine maleate, batimastat, beauvericin, becanthone hydrochloride, becaplermin, becliconazole, beclomethasone dipropionate, befloxatone, benserazide, velhosdil, belladonna, beloxamide, bemesetron, bemitrazine, bemoradan, benapridine hydrochloride, benazepril hydrochloride, benazeprilat, bendacalol mesylate, bendazac, bendroflumethiazide, benflumetol, benidipine, benortelone, benoxaprofen, benoxanthine salt acid salt, benperidol, bentazepam, bentiromide, benurestat, benzbromarone, benzethonium chloride, benzethimide hydrochloride, benzilonium bromide, benzindopyrine hydrochloride, benzisoxazole, benzocaine, benzochlorine, benzoctamine hydrochloride, benzodepa, benzidazoxan, benzonatade, benzoyl peroxide, benzoyl pass calcium, benzoylstaurosporine, benzquinamide, benzthiazide, benztropine, benztropine mesylate, benzidamine hydrochloride, benzylpenicilloyl polylysine, bepridil,Bepridil hydrochloride, beractant, beraprost, berefrin, berafenone, vertosamil, berithromycin, besipirdine, beta-arretin, betaclamycin B, betamethasone, betamipron, betaxolol, betaxolol hydrochloride, bethanechol chloride, betanidine sulfate, betulinic acid, bevantolol, bevantolol hydrochloride, bezafibrate, bFGF inhibitors, bialamicol hydrochloride, biapenem, bicalutamide, bicifadine hydrochloride, biclodil hydrochloride, bidisomide, bifemelane, bifonazole, bimakalim, bimitil (b imithil), bindarito, viniramycin, binospirone, bioxalomycin alpha 2, bipenamol hydrochloride, biperiden, biphenamine hydrochloride, biriperone, bisantrene, bisalamil, bisaziridinyl spermine, bis-benzimidazole A, bis-benzimidazole B, bisnafide, bisobrine lactate, bisoprolol, bispyrithione magsulfex, bistramid D, bistramid K, bistratene A, sodium bithionolate, bitolterol mesylate, bivalirudin, bizelesin, bleomycin sulfate, dipropionate Borandiol, Bolasterone, Boldenone Undecylenate, Boldine, Borenol, Bormantalate, Popindolol, Bosentan, Boxidine, Brefeldin, Breflate, Brequinar Sodium, Bretazenil, Bretylium Tosylate, Brifentanil Hydrochloride, Brimonidine, Brinolac, Brocresine, Brocrinate, Brofoxine, Bromadrine Maleate, Bromazepam, Bromchlorenone, Bromelain, Bromfenac, Brominidione, Bromocriptine, Bromopheniramine Hydrochloride, Bro Bromoxamide, bromperidol, bromperidol decanoate, brompheniramine maleate, broperamol, bropirimine, brotizolam, bucainide maleate, bucindolol, buclizine hydrochloride, buclomarone, budesonide, budipine, budotitane, buformin, bumetanide, bunaprolast, bunazosin, bunolol hydrochloride, bupivacaine hydrochloride, buprenorphine hydrochloride, bupropion hydrochloride, bramate, buserelin acetate, buspirone hydrochloride, busulfan, butabarbital, butacetin,Butaclamol hydrochloride, butalbital, butamben, butamirate citrate, butaperazine, butaprost, butedronate tetrasodium, butenafine,

[0041] Buteridine, buthionine sulfoximine, butikacin, butyrophenine, butirosin sulfate, butixyllate, butixocort propionate propionate, butoconazole nitrate, butonate, butopamine, butoprozine hydrochloride, butorphanol, butoxamine hydrochloride, butriptyline hydrochloride, cactinomycin, cadexomer iodine, caffeine, calanolide A, calcifediol, calcipotriene, calcipotriol, calcitonin, calcitriol, calcium undecylenate, calphostin C, calsterone, cambendazole, camonagrel, camptothecin derivatives, canagliflozin, canarypox IL-2, candesartan, candicidin, candoxatril, candoxatrilat, caniglibose, potassium canrenoate, canrenone, capecitabine, sodium capobenate, capobenic acid, capreomycin sulfate, capromab, capsaicin, captopril, purido, caracemide, carbachol, carbadox, carbamazepine, urea peroxide, carbantel lauryl sulfate, carbaspirin calcium, carbazeran, carbazomycin C, carbenicillin potassium, carbenoxolone sodium, carbetimer, carbetocin, carbidopa, carbidopa-levodopa, carbinoxamine maleate, carbifene hydrochloride, carbochloral, carbocysteine, carbofuchsine, carboplatin, carboprost, carbovir, carboxamide-amino-triazo-le, carboxyamidotriazole, carboxymethylated β-1,3-glucan, carbuterol hydrochloride, Carest M3, carfentanil citrate, carisoprodol, carmantadine, carmustine, CARN 700, Camidazole, Caroxazone, Carperitide, Carphenazine Maleate, Carprofen, Calsatrin Succinate, Cartazolate, Carteolol, Carteolol Hydrochloride, Cartilage-derived Inhibitor, Carbicin Hydrochloride, Carmonam Sodium, Carvedilol, Carbotroline, Carbotroline Hydrochloride, Carzelesin, Casein Kinase Inhibitor (ICOS), Castanospermine, Carmonam, Sevalacetam, Cecropin B, Cedefingol,Cefaclor, cefadroxil, cefamandole, cefaparole, cefatrizine, cefazaflur sodium, cefazolin, cefbuperazone, cefcapene pivoxil, cefdaloxime pentexil tosilate, cefdinir, cefditoren pivoxil, cefepime, cefetamet, cefetecol, cefixime, cefluprenam, cefmenoxime hydrochloride, cefmetazole, cefminlox, cefodizime, cefonicid sodium, cefoperazone sodium, ceforamide, cefoselis, cefotaxime Sodium, cefotetan, cefotiam, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftibuten, ceftizoxime sodium, ceftriaxone, cefuroxime, celastrol, cericarim, celiprolol, cepacidiine A A), Cephacetrile sodium, Cephalexin, Cephaloglycine, Cephaloridine, Cephalothin sodium, Cephapirin sodium, Cephradine, Cericlamine, Cerivastatin, Seronapril, Certoparin sodium, Ceruletide, Cetaben sodium, Cetalkonium chloride, Cetamolol hydrochloride, Cetiedil, Cetirizine, Cetophenicol, Cetraxate hydrochloride, Cetrorelix, Cetylpyridinium chloride, Chenodiol, Chlophedianol hydrochloride, Chloral betaine, Chlorambucil, Chloramphenicol, Clodantoin, Chlordiazepo oxide, chlorhexidine gluconate, chlorine, chlormadinone acetate, chloroorienticin A, chloroprocaine hydrochloride, chlorpropamide, chloroquine, chloroquinoxaline sulfonamide, chlorothiazide, chlorotrianisene, chloroxine, chloroxylenol, chlorphenesin carbamate, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlorprothixene, chlortetracycline bisulfate, chlorthalidone, chlorzoxazone, cholestyramine resin, chromonal hydrochloride, cibenzoline, cicaprost,Cyclafrine hydrochloride, cyclazindol, ciclesonide, cicletanine, ciclopirox, cycloprofen, cycloprolol, cidofovir, cidoxepin hydrochloride, cifenline, ciglitazone, ciladopa hydrochloride, cilansetron, cilastatin sodium, cilazapril, cilnidipine, cilobamine mesylate, cilobradine, cilofungin, cilostazol, cimaterol, cimetidine, cimetropium bromide, sinalukast, cinanserin hydrochloride, cinepazet maleate, cinflumide, syngestrone, cinitapride, cinnamedrine, cinna Lysine, cinolazepam, cinoxacin, cinperen, cinromide, synthazone, syntriamide, cioteronel, cipamfylline, cyprefadol succinate, cyprocinonide, ciprofibrate, ciprofloxacin, ciprostene, ciramadol, ciloremycin, cisapride, cisatracurium besylate, cisconazole, cisplatin, cis-porphyrin, cystinexine, citalopram, sitenamide, citicoline, citreamycin alpha, cladribine, clamoxiquin hydrochloride, clarithromycin, clausen Amide, potassium clavulanate, clazolam, clazolimine, clebopride, clemastine, clenchazem maleate, clidinium bromide, clinafloxacin, clindamycin, clioquinol, clioxamide, criprofen, clobazam, clobetasol propionate, clobetasone butyrate, clocortolone acetate, clodalenone, clodazon hydrochloride, clodronic acid, clofazimine, clofibrate, clofilium phosphate, clogestone acetate, clomacran phosphate, clomegestone acetate ston, clometerone, clomethiazole, clomiphene analogue, clominorex, clomiphene, clomipramine hydrochloride, clonazepam, clonidine, clonitrate, clonixeril, clonixin, clopamide, clopenthixol, cloperidone hydrochloride, clopidogrel, clopimozide, clopipazan mesylate, clopirac, cloprednol, cloprostenol sodium, clorazepate dipotassium, chloretate, chlorexolone, chloroperone hydrochloride, clorprenaline hydrochloride, clorsulon, chlortermine hydrochloride, closantel,Closylamine aceturate, Clothiapine, Clotixamide maleate, Cloticasone propionate, Clotrimazole, Cloxacillin benzathine, Cloxiquine, Clozapine, Cocaine, Coccidioidin, Codeine, Codoxime, Colchicine, Colestimide, Colestipol hydrochloride, Cholestrone, Colforsin, Colfosseryl palmitate, Colistin sodium methanesulfonate, Colistin sulfate, Collismycin A, Collismycin B, Corterol mesylate, Combretastatin A4, Combretastatin analogues, Combretastatin, Conagenin, Conorphon hydrochloride, Contignasterol, Contortrostatin, Colmethasone acetate, Corticorelin oubain triflutate, Corticotropin, Cortisol Acetate, Cortivazol, Cortodoxone, Cosalane, Costatolide, Cosyntropin, Cotinine, Coumadin, Coumermycin, Curambecidin 816, Crylvastatin, Crisnatol, Clomitryl Sodium, Cromolyn Sodium, Crotamiton, Cryptophycin 8, Cucumarioside, Cuprimyxin, Curacin A, Curdlan Sulfate, Curiosin, Cyclacillin, Cyclazocine, Cyclazosin, Cyclic HPMPC, Cyclindole, Cycliramine Maleate, Cyclizine, Cyclobendazole, Cyclobenzaprine, Cyclobut A A), cyclobuta G, cyclocapron, cycloguanyl pamoate, cycloheximide, cyclopentaanthraquinone, cyclopenthiazide, cyclopentolate hydrochloride, cyclophenazine hydrochloride, cyclophosphamide, cycloplatam, cyclopropane, cycloserine, cyclosine, cyclosporine, cyclothiazide, cyclothiazomycin, cyheptamide, cypemycin, cypenamine hydrochloride, cyprazepam, cyproheptadine hydrochloride, cyprolidol hydrochloride, cyproterone, cyproximide, cysteamine, cysteine ​​hydrochloride, cystine, cytarabine, cytarabine hydrochloride, cytarabine ocfosfate, cytochalasin B, cytolytic factor, cytostatin, dacarbazine, dacliximab, dactimicin, dactinomycin, daidzein,Daredalin tosilate, dalfopristin, dalteparin sodium, daltroban, dalvastatin, danaparoid, danazol, dantrolene, dapagliflozin, daphnodorin A, dapiprazole, dapitant, dapoxetine hydrochloride, dapsone, daptomycin, darglitazone sodium, darifenacin, dalrusin A, dalodipine, darsidomine, daunorubicin hydrochloride, dazadrol maleate, dazepinil hydrochloride, dazmegrel, dazopride fumarate, dazoxiben hydrochloride, debrisoquine sulfate, decitabine, deferiprone, deflazacort, dehydrocholic acid, dehydrodidemnin B, dehydo Droepiandrosterone, delapril, delapril hydrochloride, delavirdine mesylate, derequamin, delfaprazine, delmadinone acetate, delmopinol, delphinidin, demecarium bromide, demeclocycline, demecycline, demoxepam, denofungin, deoxypyridinoline, depakote, deprodon, deprostil, depsidomycin, deramciclane, dermatan sulfate, des Cyclovir, descinolone acetonide, desflurane, desipramine hydrochloride, desirudin, deslanoside, deslorelin, desmopressin, desogestrel, desonide, desoxymetasone, desoxoamiodarone, desoxycorticosterone acetate, detazimium tartrate, deterenol hydrochloride, detirelix acetate, devazepide, dexamethasone, dexamisole, dexbrompheniramine maleate, malate Dexchlorphenylamine leate, dexclamol hydrochloride, dexetimide, dexfenfluramine hydrochloride, dexphosphamide, deximaphene, dexivacaine, dexketoprofen, dexloxiglumide, dexmedetomidine, dexormaplatin, dexoxadrol hydrochloride, dexpanthenol, dexpemedrac, dexpropranolol hydrochloride, dexrazoxane, dexsotalol, dextrin 2-sulphate, dextroamphetamine, dextromethorphan, dextrorphan hydrochloride, dextrothyroxine sodium, dexverapamil,Dezaguanine, Dedinamide, Dezocine, Diacetolol Hydrochloride, Diamocine Cyclamate, Diapamide, Diatrizoate Meglumine, Diatrizoic Acid, Diaveridine, Diazepam, Diazicon, Diazoxide, Dibenzepin Hydrochloride, Dibenzothiophene, Dibucaine, Dichlorvos, Dichloralphenazone, Diclofenamide, Dicirenone, Diclofenac Sodium, Dicloxacillin, Diclanine, Dicoumarol, Dicyclomine Hydrochloride, Didanosine, Didemnin B, Didox, Dienestrol, Dienogest, Diethylcarbamazine Citrate, Diethylhomospermine, Diethylnorspermine, Diethylpropion Hydrochloride, Diethylstilbestrol, Diphenoximide Hydrochloride, , difenoxin, diflorasone acetate, difloxacin hydrochloride, difluanine hydrochloride, diflucortolone, diflumidone sodium, diflunisal, difluprednate, diphthalone, digitalis,

[0042] Digitoxin, digoxin, dihexyverine hydrochloride, dihydrexidine, dihydro-5-azacytidine, dihydrocodeine bitartrate, dihydroergotamine mesylate, dihydroestosterone, dihydrostreptomycin sulfate, dihydrotachysterol, dihydrotaxol, 9-, dilantin, dilevalol hydrochloride, diltiazem hydrochloride, dimephadan, dimefline hydrochloride, dimenhydrinate, dimercaprol, dimethadione, dimethindene maleate, dimethisterone, dimethyl prostaglandin Al, dimethyl sulfoxide, dimethylhomospermine, dimiracetam, dimoxamine hydrochloride, dinoprost, dinoprostone, dioxadrol hydrochloride, dioxamycin, diphenhydramine citrate, diphenidol, diphenoxylate hydrochloride, diphenylspiromustine spiromustine), Dipivefin Hydrochloride, Dipivefrin, Dipriencyprone, Ziprafenone, Dipropylnorspermine, Dipyridamole, Dipyrithione, Dipyrone, Dirithromycin, Discodermolide, Disobutamide, Disofenin, Disopyramide, Disoxalil, Disulfiram, Ditekiren, Divalproex Sodium, Dizocilpine Maleate, Dobutamine, Docarpamine, Docebenone, Docetaxel, Doconazole, Docosanol, Dofetilide, Dolasetron, Ebastine, Ebiratide, ebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecdisteron, echicetin, echistatin, ecothiopate iodide, eclanamine maleate, eclazolast, ecomustine, econazole, ecteinascidin 722, edaravone, edatrexate, edelfosine, edifolone acetate, edovacomab, edoxudine, edrecolomab, edrophonium chloride, edroxyprogesteone acetate, efegatran, eflornithine, efonidipine, egualcen, elantrine, elcatonin, elemene, eletriptan, ergodipine, eliprodil,Elsamitrucin, eltenae, elcaine, emalkalim, emedastine, emetine hydrochloride, emiglitate, emilium tosylate, emiteflu, emoctakin, empagliflozin, enadrine hydrochloride, enalapril, enalaprilat, enalkiren, enazadrem, ensiprate, endralazine mesylate, endrisone, enflurane, englitazone, enilconazole, enisoprost, enlimomab, enloplatin, enoferast, enolicum sodium, eno enoxacin, enoxacin, enoxaparin sodium, enoxaparin sodium, enoximone, enpiroline phosphate, enprofylline, enpromate, entacapone, enterostatin, enviraden, enviroxime, ephedrine, epicillin, epimestrol, epinephrine, epinephrylborate, epipropizine, epirizole, epirubicin, epitetracycline hydrochloride, epithiazide, epoetin alpha, epoetin beta, epoprostenol, epoprostenol sodium, epoxymexrenone, epristeride, Eprosartan, eptastigmine, equilenin, equilin, elbrozole, erdosteine, ergoloid mesylate, ergonovine maleate, ergotamine tartrate, ersentilide, ersofermin, erythritol, erythrityl tetranitrate, erythromycin, esmolol hydrochloride, esorubicin hydrochloride, esproquine hydrochloride, estazolam, estradiol, estramustine, estramustine analogs, estradiol hydrobromide, estriol, estroflate, estrogen agonists, estrogen antagonists, estrogen , conjugated estrogens, esterified estrone, estropipate, esprone, etafedrine hydrochloride, etanidazole, etanterol, etharotene, etazolate hydrochloride, eterovalve, etacidine, sodium ethacrynate, ethacrynic acid, ethambutol hydrochloride, etamivan, monoethanolamine oleate, ethchlorvynol, ether, ethinyl estradiol, ethiodized oil, ethionamide, ethambutan nitrate, ethopropazine hydrochloride, ethosuximide, ethotoin,Etoxazene hydrochloride, Ethibenztropine, Ethyl chloride, Ethyl dibunate, Ethylestrenol, Ethynodiol, Ethyndiol, Ethinerone, Ethynodiol acetate, Ethibendazole, Etidocaine, Etidronic acid disodium, Etidronic acid, Etiphenine, Ethintidine hydrochloride, Etizolam, Etodolac, Etofenamate, Etoformin hydrochloride, Etomidate, Etonogestrel, Etoperidone hydrochloride, Etoposide, Etoprine, Etoxadrol hydrochloride, Etozoline, Etrabamine (etrabamine), etretinate, etryptamine acetate, eucatropine hydrochloride, eugenol, euprosin hydrochloride, eveminomicin, examethazime, examorelin, exaprolol hydrochloride, exemestane, fadrozole, ferriefungin, famciclovir, famotidine, fampridine, fantofarone, fantridone hydrochloride, faropenem, fasidotril, fasudil, fazarabine, feni Dotodine, Felbamate, Felbinac, Felodipine, Felypressin, Fenamide, Fenamol, Fenbendazole, Fenbufen, Fencibutyrol, Fenclofenac, Fenclonine, Fenclorac, Fendosal, Fenestrel, Fenethylline hydrochloride, Fenfluramine hydrochloride, Fengabin, Fenimid, Fenisolex, Fenmethozole hydrochloride, Fenmetramide, Fenobam, Fenoctimine sulfate, Fenofibrate, Fenoldopam, Fenoprofen, Fenotero le, fenpiparone, fenprinast hydrochloride, fenprostalen, fenquizone, fenretinide, fenspiride, fentanyl citrate, fentiazac, fentichlor, fenticonazole, phenylipol hydrochloride, feprazinol, ferpifosate sodium, feristene, ferrixan, dry ferrous sulfate, ferumoxides, fermoxil, fetoxylate hydrochloride, fexofenadine, fezolamine fumarate, fiacitabine, fialuridine, fibrinogen 1 125, filgrastim, filipina, finasteride, flavodilol maleate, flavopiridol, flavoxiate hydrochloride, furazarone,Flecainidine, flerobuterol, fleroxacin, flesinoxan, flestrol sulfate, fletazepam, fleselastine, flobufen, floctafenine, flomoxef, flordipine, florfenicol, florifenin, fluosatidil, flosequinan, floxacillin, floxuridine, fluasterone, fluazacort, fluvanilate hydrochloride, flubendazole, flucindole, flucloronide, fluconazole, flucytosine, fludalanine, fludarabine phosphate, fludazonium chloride, fludeoxyglucose F 18, fludrocortisone acetate, flufenamic acid, flufenisal, flumazenil, flumecinol, flumequine, flumeridone, flumethasone, flumetramide, flumezapine, fluminorex, flumisole, flumoxonide, flunarizine, flunidazole, flunisolide, flunitrazepam, flunixin, fluocalcitriol, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorescein, fluorodaunorunicin hydrochloride, fluorodopa F 18, fluorometholone, fluorouracil, fluotracene hydrochloride, fluoxetine, fluoxymesterone, fluparoxane, fluperamide, fluperolone acetate, fluphenazine decanoate, flupirtine, fluprednisolone, fluproquazone, fluprostenol sodium, fluquazone, fluradrin hydrochloride, flurandrenolide, flurazepam hydrochloride, flurbiprofen, fluretofen, flurithromycin, flurocitabine, flurofamide, flurogestone acetate, flurothyl, fluoxetine, fluspiperone, fluspirilene, fluticasone propionate, flutrimazole, flutroline, fluvastatin, fluvastatin sodium, fluvoxamine, fludinamide, folic acid, follicle regulatory protein protein), Folliculostatin, Fomepizole, Dimethothazine mesylate, Folasartan, Forfenimex, Forfenirmex, Formestane, Formocortal,Formoterol, fosalilate, fosazepam, foscarnet sodium, fosfomycin, phosphonet sodium, fosinopril, fosinoprilat, fosphenyloin, foskidone, fostedil, fostriecin, fotemustine, fuchsin, alkaline, fumoxicillin, fungimycin, furaprofen, furazolidone, furazolium chloride, furegrelate sodium, flobufen, frodazole, furosemide, sodium fusidate, fusidic acid, gabapentin, gadobenate meglumine, gadobenic acid, gadobutrol, gadodiamide, gadolinium texaphyrin, gadopentetate dimeglumine, gadoteric acid, gadoteridol, gadoversetamide, galantamine, galdansetron, galdansetron hydrochloride, gallamine triethiodide, gallium nitrate, gallopamil, galocitabine , Gamfexine, Gamorenic acid, Ganciclovir, Ganirelix, Gelatinase inhibitors, Gemcadiol, Gemcitabine, Gemeprost, Gemfibrozil, Gentamicin sulfate, Gentian violet, Gepirone, Gestaclon, Gestodene, Gestonorone caproate, Gestrinone, Gevotroline hydrochloride, Gilisopam, Glaspimod, Glaucocalyxin A, Glemanserin, Gliamilide, Glibornuride, Glycetanyl sodium, Gliflumid, Glimepiride, Glipizide, Gloximonam, Glucagon, Glutapyrone, Glutathione inhibitors, Glutethimide, Glyburide, Glycopine, Glycopril, Glycopyrrolate, Glyhexamide, Glymidine sodium, Glyoctamide, Glyparamide, Gold Au 198, Gonadoctorinins, Gonadorelin, Gonadotropin, Goserelin, Gramicidin, Granisetron, Grepafloxacin, Griseofulvin, Guaiapart, Guaitirin, Guanabenz, Guanabenz acetate, Guanadrel sulfate, Guancidine, Guanethidine sulfate, Guanfacine hydrochloride, Guanisoquin sulfate, Guanochlor sulfate, Guanocine hydrochloride, Guanoxabenz, Guanoxane sulfate, Guanoxyfen sulfate, Gusperimus hydrochloride, Halazepam, Halcinonide, Halichondrin B, Halobetasol propionate,Halofantrine, halofantrine hydrochloride, halofenate, halofuginone hydrobromide, halomon, halopemide, haloperidol, halopredone, haloprogesterone, haloprogin, halothane, halkinol, hamycin, Han memopausal gonadotropins, hatomamicin, hatomalbegin A, hatomalbegin B,

[0043] Hatomarvigin C, Hatomarvigin D, Heparin sodium, Hepsulfam, Heregulin, Hetacillin, Heteronium bromide, Hexachlorophene: Hydrogen peroxide, Hexafluorenium bromide, Hexamethylene bisacetamide, Hexedine, Hexobendine, Hexoprenaline sulfate, Hexylresorcinol, Histamine phosphate, Histidine, Histoplasmin, Histrelin, Homatropine hydrobromide, Hoxidil hydrochloride, Human chorionic gonadotropin, Hycanthone, Hydralazine hydrochloride, Hydralazine polistirex, Hydrochlorothiazide, Tartaric acid Hydrocodone, Hydrocortisone, Hydroflumethiazide, Hydromorphone Hydrochloride, Hydroxyamphetamine Hydrobromide, Hydroxychloroquine Sulfate, Hydroxyphenamate, Hydroxyprogesterone Caproate, Hydroxycarbamide (Hydroxyurca), Hydroxyzine Hydrochloride, Hymecromone, Hyoscyamine, Hypericin, Ibafloxacin, Ibandronic Acid, Ibogaine, Ibopamine, Ibudilast, Ibufenac, Ibuprofen, Ibutilide Fumarate, Icatibant Acetate, Ichthammol, Icotidine, Idarubicin, I Doxifene, Idoxuridine, Idramanthone, Iemefloxacin, Iesopitron, Ifetroban, Ifosfamide, Ilepeimide, Irimaquinone, Ilmofosine, Ilomastat, Ilonidap, Iloperidone, Iloprost, Imafen hydrochloride, Imazodan hydrochloride, Imidapril, Imidazenil, Imidazoacridone, Imidecyl iodine, Imidocarb hydrochloride, Imidoline hydrochloride, Imidurea, Imiloxan hydrochloride, Imipenem, Imipramine hydrochloride, Imiquimod, immunostimulatory peptides, impromidine hydrochloride, indacrinone, indapamide, indecainide hydrochloride, indeloxazine hydrochloride, indigotine sulfate sodium, indinavir, indocyanine green, indolapril hydrochloride, indolidane, indomethacin, indomethacin sodium, indoprofen, indoramin, indorenate hydrochloride, indoxol, indoriline hydrochloride, inocoterone, inogatran, inolimomab, inositol niacinate, insulin, interferon, interleukin,Intrazol, Intriptyline hydrochloride, Iobenguane, Iobenzamic acid, Iobitridol, Iocalmate meglumine, Iocarmic acid, Iosetamic acid, Iodamide, Iodine, Iodipamide meglumine, Iodixanol, Iodoamiloride, Iodoantipyrine I 131, Iodocholesterol I 131, Iododoxorubicin, Sodium hippurate iodide I 131, Iodopyracet I 125, Iodoquinol, Iodoxamic acid meglumine, Iodoxamic acid (Iodoxamie Acid), Ioglic acid, Iofetamine hydrochloride I 123, Ioflatol, Yoglucol, Yoglucomide, Yoglucamic acid, Yoguramide, Iohexol, Iomeprol, Iometine I 125, Iopamidol, Iopanoic acid, Iopentol, Iofendilate, Ioprosemic acid, Iopromide, Iopronic acid, Iopidol, Iopidone, Iopyrol, Iosephamic acid, Ioselic acid, Iosulamide meglumine, Iosmetate, Iotasul, Iotetolic acid, Iothalamate sodium, Iothalamic acid, Iotriside, Iotrolan, Iotroxic acid, Iotyrosine I 131, Ioversol, Ioxagiate sodium Sodium), Ioxaglate Meglumine, Ioxaglic Acid, Ioxilan, Ioxotrizoic Acid, Ipadilide, Ipenoxazone, Ipidacrine, Ipodate Calcium, Ipomeanol, 4-, Ipratropium Bromide, Ipriflavone, Iprindole, Iprofenin, Ipronidazole, Iproplatin, Iproxamine Hydrochloride, Ipsapirone, Irbesartan, Irinotecan, Irloxacin, Ilopract, Irsogladine, Irtemazole, Isarsteine, Isamoxole, Isbos Grel, isepamicin, isobengazole, isobutamben, isocarboxazid, isoconazole, isoetharine, isofloxythepin, isoflupredone acetate, isoflurane, isoflurofate, isohomohalichondrin B, isoleucine, isomazole hydrochloride, isomylamine hydrochloride, isoniazid, isopropamide iodide, isopropyl alcohol, isopropyl unoprostone, isoproterenol hydrochloride, isosorbide, isosorbide mononitrate, isotikimide, isotretinoin,Isoxepac, Isoxicam, Isoxsuprine hydrochloride, Isradipine, Itamelin, Itasetron, Itazigrel, Itopride, Itraconazole, Ivermectin, Jasplakinolide, Josamycin, Kahalalide F, Calafungin, Kanamycin sulfate, Ketamine hydrochloride, Ketanserin, Ketazocine, Ketazolam, Ketoxal, Ketipramine fumarate, Ketoconazole, Ketoprofen, Ketorphanol, Ketorolac, Ketotifen fumarate, Kitasamycin, Labetalol hydrochloride, Lacidipine, Lactitol, Lactibicin, Laennec, Lafutidine, Lamellarin-N Triacetate, lamifiban, lamivudine, lamotrigine, lanoconazole, lanoxin, lanperisone, lanreotide, lansoprazole, latanoprost, lateritin, laurocapram, laurylisoquinolinium bromide, lavortidine succinate, lazabemide, recibidi, leinamycin, remildipine, leminoprazole, lenercept, renicincin, lenograstim, lenperone, lentin Naphthalene sulfate, leptin, leptolstatin, lercanidipine, lergotrile, lerisetron, letimide hydrochloride, letrazuril, letrozole, leucine, leucomycin, leuprolide acetate, leuprolide + estrogen + progesterone, leuprorelin, lebanfetamine succinate, levamisole, levdobutamine lactobionate, levcromakalim, levetiracetam, levecrocerin (Lev eycloserine), levobetaxolol, levobunolol, levobupivacaine, levocabastine, levocarnitine, levodopa, levodropropizine, levofloxacin, levofuraltadone, levoleucovorin calcium, levomethadyl acetate, levomethadyl acetate hydrochloride, levomoprolol, levonantradol hydrochloride, levonordefrin, levonorgestrel, levopropoxyphene napsylate, levopropylcillin potassium, levormeloxifene, levorphanol tartrate, levosimendan, levosulpiride, levothyroxine sodium, levoxadrol hydrochloride, lexipafant, lexithromycin, liarozole, libenzapril, ridamidine hydrochloride, lidocaine, lidofenine, lidoflazine, rifaridine, lifibrate, lifibrol, linarotene, lincomycin,Linear polyamine analogs, linoglilide, linopirdine, rinotroban, linsidomine, lysidotript, lintopride, liothyronine I 125, liothyronine sodium, liotrix, lirexapride, lisinopril, risoclinamide 7, lixazinone sulfate, lobaplatin, lobenzarit sodium, lobucavir, lodelaben, lodoxamide, lofemizole hydrochloride, lofentanyl oxalate, lofepramine hydrochloride, lofexidine hydrochloride, lombricine, lomefloxacin, lomerizine, lometraline hydrochloride, lometrexol, lomofungin, lornoxicam, lo Mustine, Lonapalene, Lonazolac, Lonidamine, Loperamide hydrochloride, Loracarbef, Lorazepam, Lorbamate, Lorcainide hydrochloride, Lorecrezol, Loreinadol, Lorglumide, Lormetazepam, Lornoxicam, Lortalamine, Lorzafone, Losartan, Rosigamone, Rosoxantrone, Rosurazine hydrochloride, Loteprednol, Lovastatin, Loviride, Loxapine, Loxoli Bin, lubelozole, lucantone hydrochloride, lufironil, lurosetron mesylate, lurtotecan, luteinizing hormone, lurasidone, lutetium, lutrelin acetate, luzindole, sodium liaporate, lysetamine, lyzicamycin, lyzimycin, lynestrenol, lypressin, lysine, lysofylline, lysostaphin, lytic peptide, maduramicin, mafenide, magainin 2 amide, magnesium salicylate, magnesium sulfate, magnolol, maytansine , Maretamel, Malotochromene, Malotojaponin, Malotilate, Malotilate, Mangafodipir, Manidipine, Maniwamycin A, Mannitol, Mannostatin A, Manumycin E, Manumycin F, Mapinastine, Maprotiline, Marimastat, Martek 8708, Martek 92211, Masoprocol, Maspin, Massetride, Matrilysin Inhibitors, Maytansine, Mazapertine Succiniate, Mazindol, Mebendazole, Mebeverine Hydrochloride, Mebrofenin, Mebutamate, Mecamylamine Hydrochloride, Mechlorethamine Hydrochloride, Meclocycline, Sodium Meclofenamate,Meclocalone, Meclorisone dibutyrate, Medazepam hydrochloride, Medrinone, Medrogestone, Medroxalol, Medroxyprogesterone, Medrysone, Meelizine hydrochloride Hydrochloride), Mefenamic acid, Mefenidyl, Mefenorex hydrochloride, Mefexamide, Mefloquine hydrochloride, Mefruside, Megalomycin potassium phosphate, Megestrol acetate, Meglumine, Meglutol, Melengestrol acetate, Melitracen hydrochloride, Melphalan, Memotin hydrochloride, Menabitan hydrochloride, Menoctone, Menogaril, Menotropin, Meobentine sulfate, Mepartricin, Mepenzolate bromide, Meperidine hydrochloride, Mephentermine sulfate, Mephenyloin, Mephobarbital, Mepivacaine hydrochloride, Meprobamate, Meptazinol hydrochloride, Mequidox, Melalain sodium, Melbarone, Mercaptopurine, Merck phenol chloride, Mercury, Ammoniated, Melissoprol Hg 197, meropenem, mesalamine, meseclazone, mesoridazine, mesterolone, mestranol, mesprine hydrochloride, methalol hydrochloride, metaproterenol polistirex, metaraminol bitartrate, metaxalone, metheneprost, meterelin, metformin, methacholine chloride, methacycline, methadone hydrochloride, methadyl acetate, methathiazide, methamphetamine hydrochloride, methaqualone, methazolamide, methdilazine, methenamine, methenolone acetate, methetoin, methicillin sodium, methimazole, methioninase, methionine, methisazone, methixene hydrochloride Salt, Methocarbamol, Methohexital Sodium, Metofoline, Methotrexate, Methotrimeprazine, Methoxatone, Methoxyflurane, Methsuximide, Methyclothiazide, Methyl Palmoxirate, Methyl Atropine Nitrate, Methylbenzethonium Chloride, Methyldopa, Methyldopato Hydrochloride, Methylene Blue, Methylergometrine Maleate, Methylhistamine, R-alpha, Methylinosine Monophosphate, Methylphenidate Hydrochloride, Methylprednisolone, Methyltestosterone, Methynodiol Diacelate, Methysergide, Methysergide Maleate, Methiamide,Methiapine, Methioprim, Methipamide, Metipranolol, Metizoline Hydrochloride, Metokefamide Acetate, Metoclopramide, Metocrine Iodide, Metogest, Metolazone, Metopimazine, Metoprine, Metoprolol, Metoxidine, Metrifonate, Metrizamide, Sodium Metrizoate, Metronidazole, Meturedepa, Metyrapone, Metyrosine, Mexiletine Hydrochloride, Potassium Mexilenoate, Mezlocillin, Mfonelic Acid, Mianserin Hydrochloride, Mibefradil, Mibefradil Dihydrochloride, Mibolerone, Mikelamine B, Miconazole, Mycorrhizal A, Midaflur, Midazolam Hydrochloride, Midodrine, , mifepristone, mihobato, miglitol, milacemide, miramelin, mildronate, miremperone, miripertin, milnacipran, milrinone, miltefosine, minban hydrochloride, minaprine, minaxolone, minocromil, minocycline, minoxidil, miofurazine hydrochloride, miokamycin, mipragoside, mirfentanil, mirimostim, mirincamycin hydrochloride, myrisetron maleate, mirtazapine, mismatched double-stranded RNA, misonidazole, misoprostol, mitindomide, mitocalcin, mitochromine, mitodilline, mitoguazone, mitolactol, mitomarcine, mitomycin, mitonafide, mitosper, mitotane, mitoxantrone, mivacurium chloride, mivazerol, mixanpril, mixidine, Mizolastine, mizoribine, moclobemide, modafinil, modalin sulfate, modecainide, moexipril, mofalotene, mofegiline hydrochloride, mofezolac, molgramostim, molinazon, molindone hydrochloride, molsidomine, mometasone, monatepir maleate, monensin, monoctanoin, montelukast sodium, montirelin, mopidamol, moracidine, morantel tartrate, moricizine, morniflumate, morphine sulfate, sodium morrhuate, mosapramine, mosapride, motilide, motretinide, moxalactam disodium, moxazosin, moxilaprine, moxnidazole, moxonidine, mumps skin test antigen, mustard anticancer agent, muzolimine, mycaperoxide B, mycophenolic acid, myriapolone, nabazenil, nabilone,

[0044] Nabitan hydrochloride, naboctate hydrochloride, nabumetone, N-acetylglutamate, nadifloxacin, nadolol, nadroparin calcium, nafadotride, nafamostat, nafarelin, nafcillin sodium, nafenopin, nafimidone hydrochloride, naflocculate, nafomine malate, nafoxidine hydrochloride, nafronyl oxalate, naftifine hydrochloride, naftopidil, naglivan, nagressip, nalbuphine hydrochloride, naldemedine, nalidixic acid sodium, nalmefene , Nalmexone hydrochloride, Naloxone + Pentazocine, Naltrexone, Nalmexilate, Nandrolone Phenpropionate, Nantradol hydrochloride, Napactadine hydrochloride, Napadisilate, Napamezole hydrochloride, Napaviin, Naphazoline hydrochloride, Naphterpin, Naproxen, Naproxol, Napsagatran, Naranol hydrochloride, Narasin, Naratriptan, Nartograstim, Nasaruplase, Natamycin, Nateplase, Naxagolide hydrochloride, Nebivolol, Nebramycin , Nedaplatin, Nedocromil, Nefazodone Hydrochloride, Neflumozide Hydrochloride, Nefopam Hydrochloride, Nelezaprine Maleate, Nemazoline Hydrochloride, Nemorubicin, Neomycin Palmitate, Neostigmine Bromide, Neridronic Acid, Netilmicin Sulfate, Neutral Endopeptidase, Neuthramycin, Nevirapine, Nexerizine Hydrochloride, Niacin, Nibroxan, Nicardipine Hydrochloride, Nicergoline, Niclosamide, Nicorandil, Nicotinyl Alcohol, Nifedipine, Nifilmelon merone), Nifluridide, Nifuradene, Nifuraldeson, Nifuratel, Nifuratron, Nifludazil, Nifrimide, Nifurpirinol, Nifluquinazole, Nifurthiazole, Nilutamide, Nilvadipine, Nimazone, Nimodipine, Niperotidine, Niravoline, Niridazole, Nisamycin, Nisbuterol mesylate, Nisin, Nisobate, Nisoldipine, Nisoxetine, Nisterime acetate, Nitalsone, Niltazoxamide, Nitecapone, Nitrafudam hydrochloride, Nitralamine hydrochloride, Nitramisole hydrochloride, Nitrazepam,Nitrendipine, nitrocycline, nitrodan, nitrofurantoin, nitrofurazone, nitroglycerin, nitromersol, nitromide, nitromiphene citrate, nitrogen dioxide, nitroxide antioxidants, nitrulline, nivazol, nibimedone sodium, nizatidine, noberastine, nocodazole, nogalamycin, norinium bromide, nomifensine maleate, noracimethadol hydrochloride, norbolethone, norepinephrine bitartrate, noresindrone, norethynodrel, norfloxacin, norflurane, norgestimate, norgestomycin , norgestrel, nortriptyline hydrochloride, noscapine, novobiocin sodium, N-substituted benzamides, nufenoxol, nilestriol, nystatin, O6-benzylguanine, obidoxime chloride, ocaperidone, ocfentanyl hydrochloride, ocinapron, octanoic acid, octazamide, octenidine hydrochloride, octodrine, octreotide, octriptyline phosphate, ofloxacin, ofloxacin, oxenone, olanzapine, oligonucleotides, olopatadine, olprinone, olsalazine, ol Salazine sodium, Orvanil, Omeprazole, Onapristone, Ondansetron, Ontazolast, Oocyte maturation inhibitors, Opipramol hydrochloride, Oracin, Orconazole nitrate, Orgotane, Orlistat, Ormaplatin, Ormetoprim, Ornidazole, Orpanoxin, Orphenadrine citrate, Osateron, Otenzepad, Oxacillin sodium, Oxagrelate, Oxaliplatin, Oxamarin hydrochloride, Oxamisole, Oxamniquine, Oxandrolone, Oxanter pamoate, Oxanter pamoate, Saprotilin hydrochloride, oxaprozin, oxalbazole, oxatomide, oxaunomycin, oxazepam, oxcarbazepine, oxendrone, oxethazaine, oxetrone fumarate, oxfendazole, oxfenicin, oxybendazole, oxiconazole, oxidopamine, oxidronic acid, oxyfungin hydrochloride, oxilorfan, oximonam, oximonam sodium, oxyperomide, oxiracetam, oxiramide, oxisuran, oxmetidine hydrochloride, oxodipine, oxogestone phenpropionate,Oxolinic acid, Oxprenolol hydrochloride, Oxtriphylline, Oxybutynin chloride, Oxychlorosene, Oxycodone, Oxymetazoline hydrochloride, Oxymetholone, Oxymorphone hydrochloride, Oxypertine, Oxyphenbutazone, Oxypurinol, Oxytetracycline, Oxytocin, Ozagrel, Ozolinone, Paclitaxel, Palauamine, Paldimycin, Parinavir, Palmitoyl rhizoxine, Sodium palmoxirate Sodium), Pamaqueside, Pamatorol Sulfate, Pamicogrel, Pamidronate Disodium, Pamidronic Acid, Panadiprone, Panamesin, Panaxytriol, Pancopride, Pancuronium Bromide, Panipenem, Pannoline, Panomifen, Pantethine, Pantoprazole, Papaverine Hydrochloride, Parabactin, Parachlorophenol, Paraaldehyde, Paramethasone Acetate, Paraniline Hydrochloride, Parabenzolate Bromide, Pararosaniline Pamoate Pamoate, Parbendazole, Parconazole Hydrochloride, Paregoric, Pareptide Sulfate, Pargyline Hydrochloride, Parnaparin Sodium, Paromomycin Sulfate, Paroxetine, Parthenolide, Partricin, Paulomycin, Pazeliptin, Padinaclone, Pazoxide, Pazufloxacin, Pefloxacin, Pegaspargase, Pegorgotein, Pelanserin Hydrochloride, Perdecine, Periomycin, Pelretin, Perrinone Hydrochloride, Pemedolac, Pemelide Nitrate, Pemirolast, Pemoline, Pe Namecillin, Penbutolol sulfate, Penciclovir, Penfluridol, Penicillin G benzathine, Penicillin G potassium, Penicillin G procaine, Penicillin G sodium, Penicillin V, Penicillin V benzathine, Penicillin V hydrabamine, Penicillin V potassium, Pentabamate, Pentaerythritol tetranitrate, Pentafuside, Pentamidine, Pentamorphone, Pentamustine, Pentapiperium methylsulfate, Pentazocine, Pentetic acid, Pentiapine maleate, Pentigetide, Pentisomicin,Pentizidone sodium, pentobarbital, pentomone, pentopril, pentosan, pentostatin, pentoxifylline, pentrinitrol, pentrozole, peplomycin sulfate, pepstatin, perflubron, perfofamide, perfosfamide, pergolide, perhexiline maleate, perillyl alcohol, perindopril, perindoprilat, perlapine, permethrin, perospirone, perphenazine, phenacemide, phenarizine, phenazinomycin, phenazinamide ... Zopyridine hydrochloride, phenylbutazone sodium glycerate, phencarbamide, phencyclidine hydrochloride, phendimetrazine tartrate, phenelzine sulfate, phenmetrazine hydrochloride, phenobarbital, phenoxybenzamine hydrochloride, phenprocoumon, phenserine, phensuccinal, phensuccimide, phentermine, phentermine hydrochloride, phentolamine mesylate, pentoxifylline, phenyl aminosalicylate, phenyl acetate, phenylalanine, phenylalanyl ketoconazole, phenyl Lobutazone, Phenylephrine hydrochloride, Phenylpropanolamine hydrochloride, Phenylpropanolamine polistirex, Phenylamidol hydrochloride, Phenyloin, Phosphatase inhibitors, Physostigmine, Picenadol, Picibanil, Picrotrine diolamine, Picroliv, Picmeterol, Pidotimod, Pifamine, Pilocarpine, Pilsicainide, Pimagedine, Pimetine hydrochloride, Pimilprost, Pimobendan, Pimozide, Pinacidil, Pinadrine, Pindolol, Pinenol ), pinocembrine, pinoxepin hydrochloride, pioglitazone, pipamperon, pipazetate, pipecuronium bromide, piperacetazine, piperacillin sodium, piperamide maleate, piperazine, pipobroman, piposulfan, pipotiazine palmitate, pipoxolan hydrochloride, piprozolin, piquindone hydrochloride, piquidil hydrochloride, piracetam, pirandamine hydrochloride, pirarubicin, pirazmonam sodium, pirarzolac, pirbenicillin sodium, pirbuterol acetate, pirenperon,Pirenzepine hydrochloride, piretamide, pirfenidone, pyridicillin sodium, piridronate sodium, piriprost, piritrexim, pirrimycin hydrochloride, pirlindole, pirmagrel, pirmenol hydrochloride, pirnabine, piroctone, pirodavir, pirodomast, pirogliride tartrate, pirrolate, pirrolazamide, piroxantrone hydrochloride, piroxicam, piroximone, pirprofen, pirquinozole, pirsidomine, prenylamine, picuitary ( Pituitary, Posterior, Pivampicillin Hydrochloride, Pivopril, Pizotyline, Prasetin A, Platinum Compounds, Platinum Triamine Complexes, Plicamycin, Promestane, Povilcastor Edamine, Podofilox, Poison Ivy Extract, Polzine Methyl Sulfate, Polyglusam, Polygnate Sodium, Polymyxin B Sulfate, Polythiazide, Ponalrestat, Porfimer Sodium, Porfiromycin, Potassium Chloride, Potassium Iodide , potassium permanganate, povidone-iodine, practolol, pralidoxime chloride, pramiracetam hydrochloride, pramoxine hydrochloride, pronolium hydrochloride, pravadrine maleate, pravastatin (pravachol), prazepam, prazosin, prazosin hydrochloride, prednazate, prednicarbate, prednimustine, prednisolone, prednisone, prednival, pregnenolone succinate, prenalterol hydrochloride, pridefine hydrochloride, priferon, prilocaine hydrochloride, prolosec, Primaquine phosphate, Primidrol, Primidone, Prinivil, Prinomide tromethamine, Prinoxodan, Pridigilol hydrochloride, Proadifen hydrochloride, Probenecid, Probicromil calcium, Probucol, Procainamide hydrochloride, Procaine hydrochloride, Procarbazine hydrochloride, Procaterol hydrochloride, Prochlorperazine, Procinonide, Proclonol, Procyclidine hydrochloride, Prodilidine hydrochloride, Prodol acid, Profadol hydrochloride, Progabide, Progesterone, Proglumide, Proinsulin human,Proline, Prolintan hydrochloride, Promazine hydrochloride, Promethazine hydrochloride, Propafenone hydrochloride, Propagermanium, Propanidid, Propantheline bromide, Proparacaine hydrochloride, Propatyl nitrate, Propentofylline, Propenzolate hydrochloride, Propicacin, Propiomazine, Propionic acid, Propionylcarnitine, L-propiram, Propiram + paracetamol, Propiverine, Propofol, Propoxycaine hydrochloride, Propoxyphene hydrochloride, Propranolol hydrochloride, Proprusside, Propylbis-acridone, Propylhexedrine, Propyridone, Propylthiouracil, Proquasone, Prorenoate potassium, Proloxane hydrochloride, Proscillaridine,

[0045] Prostratin, Protamine sulfate, Protegrin, Protirelin, Protofloxacin, Protriptyline hydrochloride, Proxazole, Proxazole citrate, Proxicromil, Proxilphan tartrate, Prulifloxacin, Pseudoephedrine hydrochloride, Puromycin, Purpurin, Pyrabrom, Pyrantel pamoate, Pyrazinamide, Pyrazofurine, Pyrazoloacridine, Pyridostigmine bromide, Pyrilamine maleate, Pyrimethamine, Pyrinoline, Sodium pyrithione, Zinc pyrithione, Pyrovalerone hydrochloride, Pyroxamine maleate, Pyrrocaine, Pyrrolifene hydrochloride, Pyrrolnitrin, Pyrvinium pamoate, Quadazosine mesylate, Quazepam, Quazinone, Quazodine, Quazolast, Quetiapine, Quiflapon, Quinagolide, Quina Ludin blue, Quinapril, Quinaprilat, Quinazosine hydrochloride, Quinborone, Quinctolate, Quindecamine acetate, Quindonium bromide, Quinelorane hydrochloride, Quinestrol, Quinfamide, Quingestanol acetate, Quingestrone, Quinidine gluconate, Quinielorane hydrochloride, Quinine sulfate, Quinpirole hydrochloride, Quinterenol sulfate, Quinucurium bromide, Quinupristin, Quipazine maleate, Rabeprazole sodium, Racephenicol, Racepinephrine, RAF antagonists, Rafoxamide, Ralitrine, Raloxifene, Raltitrexed, Ramatroban, Ramipril, Ramoplanin, Ramosetron, Ranelic acid, Ranimycin, Ranitidine, Ranolazine, Rauwolfia Serpentina), recainam, recainam hydrochloride, reclazepam, regavirumab, regramostim, relaxin, reromycin, remacemide hydrochloride, remifentanil hydrochloride, remiprostol, remoxipride, repirinast, repromicin, reproterol hydrochloride, reserpine, resiniferatoxin, resorcinol, demethylated reteriptin, reticulon, reviparin sodium, revidinone, rhenium Re186 etidronate, rhizoxin, ribaminol, ribavirin, ribopurin, ribozyme, ricasetron,Ridogrel, Rifabutin, Rifametane, Rifamexyl, Rifamide, Rifampin, Rifapentine, Rifaximin, RII retinamide, Rilopirox, Riluzole, Rimantadine, Rimcazole hydrochloride, Rimexolone, Rimiterol hydrobromide, Rimoprogin, Riodipine, Rioprostil, Lipazepam, Lipisartan, Risedronate sodium, Risedronic acid, Risocaine, Risotilide hydrochloride, Rispenzepine, Risperdal, Risperidone, Ritanserin, Ritzpen , Ritodrine, Litorkast, Ritonavir, Rizatriptan benzoate, Locastin hydrochloride, Rocuronium bromide, Rodocaine, Loflurane, Rogletimide, Rohitukine, Rokitamycin, Roletamicide, Lorgamidin, Rolicyprine, Rolipram, Rolitetracycline, Rorogine, Romazarit, Romurtide, Ronidazole, Ropinirole, Ropitone hydrochloride, Ropivacaine, Ropidine, Roquinimex, Rosaramycin, Rosiglitazone, Rosoxacin , Rotoxamine, Roxatidine, Roxarsone, Roxindol, Roxithromycin, Rubiginone B1, Ruboxyl, Rufloxacin, Rupatadine, Rutamycin, Ruzadran, Sabelzole, Safingol, Safilonil, Saintopine, Salbutamol, R-Sarcorex, Saletamide Maleate, Salicyl Alcohol, Salicylamide, Meglumine Salicylate, Salicylic Acid, Salmeterol, Salnacediin, Salsalate, Sameridin, Sampatrilat, Sansa Icrin, Sanfetrinem, Sanguinarium chloride, Saperconazole, Saprisartan, Sapropterin, Saquinavir, Sarafloxacin hydrochloride, Saralasin acetate, SarCNU, Sarcophytol A, Sargramostim, Salmoxicillin, Salpicillin, Sarpogrelate, Saruplase, Saterinone, Satigrel, Satumomab pendetide, Schick test control, Scopafungin, Scopolamine hydrobromide, Scrazaipine hydrochloride, Sdi 1 mimetics, Secalciferol, Secobarbital, Sealzone, Seglitide acetate, Selegiline hydrochloride, Selenium sulfide, Selenomethionine Se 75,Serhotel, sematilide, senduramycin, semothiazil, semustine, sense oligonucleotide, sepazonium chloride, ceperidol hydrochloride, seprirose, seproxetine hydrochloride, seractide acetate, sergolexol maleate, serine, sermetacin, sermorelin acetate, sertaconazole, sertindole, sertraline, setiptiline, setoperone, sevirumab, sevoflurane, sezolamide, sibopirdine, sibutramine hydrochloride, signal transduction inhibitors, silandrone, silipid, silteplase, silver nitrate, simendan, simtrazene, simvastatin, sincalide, sinefungin, cintrodil, sinnabidol, sipatridine, sirolimus, sisomicin, cytoglucide, sizofiran, sobuzoxane, sodium amylosulfate, sodium iodide I 123, sodium nitroprusside, sodium oxybate, sodium phenylacetate, sodium salicylate, sorberol, solipertine tartrate, somarapol, somantadine hydrochloride, somatomedin B, somatomedin C, somatrem, somatropin, somenopol, somidobub, sonermin, sorbinil, sorivudine, sotalol, soterenol hydrochloride, sparfloxacin, sparphosate sodium, sparfosic acid, sparsomycin, sparteine ​​sulfate, spectinomycin hydrochloride, spicamycin D, spiperone, spiradoline mesylate, spiramycin, spirapril hydrochloride, spiraprilat, spirogermanium hydrochloride, spiromustine, spironolactone, spiroplatin , spiroxazone, splenopentin, spongistatin 1, sprodiamide, squalamine, stannous pyrophosphate, stannous sulfur colloid, stanozolol, statolone, staurosporine, stavudine, stefimycin, stenbolone acetate, stepronin, stilbazium iodide, stilonium iodide, stipiamide, stiripentol, stobadine, streptomycin sulfate, streptonicozide, streptonigrin, streptozocin, stromelysin inhibitor, strontium chloride Sr89, succinum, succimer, succinylcholine chloride, sucralfate, sucralfate potassium, sudoxicam, sufentanil, sufotidine,Sulazepam, sulbactam pivoxil, sulconazole nitrate, sulfabenz, sulfabenzamide, sulfacetamide, sulfacytine, sulfadiazine, sulfadoxine, sulfalene, sulfamerazine, sulfamethazine, sulfamethoxazole, sulfamethoxazole, sulfamonomethoxine, sulfamoxole, zinc sulfanilate, sulfanitran, sulfasalazine, sulfasomizole, sulfazameth, sulfinalol hydrochloride, sulfinosine, sulfinpyrazone, sulfisoxazol. , sulfomixin, sulfonterol hydrochloride, sulfoxamine, Sulinldac, Sulmarin, Sulnidazole, Suloctidil, Sulofenur, Sulopenem, Suloxiphene oxalate, Sulpiride, Sulprostone, Sultamicillin, Sulthiame, Sultopride, Sulkast, Sumarotene, Sumatriptan, Sulpirin sodium, Suproclon, Suprofen, Sladista, Suramin, Sulfomer, Sulcainide maleate, Slitozole, Slonacrine maleate, Suxemeride sulfate, Swainsonine, Simakalim ( symakalim, symclosene, symmetine hydrochloride, synthetic glycosaminoglycan, taciamine hydrochloride, tacrine hydrochloride, tacrolimus, talampicillin hydrochloride, taleranol, tallysomycin, talimustine, talmetacin, luniflumate, talopram hydrochloride, talosalate, tametraline hydrochloride, tamoxifen, tampramine fumarate, tamsulosin hydrochloride, tandamycin hydrochloride, tandospirone, tapgen, taprosten, tasosartan, tauromustine, taxane, taxoid, tazadren succinate acid salt, tazanolast, tazarotene, tazifillin hydrochloride, tazobactam, tazoferon, tazolol hydrochloride, tebuferon, tebukin, technetium Tc99m bicisate, teclozan, tecogalan sodium, teceleukin (Teecleukin), teflurane, tegafur, tegretol, teicoplanin, telenzepine, terlapyrylium, telmesteine, telmisartan, telomerase inhibitors, teloxantrone hydrochloride, terdipine hydrochloride, temafloxacin hydrochloride, tematropium methylsulfate, temazepam, temelastine, temocapril,Temocillin, temoporfin, temozolomide, tenidap, teniposide, tenosal, tenoxicam, tepirindole, tepoxalin, teprotide, terazosin, terbinafine, terbutaline sulfate, terconazole, terfenadine, terflavoxate, terguride, teriparatide acetate, terlaquiline, terlipressin, terodiline, teroxalen hydrochloride, teroxylone, tertatolol, tesicam, tesimide, testolactone, testosterone, tetracaine, tetrachlorodecaoxide, tetracycline, tetrahydrozoline hydrochloride, tetramisole hydrochloride, tetrazolast meglumine, tetrazomine, tetrofuosmin, tetroquinone, tetroxop rim, tetridamine, thaliblastine, thalidomide, theofibrate, theophylline, thiabendazole, thiamiprine, thiamphenicol, thiamylal, thiazesim hydrochloride, thiazinamium chloride, thiethylperazine, thimelfonate sodium, thimerosal, thiocoraline, thiofedrine, thioguanine, thiomarinol, thiopental sodium, thioperamide, thioridazine, thiotepa, thiothixene, thifenamil hydrochloride, thifensillin potassium, thiram, thozalinone, threonine, thrombin, thrombopoietin, thrombopoietin mimetics, thymalfasin, thymopoietin receptor agonists, thymotrin, thyromedan hydrochloride, thyroxine 1 125, thyroxine 1 131, Thiacrylast, Thiacrylast sodium, Tiagabine, Tiamenidine, Tianeptine, Tiapafant, Tiapamil hydrochloride, Tiaramide hydrochloride, Tiazofurin, Tibenelast sodium, Tibolone, Tibullic acid, Ticabesone propionate, Ticarbodine, Ticarcillin clesyl sodium, Ticlaton, Ticlopidine, Ticrynafen, Tienoxolol, Tifurac sodium, Tigemonam dicholine, Tigestol, Tiletamine hydrochloride, Tilidine hydrochloride, Tilisolol, Tirnoprofen albamel, Tilorone hydrochloride, Tiludronic acid disodium, Tiludronic acid, Timefurone, Timobezone acetate, Timolol, Ethyl etiopurinse, Tinabinol, Timidazole, Tinzaparin sodium, Tioconazole, Tiodazocin, Thiodonium chloride, Thioperidone hydrochloride, Tiopinac, Thiospirone hydrochloride,Tiotidine, tiotropium bromide, tioxidazole, tipentosin hydrochloride, tipredan, tiprenol hydrochloride, tiplinast meglumine, tipropidil hydrochloride, tiqueside, tiquinamide hydrochloride, tilandalidigine, tirapazamine, tirilazad, tirofiban, tiropramide, titanocene dichloride, tixanox, tixocortol pivalate, tizanidine hydrochloride, tobramycin, tocainide, tocamfil, tofenacin hydrochloride, tolamolol, tolazamide, tolazoline hydrochloride, tolbutamide, tolcapone, tolciclate, tolfamide, tolgabide, lamotrigine, tolumidone, trindate (, Tolindate), tolmetin, tolnaftate, tolpovidone 1 131, tolpiramide, tolrestat, tomerkast, tomoxetine hydrochloride, tonazosine mesylate, topiramate, topotecan, topotecan hydrochloride, topsentin, topterone, toxidine, torasemide, toremifene, torsemide, tosifen, tosufloxacin, totipotent stem cell factor, tracazolate, trafermin, tralonide, tramadol hydrochloride, tramazoline hydrochloride, trandolapril, tranexamic acid, tranilast, transcainide, translation inhibitors, traxanox, trazodone hydrochloride, trazodone-HCL, trebenzomine hydrochloride, trefentanil hydrochloride, toleroxinate, trepipam maleate, trestron acetate, tretinoin, triacetin, triacetyluridine, triafungin, triamcinolone, triampidine sulfate, triamidine Muterene, triazolam, tribenoside, tricaprylin, tricetamide, trichlormethiazide, trichohyalin, triciribine, tricitrate, triclofenol piperazine, triclofos sodium, triclonide, trientine, triphenagrel, triflavin, triflosine, triflubazam, triflumidate, trifluoperazine hydrochloride, trifluperidol, trifluoperazine, triflupromazine hydrochloride, trifluridine, trihexyphenidyl hydrochloride, trilostane, trimazosin hydrochloride, trimegestone, trimeprazine tartrate, trimethadione, trimethaphan camsylate, trimethobenzamide hydrochloride, trimethoprim, trimetozine, trimetrexate, trimipramine, trimoprostil, trimoxamine hydrochloride, triolein 1 125, Triolein 1 131, Trioxyphene mesylate, Tripamide, Tripelennamine hydrochloride,

[0046] Triprolidine hydrochloride, triptorelin, trisulfapyrimidine, troclosen potassium, troglitazone, trolamine, troleandomycin, thrombodipine, trometamol, tropanserine hydrochloride, tropicamide, tropine ester, tropisetron, trospectomycin, trovafloxacin, trovirdine, tryptophan, tuberculin, tubocurarine chloride, tuborzole hydrochloride, tucarcsol, tulobuterol, turosteride, thibamate, thyroxine, thyroxine sodium sodium, tyrosine, tyrothricin, tyrphostin, ubenimex, urdazepam, undecylenic acid, uracil mustard, urapidil, urea, uredepa, uridine triphosphate, urofollitropin, urokinase, ursodiol, valacyclovir, valine, valnoctamide, sodium valproate, valproic acid, valsartan, vamicamide, vanadeine, vancomycin, vaninolol, bapiprost hydrochloride, vapreotide, valiolin B, vasopressin, vecuronium bromide, veraresol, val Nacrine maleate, venlafaxine, veradrine hydrochloride, veramine, verapamil hydrochloride, verudine, berilopam hydrochloride, verlukast, verofylline, veloxan, verteporfin, vesnarinone, bexivinol, vidarabine, vigabatrin, viloxazine hydrochloride, vinblastine sulfate, vinbrunin citrate, vincophos, vinconate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglicin sulfate, vinoleucine sulfate, vinorelbine, vinpocetine, vinblastine sulfate ... Nthoperol, Vinxartin, Vinzolidine Sulfate, Biprostol, Virginiamycin, Viridofulvin, Viloxime, Vitaxin, Borazosine, Voriconazole, Vorozole, Voxergolide, Warfarin Sodium, Xamoterol, Xanomeline, Xanoxate Sodium, Xanthinol Niacinate, Zemilofiban, Xenaripine, Xenbucin, Xylobam, Xymoprofen, Xipamide, Zolphanol Mesylate, Xylamidine TosylateTosylate), xylazine hydrochloride, xylometazoline hydrochloride, xylose, yangambin, zavicipril, zacopride, zafirlukast, zalcitabine, zaleplon, zalospirone, zarutidine hydrochloride, zaltoprofen, zanamivir, zankiren, zanoteron, zantac, zarirlukast, zatebradine, zatosetron, zatosetron maleate, zenarestat, zenazosin mesylate, zeniplatin, zeranol, zidometacin, zidovudine, diflosilone, dilantel, zilascob, z Lawton, Zimeldine hydrochloride, Zinc undecylenate, Zindotrin, Dinoconazole hydrochloride, Zinostatin, Zinterol hydrochloride, Zinviroxime, Ziprasidone, Zovolt, Zofenopril calcium, Zofenoprilat, Zolamine hydrochloride, Zolazepam hydrochloride, Zoledronic acid, Zolertine hydrochloride, Zolmitriptan, Zolpidem, Zomepirac sodium, Zometapine, Zoniclezole hydrochloride, Zonisamide, Zopiclone, Zopolrestat, Zorbamyciin, Zorubicin hydrochloride, Zotepine, Zucapsaicin.

[0047] Additional pharma- ceutically active agents acceptable for use herein include those disclosed in U.S. Pat. Nos. 9,745,300, 9,708,322, 7,183,282, 7,071,186, 6,552,017, 8,648,077, 8,598,119, 9,751,883, 9,371,324, 9,315,504, 9,428,506, 8,993,572, 8,309,722, 6,713,471, 8,779,139, Nos. 9168258, RE039680E1, 9616061, 9586960, and U.S. Patent Application Publication Nos. 2017114037, 2017183350, 2015072964, 2004034015, 2017189398, 2016310502, and 2015080404, the contents of which are incorporated herein by reference in their entireties.

[0048] Further examples of antidiabetic active agents 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 29311 Na, FK 614, BMS 298585, R 483, TAK 559, DRF 2725 (ragaglitazar), L-686398, L-168049, L-805645, L-054852, demethylasteriquinone B1 (L-783281), L-363586, KRP-297, P32 / 98, CRE-16336, and EML-16257.

[0049] Erectile dysfunction treatment agents useful herein include, but are not limited to, agents for promoting blood flow to the penis and agents for effecting autonomic activity, such as increasing parasympathetic (cholinergic) activity and decreasing sympathetic (adrenergic) activity. Useful active agents for treating erectile dysfunction include, but are not limited to, alprostadil, tadalafil, vardenafil, apomorphine, yohimbine hydrochloride, sildenafil citrate, and any combination thereof. In some embodiments, the active agent is tadalafil. Active agents or drugs for the treatment of headaches and / or migraines can also be used herein. Examples of specific active agents include, but are not limited to, triptans such as eletriptan, naratriptan, rizatriptan (rizatriptan benzoate), sumatriptan, and zolmitriptan. In some embodiments, the active agent is rizatriptan, optionally in combination with an NSAID.

[0050] In certain embodiments, the active agent can be clobazam, diazepam, tadalafil, riluzole, buprenorphine, naloxone, or a combination of buprenorphine and naloxone. The active agent may be diazepam. When the active agent is diazepam, each individual unit dose may contain 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 contains about 5 mg, about 10 mg, or about 15 mg of diazepam. The active agent can be riluzole. When the active agent is riluzole, each individual unit dose can contain about 10 mg, about 20 mg, about 25 mg, about 30 mg, or about 50 mg of riluzole. In some embodiments, the oral film contains about 50 mg of riluzole. The active agent can be clobazam. When the active agent is clobazam, each individual unit dose can contain about 1 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg of clobazam. In certain embodiments, the oral film contains about 5 mg or about 20 mg of clobazam.

[0051] Micronization The active agents used in the oral films disclosed herein may be micronized. The active agents may be micronized by any means known in the art. The active agent may have an average particle size D90 of 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 less than about 8 microns. The active agent may have an average particle size D50 of less than about 30 microns, less than about 20 microns, less than about 10 microns, less than about 5 microns, less than about 4 microns, or a D50 of about 3 microns. The active agent may have an average particle size D10 of less than about 10 microns, less than about 5 microns, less than about 3 microns, less than about 2 microns, or a D10 of about 1 micron. The active agent may have an average particle size D90 of less than about 15 microns, a D50 of less than about 4 microns, and a D10 of less than about 2 microns. The active agent may have an average particle size D90 of about 8 microns, a D50 of about 3 microns, and a D10 of about 1 micron.

[0052] Particle size is most commonly measured using laser diffraction light scattering for particles in the 0.02-2000μm / 0.01-3500μm range. In this technique, particles pass through the path of a laser, diffracting the light. The angle of this diffracted light is then correlated to particle size using the difference in refractive index between the particle and the medium. The output of this measurement is a volume distribution, often expressed as D x where x is the representation of the distribution. For example, D 90 represents the volume distribution of the analyzed particles, below which 90% of the observed diffraction falls, and thus 90% of the particles are smaller than this size. Because larger particles may have a disproportionately larger impact on the volume, other descriptions of particle size, such as "number distributions" that correlate to the number of particles of this size, are also commonly used. However, these alternative statistical descriptions of particle size based on laser diffraction light scattering are mathematical calculations based on volume distributions, and therefore, unless specifically stated otherwise, D x The particle size description is a volume distribution. It was known that an average particle size of less than 200 microns was preferred to obtain a smooth oral film. However, further developments have shown that smaller average particle sizes, i.e., finely divided particles, can improve film aesthetics and dissolution. Furthermore, it has been found that dissolution test results of lower dose films (e.g., 5 mg and 10 mg) have shown that micronized active agents perform better than films containing milled active agents (e.g., average particle size D90 of about 100 microns).

[0053] Dissolution Profile PION devices, such as the PION Rainbow Dynamic Dissolution Monitor (RDDM®) ("PION Technology"), are powerful analytical instruments that precisely and effectively measure percent dissolution in real time. PION Technology utilizes advanced fiber optics for in situ kinetic solubility and supersaturated UV monitoring for dissolution testing to determine drug substance release rates and their dissolution over time. PION Technology uses an individual diode array spectrophotometer with 6-8 acquisition channels, immersion probes, and interchangeable pathlength chips. PION Technology provides real-time data display, thereby providing rapid and reproducible results for testing of active agents, formulations, and drug products. These measurements are accurate even in small volumes and complex matrices.

[0054] Fiber optic based dissolution systems such as PION technology have been used in the past for dosage forms other than oral films. However, the size and density of oral films prevented these systems from being used properly, e.g., the film has already dissolved and released the active agent before measurements are taken. To overcome this, a custom film introduction system / holder had to be designed and developed. This custom film introduction system / holder ensures that the film is suspended in the dissolution vessel and not agitated. It also allows for the simultaneous introduction of multiple films at the same time, which is important for rapid data collection. Furthermore, both the sample holder, its distance from the paddle, and the distance and angle from the fiber optic probe play an important role in consistent and accurate data collection while ensuring USP flow dynamics requirements. A non-limiting example configuration of the equipment used for PION technology is shown in Figure 1. As shown in this figure, the system is composed of multiple systems set up to test different samples in parallel at the same time. 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 modified to accommodate the films. In addition, as will be readily appreciated by those skilled in the art, the optical path length of the probe can also be varied: if the path length is too wide, the signal will be overloaded; if the path length is too narrow, the signal will be too weak.

[0055] FIG. 2 is another exemplary configuration of paddles, holders, and means for adjusting the height of the probe and holder used in obtaining dissolution profiles by PION technology. With sufficient paddle agitation, the height of the probe does not appear to affect the results, but the orientation of the sample holder can affect the disintegration of the film and thus the dissolution rate of the active agent. As shown in FIGS. 1 and 2, for example, the sample holder is positioned perpendicular to the wall of the dissolution vessel to maximize exposure. The angle of the holder relative to the dissolution vessel can be changed by changing the holder orientation (twisting the holder from perpendicular to the desired angle). The holder can be made larger to accommodate larger films, but there is a limit to the acceptable range of angles, e.g., if the holder is larger for a larger film, there is less freedom of adjustment. Too much twisting can cause the holder or film to contact the side wall of the vessel or to contact the rotating paddle, adversely affecting the test.

[0056] It has been found that PION technology can be used to test the dissolution of the oral films disclosed herein by customizing the sample holder and sampling manifold. The use of PION technology has several advantages: 1. No offline analysis is required. 2. Many sampling points are available. 3. Multiple wavelengths can be evaluated. 4. The rate of change (e.g., inflection point acceptance criteria) can be assessed. 5. Profile comparison shows potential discrimination between strengths and storage conditions. It was found that the active agent dissolution profiles and rates of the oral films disclosed herein measured by PION technology were generally comparable to those measured by conventional dissolution, except that the curves were tighter and more accurate, and therefore the inflection points could be determined. A more accurate and precise dissolution profile of the oral film is possible using a fiber optic UV monitoring system such as PION technology. The dissolution profile is the average collection of data points that show the percent dissolution of the dosage form or active agent over time from t=0 to past the point where 100% of the dosage form or active agent is dissolved. "Active agent dissolution profile" refers to the dissolution profile of the active agent after it is released from the film. The film itself and the carrier therein have some effect on the dissolution rate of the active agent as it dissolves after it is released from the oral film dosage form. For example, Figures 9 and 10 show active agent dissolution profiles and Figures 13-23 show the improved and more precise data and derivatives possible with PION technology, whereas Figure 8 shows an active agent dissolution profile measured by conventional dissolution, which lacks the ability to discriminate at very early time points for fast releasing dosage forms.

[0057] Using PION technology, the first derivative of the active agent dissolution profile of the oral film can be graphed, for example, as shown in Figures 19, 21 and 23. The first derivative graph gives insight into the release rate of the active agent from the film. The strength and width of the first derivative are proportional to the release rate. For example, by plotting these derivatives, one can learn that oral films containing 5 mg and 10 mg release faster and more fully within 1 minute than comparable oral films containing 20 mg of active agent, as shown by the height and width of the first derivative curves. In such a display, the oral film containing 20 mg of active agent has a broader curve, indicating a slower release. For all curves, the first derivative approaches 0 when release is complete and the concentration of drug in the container reaches a plateau. If the active agent has the same particle size distribution in different film dosage forms, it is expected that the active agent dissolution profile will be the same. However, this is not always the case. By using PION technology, it is possible to see discernible differences between dosage forms, which indicates that the film and carrier affect the dissolution rate of the active agent. The second derivative graph gives a qualitative assessment of the curve. Both first and second derivative curves give maxima, minima and inflection points, making it possible to determine when the curve is increasing / decreasing and at what rate.

[0058] When the film is placed in a medium, the active agent may optionally exhibit an average dissolution of 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 as measured by PION technology. The active agent may optionally exhibit an average dissolution of 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%, greater than about 65%, or greater than about 70% at about 3 minutes as measured by PION technology. The active agent may optionally exhibit an average dissolution of 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%, greater than about 65%, or greater than about 70% at about 5 minutes as measured by PION technology. The active agent may optionally exhibit an average dissolution of 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 as measured by PION technology. The active agent may optionally exhibit an average dissolution of 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 as measured by PION technology. The active agent may optionally exhibit an average dissolution of 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 as measured by PION technology.As measured herein, dissolution of the active agent occurs after the film is placed in a medium, whereupon the film dissolves and releases the active agent into the medium.

[0059] Dissolution rate is the rate at which the oral film or active agent dissolves and is a calculation of the % of the amount released at a given time. Dissolution rate is obtained by performing dissolution testing in a selected apparatus and is measured according to a specific dissolution parameter. Dissolution parameters include storage conditions such as time, temperature, and relative humidity, and test parameters such as apparatus, rotation speed, medium, medium temperature, sampling time point, sample volume, sample filter, HPLC column, mobile phase, flow rate, column temperature, injection volume, detection wavelength, and measurement time.

[0060] "Active agent dissolution rate" is the rate at which the active agent dissolves and is a calculation of the % of the amount released at a given time. In the case of oral film dosage forms as disclosed herein, the oral film dissolves and releases the active agent, which then undergoes dissolution at a precise rate (i.e., the active agent dissolution rate). The dissolution of the active agent can also be expressed as the % of the active agent dissolved (on average) at a given time. Unless otherwise stated, dissolution of the active agent is measured under storage conditions of the oral film from about 0 months to about 36 months, from greater than 0 months to about 36 months, from about 6 to about 36 months, from about 6 to about 24 months, from about 9 months to about 18 months, or about 12 months at about 20° C. to about 60° C., from about 25° C. to about 40° C., or about 25° C., and up to about 75% relative humidity (RH), e.g., about 60% RH.

[0061] Dissolution testing is USP <1092> The dissolution method may be performed under "soaking" conditions, as defined by USP 1462455, "at least three times the volume of medium required to form a saturated solution of the drug substance. If soaking conditions are present, the dissolution results are more likely to represent the characteristics of the dosage form." Different media may be required for different pharmaceuticals based on the characteristics of the active agent, such as solubility and route of administration. As will be readily understood by those skilled in the art, the above factors can be taken into consideration in developing a dissolution method. Using the same, the dissolution method may be performed under "soaking" conditions, as defined by USP 1462455, "at least three times the volume of medium required to form a saturated solution of the drug substance. If soaking conditions are present, the dissolution results are more likely to represent the characteristics of the dosage form." Different media may be required for different pharmaceuticals based on the characteristics of the active agent, such as solubility and route of administration. As will be readily understood by those skilled in the art, the above factors can be taken into consideration in developing a dissolution method. <1092> also specifies the range of media to be evaluated. "Typical media for dissolution may include (not listed in order of preference): dilute hydrochloric acid, buffers (phosphate or acetate) in the physiological pH range of 1.2-7.5, simulated gastrointestinal fluids (with or without enzymes), water, and surfactants (with or without acids or buffers)." Surfactants may 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 may affect the choice of buffer. The molarity of the buffer and acid used may affect the solubilization effect, and this factor can be evaluated. The aqueous solution (acid or buffer solution) may contain a percentage of surfactant, e.g., sodium dodecyl sulfate (SDS), polysorbate, or lauryl dimethylamine oxide, to enhance the solubility of the drug.

[0062] In one embodiment, dissolution of the active agent is measured in dilute hydrochloric acid, buffers (phosphate or acetate) in the physiological pH range of 1.2 to 7.5 (including but not limited to 0.05 molar monobasic potassium phosphate buffer pH 6.8), simulated gastrointestinal fluids (with or without enzymes) (e.g., 0.1N HCL), water, and surfactants (e.g., polysorbate 80, sodium lauryl sulfate, and bile salts). In another embodiment, dissolution of the active agent is measured in dilute hydrochloric acid, 0.05 molar monobasic potassium phosphate buffer pH 6.8, 0.1N HCL), water, or 0.5% sodium lauryl sulfate.

[0063] In oral films containing diazepam, when the film is placed in a medium, more than about 2% of the diazepam may dissolve after about 3 minutes, more than about 10% of the diazepam may dissolve after about 5 minutes, more than about 15% of the diazepam may dissolve after about 5 minutes, or about 20% to about 25% of the diazepam may dissolve after about 5 minutes, optionally as measured by PION technology. More than about 25%, more than about 30%, or about 35% to about 40% of the diazepam may dissolve after about 10 minutes, optionally as measured by PION technology. More than about 42%, more than about 48%, or about 50% to about 55% of the diazepam may dissolve after about 15 minutes, optionally as measured by PION technology. More than about 55%, more than about 60%, or about 60% to about 70% of the diazepam may dissolve in about 20 minutes, optionally as measured by PION technology. Optionally, greater than about 85%, greater than about 90%, or about 92% to about 98% of the diazepam may be dissolved after about 30 minutes as measured by PION technology. Any combination of the above dissolutions at different time points is within the scope of the present invention.

[0064] In an oral film containing about 5 mg of diazepam, optionally as measured by PION technology, more than about 2% of the diazepam may be dissolved after about 3 minutes, more than about 15% of the diazepam may be dissolved after about 5 minutes, or about 21% of the diazepam may be dissolved after about 5 minutes. In an oral film containing about 5 mg of diazepam, optionally as measured by PION technology, more than about 30%, less than about 38%, or about 36% of the diazepam may be dissolved after about 10 minutes. In a film containing about 5 mg of diazepam, optionally as measured by PION technology, less than about 55%, more than about 45%, or about 50% of the diazepam may be dissolved after about 15 minutes. In a film containing about 5 mg of diazepam, optionally as measured by PION technology, less than about 70%, more than about 60%, or about 64% of the diazepam may be dissolved after about 20 minutes. Any combination of the above dissolutions at different times is within the scope of the present invention.

[0065] An oral film containing about 15 mg of diazepam may have more than about 2% of the diazepam dissolved after about 3 minutes, more than about 20% of the diazepam dissolved after about 5 minutes, more than about 25% of the diazepam dissolved after about 5 minutes, and / or about 27% of the diazepam dissolved after about 5 minutes, optionally as measured by PION technology. A film containing about 15 mg of diazepam may have more than about 35%, less than about 45%, or about 41% of the diazepam dissolved after about 10 minutes, optionally as measured by PION technology. A film containing about 15 mg of diazepam may have less than about 60%, more than about 45%, more than about 50%, or about 55% of the diazepam dissolved after about 15 minutes, optionally as measured by PION technology. In a film containing about 15 mg of diazepam, less than about 70%, more than about 60%, more than about 65%, or about 68% of the diazepam is dissolved after about 20 minutes, optionally as measured by PION technology. Any combination of the above dissolutions at different times is within the scope of the present invention.

[0066] In the oral film containing riluzole, more than about 2% of riluzole may be dissolved after about 3 minutes, more than about 30% of riluzole may be dissolved after about 5 minutes, and / or more than about 35% of riluzole may be dissolved after about 5 minutes, as optionally measured by PION technology. In the film containing riluzole, less than about 75%, less than about 73%, more than about 60%, more than about 65%, and / or more than about 68% of riluzole may be dissolved after about 10 minutes, as optionally measured by PION technology. In the film containing riluzole, less than about 98%, less than about 95%, more than 75%, and / or more than about 80% of riluzole may be dissolved after about 15 minutes, as optionally measured by PION technology. Any combination of the above dissolutions at different times is within the scope of the present invention.

[0067] In an oral film containing about 50 mg of riluzole, optionally measured by PION technology, more than about 2% of the riluzole may be dissolved after about 3 minutes, more than 10% of the riluzole may be dissolved after about 5 minutes, more than 20% of the riluzole may be dissolved after about 5 minutes, more than 30% of the riluzole may be dissolved after about 5 minutes, less than about 45% of the riluzole may be dissolved after about 5 minutes, or about 40% of the riluzole may be dissolved after about 5 minutes. In a film containing 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 may be dissolved after about 10 minutes. In a film containing 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 may be dissolved after about 15 minutes. Any combination of the above dissolutions at different times is within the scope of the present invention.

[0068] In oral films containing clobazam, more than about 3%, more than about 5%, more than about 10%, or more than about 15% of the clobazam may be dissolved after about 1 minute, optionally 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 may be dissolved after about 1.5 minutes, optionally 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 may be dissolved after about 2.5 minutes, optionally 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 may be dissolved after about 3 minutes, optionally as measured by PION technology. Optionally, greater than about 55%, greater than about 65%, greater than about 70%, or greater than about 75% of the clobazam may be dissolved after about 5 minutes as measured by PION technology. Optionally, greater than about 85%, greater than about 90%, or greater than about 91% of the clobazam may be dissolved after about 6.5 minutes as measured by PION technology. Optionally, greater than about 95% or greater than about 99% of the clobazam may be dissolved after about 10 minutes as measured by PION technology. Any combination of the above dissolutions at different time points is within the scope of the present invention.

[0069] An oral film containing about 5 mg of clobazam may have greater than about 25%, greater than about 30%, or about 38% of the clobazam dissolved after about 1 minute, as measured optionally by PION technology, measured after storage of the film at about 25° C., and greater than about 45%, greater than about 50%, or about 59% of the clobazam dissolved after about 1 minute, as measured optionally by PION technology, measured after storage of the film at about 40° C. A film containing about 5 mg of clobazam may have greater than about 60%, or greater than about 65% of the clobazam dissolved after about 1.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 25° C., and greater than about 75%, or greater than about 80% of the clobazam dissolved after about 1.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 40° C. A film containing 5 mg of clobazam may have greater than about 80% or greater than about 85% of the clobazam dissolved after about 2 minutes, as measured optionally by PION technology, measured after storage of the film at about 25° C., and greater than about 85% or greater than about 90% of the clobazam dissolved after about 2 minutes, as measured optionally by PION technology, measured after storage of the film at about 40° C. A film containing about 5 mg of clobazam may have greater than about 95% or greater than about 97% of the clobazam dissolved after about 2.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 25° C., and greater than about 95% or greater than about 100% of the clobazam dissolved after about 2.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 40° C. Any combination of the above dissolutions at different time points is within the scope of the present invention.

[0070] An oral film containing about 10 mg of clobazam may have greater than about 15% or greater than about 20% of the clobazam dissolved after about 1 minute, as measured optionally by PION technology, measured after storage of the film at about 25° C., and may have greater than about 35% or greater than about 40% of the clobazam dissolved after about 1 minute, as measured optionally by PION technology, measured after storage of the film at about 40° C. A film containing about 10 mg of clobazam may have greater than about 50% or greater than about 55% of the clobazam dissolved after about 1.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 25° C., and may have greater than about 65% or greater than about 70% of the clobazam dissolved after about 1.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 40° C. For a film containing about 10 mg of clobazam, greater than about 70% or greater than about 75% of the clobazam may be dissolved after about 2 minutes, optionally as measured by PION technology, measured after storage of the film at about 25° C., and greater than about 80% or greater than about 85% of the clobazam may be dissolved after about 2 minutes, optionally as measured by PION technology, measured after storage of the film at about 40° C. Any combination of the above dissolutions at different time points is within the scope of the present invention.

[0071] An oral film containing about 20 mg of clobazam may have greater than about 2% or about 4% of the clobazam dissolved after about 1.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 25° C., and may have greater than about 5% or about 6% of the clobazam dissolved after about 1.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 40° C. A film containing about 20 mg of clobazam may have greater than about 10% or about 15% of the clobazam dissolved after about 2.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 25° C., and may have greater than about 25% or about 30% of the clobazam dissolved after about 2.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 40° C. A film containing about 20 mg of clobazam may have greater than about 40% or about 46% of the clobazam dissolved after about 3.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 25° C., and greater than about 65% or about 68% of the clobazam dissolved after about 3.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 40° C. A film containing about 20 mg of clobazam may have greater than about 80% or about 83% of the clobazam dissolved after about 5.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 25° C., and greater than about 90% or about 94% of the clobazam dissolved after about 5.5 minutes, as measured optionally by PION technology, measured after storage of the film at about 40° C. Any combination of the above dissolutions at different time points is within the scope of the present invention.

[0072] The dissolution rate of the active agent can contribute to the sensory properties of the oral film. There is a certain balance between the amount of active agent dispersed in the film and the amount dissolved in the film. If the amount dissolved is too high relative to the amount dispersed in the film, the patient will taste the active agent when the film is placed in the oral cavity, and the active agent will often have a very unpleasant flavor. In some embodiments, less than about 10% by weight of the active agent is dissolved (sometimes referred to as solubilized) in the oral film, and more than about 90% is dispersed. In other embodiments, less than about 8% by weight, less than about 5% by weight, less than about 2% by weight, about 0.1 to about 10% by weight, about 0.5 to about 5% by weight, about 0.5 to about 2.5% by weight, about 1.0 to about 2.0% by weight, about 0.5% by weight, about 0.8% by weight, about 1.0% by weight, about 1.2% by weight, about 1.5% by weight, about 1.8% by weight, or about 2.0% by weight of the active agent is dissolved in the oral film.

[0073] Comparison of dissolution profiles For more major changes in drug products, a comparison of dissolution profiles performed under identical conditions for the reference and changed products is recommended ("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.htm). Dissolution profiles can be considered similar on the basis of (1) similarity of the overall profiles and (2) similarity of the dissolution sample time points.

[0074] One means of comparing dissolution profiles is by using a model-independent method using similarity coefficients. A simple model-independent approach uses dissimilarity coefficients (f1) and similarity coefficients (f2) to compare dissolution profiles (Moore, JW and HH Flanner, 1996, “Mathematical Comparison of Dissolution Profiles,” Pharmaceutical Technology, 20 (6):64-74). The dissimilarity coefficient (f1) calculates the percent (%) of difference between the two curves at each time point and is a measure of the relative error between the two curves.

number

number

[0075] The specific procedure for calculating the dissimilarity coefficient and similarity coefficient is as follows: a. Determine the dissolution profile of two products: the test product (before change) and the reference product (after change). b. Using the average dissolution values ​​from both curves at each time interval, calculate the difference coefficient (f1) and similarity coefficient (f2) using the formula above. c. The curves are considered similar if the f1 value is less than or equal to 15 (i.e., between 0 and 15) and the f2 value is greater than 50 (i.e., between 50 and 100), thus ensuring the identity of the two items. With the improved accuracy and enhancements of PION technology, it is possible to compare dissolution profiles of active agents with greater precision and with respect to previously ununderstood variables to obtain calculable differences in dissolution.

[0076] polymer The film and / or its components may be water-soluble, water-swellable, water-insoluble, or a combination of one or more thereof. The term "water-soluble" may refer to a material that is at least partially soluble in an aqueous solvent, including but not limited to water. The term "water-soluble" may not necessarily mean that a material is 100% soluble in an aqueous solvent. The term "water-insoluble" refers to a material that is not soluble in an aqueous solvent, including but not limited to water. The solvent may include water, or may instead include other solvents (preferably polar solvents), alone or in combination with water.

[0077] The film can be made by combining at least one polymer and a solvent, optionally including other ingredients. The solvent can be a polar organic solvent, including but not limited to water, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent can be a non-polar organic solvent, such as methylene chloride. The film can be made using a selected casting or deposition method and a controlled drying process. For example, the film can be made by a controlled drying process that includes applying heat and / or radiation energy to a wet film substrate to form a viscoelastic structure, thereby controlling the content uniformity of the film. This controlled drying process can include contacting air alone, heat alone, or heat and air together with the top surface of the film, the bottom surface of the film, or the substrate supporting the cast, deposited, or extruded film, or with two or more surfaces at the same time or at different times during the drying process. Some such processes are described in more detail in U.S. Pat. Nos. 8,765,167 and 8,652,378, which are incorporated herein by reference. Alternatively, the film can be extruded as described in US Patent Application Publication No. 2005 / 0037055, which is incorporated herein by reference.

[0078] The polymeric substrate included in the film can be water soluble, water swellable, or a combination thereof. The polymeric substrate comprises a polymer. The polymer may be polyethylene oxide. The polymer may comprise cellulose, a cellulose derivative, or a gum. The polymer may comprise polyethylene oxide, cellulose, a cellulose derivative, such as a cellulose ether, or a combination thereof. The polymer may be a cellulosic polymer. In certain embodiments, the cellulosic polymer may be hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, and / or sodium carboxymethylcellulose. In certain embodiments, the polymer may comprise hydroxypropyl methylcellulose. In certain embodiments, the polymer may comprise polyethylene oxide and a cellulose ether, such as hydroxypropyl methylcellulose. In certain embodiments, the polymer may comprise polyethylene oxide and / or polyvinylpyrrolidone. In certain embodiments, the polymeric substrate may comprise polyethylene oxide and / or a polysaccharide. In certain embodiments, the polymeric substrate may comprise polyethylene oxide, hydroxypropyl methylcellulose, and / or a polysaccharide. In certain embodiments, the polymeric substrate may comprise polyethylene oxide, a cellulosic polymer, a polysaccharide, and / or polyvinylpyrrolidone. In certain embodiments, the polymer matrix may comprise 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 copolymers, carboxyvinyl copolymers, starch, gelatin, ethylene oxide, propylene oxide copolymers, collagen, albumin, polyamino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof.Other 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, gum arabic, polyacrylic acid, methyl methacrylate copolymers, carboxyvinyl copolymers, starch, gelatin, polysaccharides, and combinations thereof.

[0079] As used herein, the phrase "water-soluble polymer" and variations thereof refer to a polymer that is at least partially soluble in water, preferably completely or mostly soluble in water, or that absorbs water. Polymers that absorb water are often referred to as water-swellable polymers. Materials useful in the present invention can be water-soluble or water-swellable at room temperature and other temperatures, such as temperatures above room temperature. Additionally, these materials can be water-soluble or water-swellable at pressures below atmospheric pressure. Desirably, the water-soluble polymer is water-soluble or water-swellable with at least 20% water uptake by weight. Water-swellable polymers with 25% or more water uptake by weight are also useful. In some embodiments, films formed from such water-soluble polymers can be sufficiently water-soluble to be dissolvable upon contact with bodily fluids.

[0080] Other polymers useful for incorporation into the film include biodegradable polymers, copolymers, block polymers, or combinations thereof. It is understood that the term "biodegradable" is intended to include materials that degrade chemically rather than materials that break down physically (i.e., bioerodible materials). The polymers incorporated into the film may also include combinations of biodegradable or bioerodible materials. Known useful polymers or classes of polymers that meet the above criteria are poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanes, polyoxalates, poly(α-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymers thereof. Further useful polymers include stereopolymers of L-lactic acid and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propanoic 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, polyhydroxy-alkanoates, or mixtures thereof. Binary and ternary systems are also contemplated. The polymeric substrate may comprise one, two, three, four or more components.

[0081] Other specific polymers that are useful include those sold under the trademarks Medisorb and Biodel. The Medisorb materials are sold by DuPont of Wilmington, Delaware, and are generally identified as "lactide / glycolide copolymers" containing "propanoic acid, 2-hydroxy-polymers, hydroxy-polymers, and hydroxyacetic acid." Four such polymers include Lactide / Glycolide 100L, believed to be 100% lactide, having a melting point within the range of 338-347°F (170-175°C); Lactide / Glycolide 100L, believed to be 100% glycolide, having a melting point within the range of 437-455°F (225-235°C); Lactide / Glycolide 85 / 15, believed to be 85% lactide and 15% glycolide, having a melting point within the range of 338-347°F (170-175°C); and Lactide / Glycolide 50 / 50, believed to be a copolymer of 50% lactide and 50% glycolide, having a melting point within the range of 338-347°F (170-175°C). The Biodel materials represent a family of chemically distinct polyanhydrides.

[0082] A variety of different polymers can be used, but it is desirable to select a polymer that provides the film with mucoadhesive properties and a desired dissolution and / or disintegration rate. In particular, the time that it is desired to maintain the film in contact with the mucosal tissue will vary depending on the type of pharmacoactive agent contained in the composition. Some pharmacoactive agents may require only a few minutes to be delivered through the mucosa, while others may require up to several hours or longer. Thus, in some embodiments, one or more water-soluble polymers may be used to form the film, as described above. However, in other embodiments, it may be desirable to use a combination of a water-soluble polymer and a water-swellable, water-insoluble, and / or biodegradable polymer. The inclusion of one or more water-swellable, water-insoluble, and / or biodegradable polymers may provide the film with a slower dissolution or disintegration rate than a film formed from a water-soluble polymer alone. Thus, the film may adhere to the mucosa for a longer period of time than may be desirable for the delivery of a particular pharmacoactive agent, such as up to several hours.

[0083] The polymer substrate may include dendritic polymers, which may include highly branched macromolecules having a variety of structural configurations. Dendritic polymers may include dendrimers, dendronized polymers (dendrigraft polymers), linear dendritic hybrids, multi-arm star polymers, or hyperbranched polymers. The polymer substrate may include hyperbranched polymers, which are highly branched polymers with imperfections in their structure. However, they can be synthesized in a one-step reaction, which may be advantageous over other dendritic structures, and therefore are suitable for bulk volume applications. In addition to the globular structure, the properties of these polymers are abundant functional groups, intramolecular cavities, low viscosity, and high solubility. Dendritic polymers have been used in several drug delivery applications. See, for example, 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.

[0084] Dendritic polymers may have internal cavities that can encapsulate drugs. Steric hindrance caused by high density of polymer chains may prevent drug crystallization. Thus, branched polymers may offer additional advantages in incorporating crystalline drugs into polymer matrices. Examples of suitable dendritic polymers 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(aryl alkylene ether)-based dendrons, dendrimers and hyperbranched polymers, poly(alkylene imine)-based dendrons, dendrimers and hyperbranched polymers, poly(amido amine)-based dendrons, dendrimers or hyperbranched polymers. Other examples of hyperbranched polymers include poly(amines), polycarbonates, poly(ether ketones), polyurethanes, polycarbosilanes, polysiloxanes, poly(ester amines, poly(sulfone amines), poly(urea urethanes) and polyether polyols, such as polyglycerol.

[0085] For example, in some embodiments, the self-supporting film may comprise polyethylene oxide alone or in combination with a second polymer component. The second polymer may 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, but are not limited to, any of those listed above. In some embodiments, the water-soluble polymer may be a hydrophilic cellulose-based polymer, such as hydroxypropyl cellulose and / or hydroxypropyl methylcellulose. In other embodiments, the polyethylene oxide-based film may also comprise one or more water-swellable, water-insoluble, and / or biodegradable polymers. Any of the water-swellable, water-insoluble, or biodegradable polymers listed above may be used. The second polymer may be used in an amount of about 0 to about 80% by weight of the polymer substrate, more specifically about 30 to about 70% by weight, and even more specifically about 40 to about 60% by weight, for example, greater than about 5% by weight, greater than about 10% by weight, greater than about 15% by weight, greater than about 20% by weight, greater than about 30% by weight, greater than about 40% by weight, greater than about 50% by weight, greater than about 60% by weight, and greater than about 70% by weight, less than about 70% by weight, less than about 60% by weight, less than about 50% by weight, less than about 40% by weight, less than about 30% by weight, less than about 20% by weight, less than about 10% by weight, or less than about 5% by weight.

[0086] The polymer plays an important role in determining the viscosity of the film. Viscosity is one property of the liquid that controls the stability of the active agent in the emulsion, colloid or suspension. In general, the viscosity of the substrate varies 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. It is desirable that the viscosity of the film-forming substrate increases rapidly at the beginning of the drying process.

[0087] The viscosity can be adjusted based on the active agent selected, depending on the other ingredients in the base. For example, if the ingredient is not soluble in the selected solvent, the appropriate viscosity can be selected so that the ingredient does not adversely affect the uniformity of the resulting film. Viscosity can be adjusted in a variety of ways. To increase the viscosity of the film base, a polymer with a higher molecular weight can be selected or a crosslinking agent such as calcium, sodium and potassium salts can be added. Viscosity can also be adjusted by adjusting the temperature or by adding a thickening ingredient. Ingredients that increase viscosity or stabilize the emulsion / suspension include higher molecular weight polymers and polysaccharides and gums, including but not limited to alginates, carrageenan, hydroxypropyl methylcellulose, locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gum and combinations thereof. It has also been found that certain polymers that normally require a plasticizer to achieve a flexible film when used alone also achieve a flexible film without the need for a plasticizer in combination. For example, HPMC and HPC, when used in combination, provide a flexible, strong film with suitable plasticity and elasticity for manufacturing and storage. No additional plasticizer or polyalcohol is required for flexibility.

[0088] Additives Additives may be added to the films disclosed herein. The various additives that can be incorporated into the films of the present invention can provide a variety of different functions. Examples of additive types include excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, bulking agents, sweeteners, flavorings, fragrances, release modifiers, adjuvants, plasticizers, glidants, release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, anti-caking agents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, and mixtures thereof. These additives can be added before or with the active agent. The amount of additive in the film can range from up to about 80%, from about 0.005% to about 50%, from about 1% to about 20%, or from about 3% to about 20%, based on the weight of the film composition (which is the total weight of all components therein), for example, 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%, less than about 3%, or less than about 1%. The additives may be selected from the group consisting of sweeteners, flavoring agents, flavor enhancers, fillers, plasticizers, colorants, e.g., dyes or pigments, permeation enhancers, buffers, preservatives, silicon dioxide, anti-adherents, and any combination thereof.

[0089] Flavoring agents can be selected from natural and synthetic flavor liquids.An exemplary list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatic oils, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof.A non-limiting representative list of examples includes mint oil, cocoa, and citrus oils such as lemon, orange, grape, lime, and grapefruit, and fruit essential oils such as apple, pear, peach, grape, strawberry, raspberry, lemon, lime, orange, cherry, plum, pineapple, apricot, or other fruit flavors. Useful flavorings or flavoring agents include natural and artificial flavorings. These flavors can be selected from synthetic flavor oils and flavoring oils, and / or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, etc., and combinations thereof. Non-limiting flavoring oils include spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, and bitter almond oil. 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 essential oils including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. These flavors can be used individually or in combination. Commonly used flavoring agents include mints such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavors, whether used individually or in combination. Flavoring agents such as aldehydes and esters, including cinnamyl acetate, cinnamon aldehyde, citral, diethyl acetal, dihydrocarbyl acetate, eugenyl formate, p-methylanisole, and the like, can also be used.Further examples of aldehyde flavorings include, but are not limited to, acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamic aldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime); neral, i.e., beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropin, i.e., piperonal (vanilla, cream); vanillin (vanilla, cream); alpha-amyl cinnamaldehyde (spice fruit flavoring); butyraldehyde (butter, cheese); valeraldehyde. (butter, cheese); citronellal (modified, various); decanal (citrus fruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); 2-ethylbutyraldehyde (berry fruits); hexanal, i.e., trans-2 (berry fruits); tolylaldehyde (cherries, almonds); veratraldehyde (vanilla); 12,6-dimethyl-5-heptenal, i.e., melonal (melon); 2 dimethyloctanal (unripe fruits); and 2-dodecenal (citrus, mandarin); cherries; grapes; mixtures thereof, and the like.

[0090] Other useful flavoring agents 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), tolylaldehyde (cherry, almond), 2,6-dimethyloctanol (unripe fruits), and 2-dodecenal (citrus, mandarin), combinations thereof, and the like.

[0091] The amount of flavoring used is typically a matter of preference, depending on factors such as the type of flavoring, the particular flavoring, and the intensity desired. This amount can be varied to obtain the desired result in the final product. Such variations are within the ability of one of ordinary skill in the art without undue experimentation. In general, amounts of about 0.1 to about 30% by weight are useful in the practice of the present invention. In one embodiment, the film comprises a berry flavoring. The berry flavoring can be raspberry, strawberry, blueberry, boysenberry, blackberry, or a combination thereof. In another embodiment, the film comprises a raspberry flavoring. The berry, raspberry, strawberry, blueberry, boysenberry, or blackberry flavoring can be natural or artificial and can be purchased and / or produced by any means known in the art. For example, raspberry flavoring, including aroma, can be achieved by incorporating a mixture of volatile compounds disclosed in “Volatile Compounds of Raspberry Fruit: From Analytical Methods to Biological Role and Sensory Impact,” E. Aprea et al., Molecules 2015, 20, 2445-2474, the entire contents of which are incorporated herein by reference. When used, the berry flavoring can be present at about 0.1 to about 15% by weight of the composition. In certain embodiments thereof, the berry flavor 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.

[0092] Suitable sweeteners include both natural and artificial sweeteners. Non-limiting examples of suitable sweeteners include 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, sodium, ammonium or calcium salts of 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, ... and potassium salts of saccharin (acesulfame-K), the free acid form of saccharin, and the like; dipeptide-based sweeteners, such as L-aspartic acid derived sweeteners, such as L-aspartyl-L-phenylalanine methyl ester (aspartame), L-α-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide hydrate, L-aspartyl-L-phenylglycerin and L-aspartyl-L-2,5,dihydrophenylglycine, L-aspartyl-2,5-dihydro-L-phenylalanine, the methyl ester of L-aspartyl-L-(1-cyclohexene)-alanine, and the like; water-soluble sweeteners derived from natural water-soluble sweeteners, such as the chlorinated derivatives of ordinary sugar (sucrose), known for example as sucralose; and protein-based sweeteners, such as thaurnatoccous danielli (thaumatins I and II). Natural high intensity sweeteners such as swingle, stevia, stevioside, monellin, and glycyrrhizin may also be used.

[0093] Generally, an effective amount of sweetener is used to provide a desired sweetness level for a particular composition, and this amount varies depending on the sweetener selected. This amount will usually be 0.01 to about 10% by weight of the composition. These amounts can be used to achieve a desired sweetness level independent of the flavor level achieved from any optional flavor oil used. In certain embodiments, the sweetener is present in about 0.5 to about 5%, about 1 to about 5%, 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. The sweetener may be selected from the group consisting of sucralose, stevia, acesulfame potassium, saccharin, fructose, aspartame, and any combination thereof, and is present at about 0.5 to about 5%, about 1 to about 5%, 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 some embodiments, about 3 to about 4%, about 3%, or about 3.5% of sucralose, saccharin, aspartame, and any combination thereof is present in the film by weight of the composition.

[0094] Color additives useful in the present invention include Food, Drug and Cosmetic Colors (FD&C), Drug and Cosmetic Colors (D&C), or External Drug and Cosmetic Colors (Ext. D&C). These colors are dyes, their corresponding lakes, and contain certain natural and derived colorants. Lakes are dyes absorbed onto aluminum hydroxide. Other examples of colorants include known azo dyes, organic or inorganic pigments, or colorants of natural origin. Inorganic pigments such as oxides or iron or titanium, oxides thereof, are preferred and are added at a concentration ranging from about 0.001 to about 10%, preferably about 0.5 to about 3%, based on the weight of the total components. The film may be any color, including, but not limited to, white, clear, blue, green, red, pink, purple, orange, or yellow. In some embodiments, the film is clear and translucent.

[0095] The film further desirably contains a buffering agent to control pH. Any desired level of buffer tray may be incorporated into the polymeric matrix to provide a desired pH level that the pharma- ceutical active agent encounters when released from the film. The buffering agent is preferably provided in an amount sufficient to control the release of the active agent from the film and / or its absorption into the body. The buffering agent may include sodium citrate, citric acid, bitartrate, or any combination thereof.

[0096] In certain embodiments, the film may be made of polyalkylene oxides (e.g., polyethylene glycol, polypropylene glycol, polyethylene-propylene glycol), low molecular weight organic plasticizers (e.g., glycerol, glycerol monoacetate, diacetate, or triacetate, triacetin, polysorbates, cetyl alcohol, propylene glycol, sugar alcohols, etc. The film composition may include a plasticizer, which may include sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, plant extracts, fatty acid esters, fatty acids, oils, and the like. The plasticizer may be added at a concentration of about 0.1% to about 40%, or about 0.5% to about 20%, for example, 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%, greater than 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%, based on the weight of the film composition. Additionally, animal or vegetable fats, preferably in their hydrogenated form, particularly those that are solid at room temperature, may be added to the compound to improve the textural properties of the film material. These fats preferably have a melting point of 50° C. or higher. C 12 -, C 14 -, C 16 -, C 18 -, C 20 - and C 22These fats can be added alone, without the addition of extenders or plasticizers, advantageously alone or together with mono- and / or diglycerides or phosphatides, in particular lecithin. The mono- and diglycerides are preferably of the above-mentioned types of fats, i.e., triglycerides having C-fatty acids. 12 -, C 14 -, C 16 -, C 18 -, C 20 - and C 22 The total amount of fat, monoglycerides, diglycerides and / or lecithin used is up to about 5% or in the range of about 0.5% to about 2% by weight of the film composition.

[0097] A variety of other ingredients and fillers can also be added to the films disclosed herein. These can include, but are not limited to, surfactants; other antifoaming agents; simethicone, which releases oxygen from the film, thereby providing a smoother film surface; thermosetting gels such as pectin, carrageenan, and gelatin, which help keep ingredients dispersed; and inclusion compounds such as cyclodextrins and caged molecules, which improve the solubility and / or stability of certain active ingredient components.

[0098] Further additives may be inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium, etc., desirably in a concentration range of from about 0.02% to about 3% by weight, desirably from about 0.02% to about 1% by weight of the film composition. It may be useful to add silicon dioxide, calcium silicate, or titanium dioxide at a concentration of about 0.02 to about 1% by weight of the total composition. These compounds act as modifiers. These additives should be used in amounts sufficient to achieve their intended purpose. In general, certain combinations of these additives can be used to modify, i.e., inhibit or accelerate, the overall release profile of the active ingredient.

[0099] Anti-adherents may be incorporated into the oral film of the present disclosure. Anti-adherents may be selected from the group consisting of lubricants, antiadherents, glidants, and combinations thereof. Anti-adherents aid in the flow properties of the material, for example, by reducing adhesion to the die during the extrusion process and by reducing adhesion to the palate during administration of the dosage form. Upon consumption of the film, particles tend to adhere to the palate. This is undesirable for films containing bitter drugs, such as dextromethorphan, because the adhered particles elude the drug, which increases the amount of bitterness perceived by the user. The addition of an anti-adherent to the film reduces adhesion to the palate, thereby effectively reducing the bitterness that may be perceived by the user during consumption.

[0100] Anti-blocking agents also impart a low inter-film coefficient of friction, which can alleviate the problem of film dosage units, i.e., strips, sticking to one another. More specifically, in many types of film packaging, the strips are laminated together. The inclusion of an anti-blocking agent allows the individual strips to slide smoothly over one another as each unit is removed from the package. Examples of lubricants suitable for use as anti-adherents include, but are not limited to, stearates, such as magnesium stearate, calcium stearate, and sodium stearate; stearic acid; vegetable oil (commercially available as Sterotex); talc; wax; 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, molecular weight 4000 (commercially available as Carbowax 4000); polyethylene glycol, molecular weight 6000 (commercially available as Carbowax 6000); sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and combinations thereof. Examples of suitable antiadherants include, but are not limited to, talc; cornstarch; synthetic amorphous silicon dioxide crystalline free (commercially available as Cab-O-Sil; Syloid; DL-leucine; sodium lauryl sulfate; metal stearates; and combinations thereof. Examples of suitable lubricants include, but are not limited to, talc; cornstarch; synthetic amorphous silicon dioxide crystalline free (commercially available as Cab-O-Sil); Syloid; aerosol; and combinations thereof.

[0101] Vitamin E is another suitable anti-adherent for use in some embodiments of the present invention. Vitamin E can act as both an anti-adherent and an active ingredient in the film. Desirably, Vitamin E TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate) is used. Vitamin E TPGS is a water-soluble form of Vitamin E derived from natural sources. Compared to other forms, Vitamin E TPGS is easily absorbed. Furthermore, Vitamin E TPGS imparts virtually no flavor to the film. Vitamin E TPGS can be used in solution, such as a 10% or 20% aqueous solution. Vitamin E TPGS is particularly useful for reducing film thickness and tendency to stick to the palate of the user. Vitamin E can be present in an amount of about 0.01% to about 20% by weight of the composition. When present, the anti-blocking agent can be included in an amount of from about 0.01 to about 20% by weight of the film composition. More specifically, the anti-blocking agent may be present in an amount of from about 0.01 to about 10% by weight of the film composition, and even more specifically, from about 0.25 to about 5% by weight of the film composition.

[0102] Combinations of anti-blocking agents can also be used. For example, a combination of a stearate, such as magnesium stearate, and silica can be used. SIPERNAT ABOUT 500LS, a silica product with an average particle size of 4.5 μm, is suitable for use herein (commercially available from Degussa). The combination of magnesium stearate and silica can provide improved lubrication properties, i.e., help the film strips slide smoothly over each other in the packaging. Thus, magnesium stearate can be present at about 0.1 to about 2.5% by weight of the film composition, and silica can be present at about 0.1 to about 1.5% by weight of the film composition. Such combinations of anti-blocking agents can be useful in a variety of films containing various flavors and / or actives. The anti-sticking agent may be included in the film composition itself. For example, a single layer or multi-layer film containing the anti-sticking agent can be formed. The multi-layer film can include, for example, two, three or more layers of film substantially in contact with each other. These film layers can be laminated together. The anti-sticking 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-sticking agent is present in one of the two film layers. Some embodiments can include a three-layer film in which the anti-sticking agent is present in each outer layer of the three-layer film but not in the inner or middle layers. Various different combinations of layers can be formed accordingly.

[0103] Alternatively, the composition may include an anti-adhesive agent that is used to coat the outer surface of the film. For example, the anti-adhesive agent may be applied to the film in the form of a wet or dry coating, such as, for example, a sugar coating or a sugar-free coating. The film may be coated with the anti-adhesive agent in any conventional manner, such as, but not limited to, dip coating, spray coating, powder coating, or fluidized bed. One or more film surfaces may be coated. In some embodiments, the anti-adhesive coating may be applied to a substrate, such as a backing material of the film, rather than directly to the film itself. The anti-adhesive coating may adhere to the film when the film is removed from the backing material. Some embodiments may include fats and / or waxes as anti-blocking agents. Any other optional ingredients described in the above-referenced commonly-assigned US Pat. Nos. 7,425,292 and 8,765,167 may also be included in the films described herein.

[0104] Penetration enhancers The films disclosed herein may contain a permeation enhancer. The active agent may be combined with the permeation enhancer in a single layer of the film, or may be contained in separate layers, or may be contained in separate regions of the same dosage form. In certain embodiments, the active agent contained in the polymeric substrate may be dispersed within the matrix. In certain embodiments, the permeation enhancer contained in the polymeric substrate may be dispersed within the matrix. Any permeation enhancer known for use in the art can be incorporated into the films of the present disclosure. The term "permeation enhancer" is interchangeable with absorption enhancer and permeation enhancer. A permeation enhancer is an ingredient that can increase the permeability of a medicamentously active agent through the mucous membrane into the blood of a subject when delivered into the oral cavity through the film.

[0105] The penetration enhancer may be a non-ionic alkyl glucoside having a hydrophobic alkyl group linked by a bridge to a hydrophilic saccharide. The penetration enhancer may be selected from the group consisting of maltoside or a maltoside derivative, sucroside or a sucroside derivative, and an essential oil or an essential oil component. The penetration enhancer may be selected from the group consisting of alkylthiomaltoside, maltoside, maltotrioside, maltopyranoside, dodecylmaltoside, tridecylmaltoside, tetradecylmaltoside, tetradecyl-β-D-maltoside, dodecyl-β-D-maltoside, tridecyl-β-D-maltoside, sucroside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, and combinations thereof. The penetration enhancer may increase the rate and amount of absorption of the medicament active agent by more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more 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 ingredients in the composition.

[0106] In certain embodiments, the film comprises a pharma- ceutically acceptable, non-toxic, non-ionic alkyl glucoside having a hydrophobic alkyl group linked by a cross-link to a hydrophilic saccharide, the alkyl glucosides being capable of acting as a pharma-ceutical agent, such as: (a) an aggregation inhibitor; (b) a charge modifier; (c) a pH control agent; (d) a degradative enzyme inhibitor; (e) a mucolytic or mucus-clearing agent; (f) a ciliostatic agent; agent); (g) a membrane permeation enhancer selected from: (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome, or carrier; (iii) an alcohol; (iv) an enamine; (v) an NO donor compound; (vi) a long chain amphipathic molecule; (vii) a small hydrophobic permeation enhancer; (viii) a sodium or salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or a β-cyclodextrin derivative; (xi) a medium chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) an N-acetyl amino acid or a salt thereof; (xv) a permeation enhancer for a selected membrane component. Degradative enzymes; (ix) fatty acid synthesis inhibitors; (x) cholesterol synthesis inhibitors; and (xi) any combination of the membrane permeation enhancers listed in (i)-(x); (h) regulators of epithelial junction physiology; (i) vasodilator drugs; (j) selective transport enhancers; and (k) the compound is effectively combined, associated, contained, encapsulated or bound to a mucosal delivery enhancer selected from a stabilizing delivery vehicle, carrier, mucoadhesive, support or complexing species that provides stabilization of the compound for enhanced mucosal delivery, and formulations of the compound with these mucosal delivery enhancers provide 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.

[0107] Surfactants and bile salts have been shown to increase the permeability of a variety of compounds across the oral mucosa both in vitro and in vivo. Data from these studies strongly suggest that the increased permeability is due to the effect of the surfactant on the intercellular lipids of the mucosa. Fatty acids have been shown to enhance the penetration of several drugs through the skin and have been shown by differential scanning calorimetry and Fourier transform infrared spectroscopy to be associated with increased fluidity of intercellular lipids. In addition, pretreatment with ethanol has been shown to increase the permeability of tritiated water and albumin across the ventral lingual mucosa, and caffeine across porcine oral mucosa. There are also several reports of the enhancing effect of Azone® on the permeability of compounds across the oral mucosa. Furthermore, chitosan, a biocompatible and biodegradable polymer, has been shown to enhance drug delivery across various tissues, including the intestinal and nasal mucosa. It has been shown that oral permeation can be improved by using various classes of transmucosal and transdermal permeation enhancers such as bile salts, surfactants, fatty acids and their derivatives, chelators, cyclodextrins and chitosan, etc. Bile salts are the most common of these chemicals used to enhance drug penetration.

[0108] In vitro studies on the enhancing effect of bile salts on the oral permeation of compounds are described 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 describes recent studies on 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 oral epithelium permeability at concentrations of about 100 mM, including permeability changes correlated with histological effects. Fluorescein isothiocyanate (FITC) and morphine sulfate, respectively, were used as model compounds. Chitosan has also been shown to enhance the absorption of small polar molecules and peptide / protein drugs across the nasal mucosa in animal models and human volunteers. Other studies have also demonstrated an enhancing effect on the permeation of compounds through the intestinal mucosa and cultured Caco-2 cells.

[0109] The penetration enhancer may be a plant extract. The plant extract may be an essential oil or a composition containing an essential oil extracted by distillation of the plant material. In certain circumstances, the plant extract may contain a synthetic analog of a compound extracted from the plant material (i.e., a compound produced by organic synthesis). The plant extract may contain a phenylpropanoid, such as phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid esters, cinnamic aldehyde, hydrocinnamic acid, chavicol, or safrole, or a combination thereof. The plant extract may be an essential oil extract of a clove plant, such as from the leaves, stems, or flower buds of a clove plant. The clove plant may be Syzygium aromaticum. The plant extract may contain about 20% to about 95% eugenol, such as about 40% to about 95% eugenol, such as about 60% to about 95% eugenol, such as about 80% to about 95% eugenol. The extract may also contain about 5% to about 15% eugenol acetate. The extract may also contain caryophyllene. The extract may also contain up to about 2.1% α-humulene. Other volatile compounds contained in lower concentrations by clove essential oil may be β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone, or ethyl hexanoate. Other penetration enhancers may be added to the composition to improve drug absorption. Suitable penetration enhancers include natural or synthetic bile salts, such as sodium fusidate; glycocholic or deoxycholic acid and their salts; fatty acids and derivatives, such as sodium laurate, oleic acid, oleyl alcohol, monoolein, or palmitoyl carnitine; chelators, such as disodium EDTA, sodium citrate and sodium lauryl sulfate, aton, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth-9, polysorbates, sterols, or glycerides, such as caprylocaproyl polyoxylglycerides, such as Labrasol. The penetration enhancer may include plant extract derivatives and / or monolignols. The penetration enhancer may also be a fungal extract.

[0110] Some natural products of plant origin are known to have vasodilatory effects. For a review, see McNeill JR and Jurgens, TM, Can. J. Physiol. Pharmacol. 84:803-821 (2006), which is incorporated herein by reference. In particular, the vasorelaxant effect of eugenol has been reported in several animal studies. See, for example, Lahlou, S., et al., J. Cardiovasc. Pharmacol. 43:250-57 (2004); Damiani, CEN, et al., Vascular Pharmacol. 40:59-66 (2003); Nishijima, H., et al., Japanese J. Pharmacol. 79:327-334 (1998); and Hume WR, J. Dent Res. 62(9):1013-15 (1983), each of which is incorporated herein by reference. Calcium channel blockade is suggested to be the primary vasorelaxation induced by plant essential oils or their main component, eugenol. See Interaminense LRL et al., Fundamental & Clin. Pharmacol. 21: 497-506 (2007), incorporated herein by reference.

[0111] Fatty acids can be used as inactive ingredients in drug preparations or drug vehicles. Fatty acids can also be used as formulation components due to their specific functional effects and their biocompatibility. Fatty acids are the major metabolic fuel (storage and transport energy) that is an essential component of all membranes and gene regulators, free of and as part of complex lipids. For a review, see Rustan AC and Drevon, CA, Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences (2005), incorporated herein by reference. There are two classes of polyunsaturated fatty acids (PUFAs) that are essential fatty acids metabolized in the human body: Ω-3 and Ω-6. If the first double bond is found between the third and fourth carbon atoms from the Ω carbon, they are called Ω-3 fatty acids. If the first double bond is between the sixth and seventh carbon atoms, they are called Ω-6 fatty acids. PUFAs are further metabolized in the body by the addition of carbon atoms and desaturation (abstraction of hydrogen). The omega-6 fatty acid, linoleic acid, is metabolized to gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, and docosapentaenoic acid. The omega-3 fatty acid, alpha-linolenic acid, is metabolized to octadecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosamentaenoic acid, tetracosahexaenoic acid, and docosahexaenoic acid (DHA).

[0112] Fatty acids such as palmitic acid, oleic acid, linoleic acid and eicosapentaenoic acid contain sodium + K +It has been reported that fatty acids with increased cis-unsaturation induced relaxation and hyperpolarization of porcine coronary artery smooth muscle cells through a mechanism involving activation of the -APTase pump, with fatty acids with increased cis-unsaturation having higher potency. See Pomposiello, SI et al., Hypertension 31:615-20 (1998), incorporated herein by reference. Interestingly, the pulmonary vascular response to arachidonic acid, a metabolic product of linoleic acid, can be either vasoconstrictive or vasodilatory, depending on the dose, animal species, mode of arachidonic acid administration, and tone of the pulmonary circulation. For example, it has been reported that arachidonic acid causes cyclooxygenase-dependent and -independent pulmonary vasodilation. See Peddersen, CO et al., J. Appl. Physiol. 68(5):1799-808 (1990), also see Sparwhake, EW, et al., J. Appl. Physiol. 44:397-495 (1978) and Wicks, TC et al., Circ. Res, 38:167-71 (1976), each of which is incorporated herein by reference.

[0113] Many studies have reported the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on vascular reactivity after administration in ingestible forms. Some studies have found that EPA-DHA or EPA alone inhibits the vasoconstrictor effect of norepinephrine or enhances the vasodilator response to acetylcholine in the forearm microcirculation. See Chin, JPF, 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 has found that both EPA and DHA tend to increase systemic arterial compliance and reduce 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. On the other hand, one study found that DHA promoted vasodilatory mechanisms and attenuated contractile responses in the forearm microcirculation of overweight individuals with hyperlipidemia, but EPA did not.See Mori, TA, et al., Circulation 102:1264-69 (2000), incorporated herein by reference.Another study found the vasodilatory effect of DHA on the rhythmic contraction of isolated human coronary arteries in vitro.See Wu, K.-T. et al., Chinese J. Physiol. 50(4):164-70 (2007), incorporated herein by reference.

[0114] Adrenergic receptors (or adrenoceptors) are a type of G protein-coupled receptor that is the target of catecholamines, particularly norepinephrine (noradrenaline) and epinephrine (adrenaline). Epinephrine (adrenaline) interacts with both α-adrenoceptors and β-adrenoceptors, resulting in vasoconstriction and vasodilation, respectively. Although α-receptors are less sensitive to epinephrine, when activated, they override β-adrenoceptor-mediated vasodilation, since there are more peripheral α1 receptors than β-adrenoceptors. As a result, high levels of circulating epinephrine cause vasoconstriction. At low levels of circulating epinephrine, β-adrenoceptor stimulation dominates, resulting in vasodilation and a subsequent decrease in peripheral vascular resistance. α1-adrenoceptors are known for smooth muscle contraction in the skin, mucous membranes and abdominal organs, mydriasis, vasoconstriction, and sphincter contraction in the gastrointestinal (GI) tract and bladder. q It is a member of the protein-coupled receptor superfamily. Upon activation, it binds the heterotrimeric G protein G q activates phospholipase C (PLC). Its mechanism of action involves interaction with calcium channels and alteration of intracellular calcium content. For review, see Smith RS et al., Journal of Neurophysiology, 102(2): 1103-14 (2009), incorporated herein by reference. Many cells have these receptors.

[0115] α1-adrenergic receptors may be the main receptors for fatty acids.For example, saw palmetto extract (SPE) is widely used to treat benign prostatic hyperplasia (BPH), and has been reported to bind to α1-adrenergic, muscarinic and 1,4-dihydropyridine (1,4-DH P) 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 contains various fatty acids, such as lauric acid, oleic acid, myristic acid, palmitic acid and linoleic acid. Lauric and oleic acids can bind noncompetitively to α1-adrenergic, muscarinic and 1,4-DHP calcium channel antagonist receptors.

[0116] In certain embodiments, the penetration enhancer can be an adrenergic receptor interactor. An adrenergic receptor interactor refers to a compound or substance that modifies and / or otherwise alters the action of an adrenergic receptor. For example, an adrenergic receptor interactor can prevent the stimulation of the receptor by enhancing or reducing their binding capacity. Such interactors can be provided in either short-acting or long-acting forms. Some short-acting interactors can act quickly, but their effects last only a few hours. Some long-acting interactors take time to act, but their effects can last longer. The interactor can be selected and / or designed based on, for example, one or more of the desired delivery and dosage, active pharmaceutical ingredient, penetration modifier, penetration enhancer, matrix, and condition to be treated. The adrenergic receptor interactor can be an adrenergic receptor blocker. The adrenoceptor interactor may be a terpene (e.g., a volatile unsaturated hydrocarbon found in plant essential oils derived from isoprene units) or a C3-C22 alcohol or acid, preferably a C7-C18 alcohol or acid. In certain embodiments, the adrenoceptor interactor may include farnesol, linoleic acid, arachidonic acid, docosahexanoic acid, eicosapentanoic acid, and / or docosapentanoic acid. The acid may be a carboxylic acid, a phosphoric acid, a sulfuric acid, a hydroxamic acid, or a derivative thereof. The derivative may be an ester or an amide. For example, the adrenoceptor interactor may be a fatty acid or a fatty alcohol. The C3-C22 alcohol or acid may be an alcohol or acid having a linear C3-C22 hydrocarbon chain, for example, a C3-C22 hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; the hydrocarbon chain may optionally be a C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, hydroxyl, halo, amino, nitro, cyano, C 3-5Cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4 Alkylcarbonyloxy, C 1-4 Alkylsiloxycarbonyl, C 1-4 may be optionally substituted with alkylcarbonyl, alkylcarbonyl, or formyl; a )--, --N(R a )--C(O)--O--, --O--C(O)--N(R a )--, --N(R a )--C(O)--N(R b )-- or --O--C(O)--O-- may be inserted. a and R b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.

[0117] Fatty acids with higher unsaturation are effective candidates for enhancing drug penetration. Unsaturated fatty acids showed higher enhancement than saturated fatty acids, and enhancement increased 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, incorporated herein by reference. The position of the double bond also affects the enhancing activity of fatty acids. The difference in physicochemical properties of fatty acids due to the difference in the position of the double bond probably determines the effectiveness of these compounds as skin penetration enhancers. Skin distribution increases as the position of the double bond moves toward the hydrophilic end. It has also been reported that fatty acids with double bonds at even positions perturb the structure of both the stratum corneum and dermis more quickly than fatty acids with double bonds at odd positions. Cis-unsaturation within the chain may tend to enhance activity.

[0118] The adrenergic receptor interactor may be a terpene. Antihypertensive activity of terpenes in essential oils has been reported. See Menezes IA et al., Z. Naturforsch. 65c:652-66 (2010), incorporated herein by reference. In certain embodiments, the penetration enhancer may be a sesquiterpene. Sesquiterpenes consist of three isoprene units and have the empirical formula C 15 H 24 Sesquiterpenes are a type of terpene having the formula: 1. Like monoterpenes, sesquiterpenes can be acyclic or contain rings with many unique combinations. Biochemical modifications such as oxidation or rearrangement give rise to related sesquiterpenoids. The adrenergic receptor interactor may be an unsaturated fatty acid, such as linoleic acid. In certain embodiments, the penetration enhancer may be farnesol. Farnesol is a 15-carbon organic compound that is an acyclic sesquiterpene alcohol and is the naturally occurring dephosphorylated form of farnesyl pyrophosphate. Under standard conditions, farnesol is a colorless liquid. Farnesol is hydrophobic and therefore insoluble in water, but miscible with oil. Farnesol can be extracted from the fats of plants such as citronella, neroli, cyclamen, and tuberose. It is an intermediate step in the biosynthesis of cholesterol from mevalonic acid in vertebrates. Farnesol has a delicate floral or weak citrus-lime scent and is used in air fresheners and fragrances. Farnesol has been reported to selectively kill acute myeloid leukemia blasts and leukemia cell lines over primary hematopoietic cells. See Rioja A. et al., FEBS Lett 467 (2-3): 291-5 (2000), incorporated herein by reference. Vasoactive properties of farnesyl analogs have been reported. See Roullet, J.-B., et al., J. Clin. Invest., 1996, 97:2384-2390, incorporated herein by reference. Farnesol and a synthetic mimetic of the carboxyl terminus of farnesylated proteins, N-acetyl-S-trans,trans-famesyl-L-cysteine ​​(AFC), both inhibit blood contraction in rat aortic rings.

[0119] In some embodiments, the film includes a penetration enhancer comprising one or more of a phenylpropanoid, farnesol, labrasol, and linoleic acid, In some embodiments, the penetration enhancer is a phenylpropanoid selected from the group consisting of eugenol, eugenol acetate, cinnamic acid, cinnamic acid esters, cinnamic aldehyde, hydrocinnamic acid, chavicol, safrole, or combinations thereof. In some embodiments, the film includes a penetration enhancer that is a botanical extract. The botanical extract can be an essential oil extract of a clove plant, an essential oil extract of the leaves of a clove plant, an essential oil extract of the flower buds of a clove plant, an essential oil extract of the stems of a clove plant, or a combination thereof. In some embodiments, the botanical extract can be synthetic. The botanical extract can include 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.

[0120] Uniformity and Manufacturing For purposes of the present invention, the term non-self-aggregating uniform heterogeneity refers to the ability of the film of the present invention formed from one or more components in addition to a polar solvent to provide a substantial reduction (i.e., little or no) in the occurrence of strong or weak aggregation of the components within the film, as would normally occur if the film were formed by conventional drying methods, such as a hot air bath using a drying oven, drying tunnel, vacuum dryer, or other such drying equipment. The term heterogeneity, as used herein, includes films incorporating a single component, such as a polymer, as well as a combination of components, such as a polymer and an active agent. Uniform heterogeneity includes the substantial absence of strong or weak aggregation, as is typical of conventional mixing and thermal drying used to form films. Additionally, the films disclosed herein have a substantially uniform thickness, which is also not provided by the use of conventional drying methods used to dry water-based polymer systems, the absence of uniform thickness can adversely affect the uniformity of component distribution over a given area or region of the film.

[0121] The films disclosed herein are produced by combining appropriately selected polymers and polar solvents, optionally containing active ingredients and other fillers known in the art, using selected casting or deposition techniques and controlled drying steps to provide uniform, non-aggregated heterogeneity of the ingredients within the film. Examples of controlled drying processes include, but are not limited to, the use of the apparatus 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 all incorporated herein by reference in their entirety. Another drying technique to obtain a film is controlled radiation drying in the absence of uncontrolled airflow, such as infrared and radio frequency radiation (i.e., microwave).

[0122] The objective of this drying step is to provide a method of drying a film that avoids the complications associated with conventional drying methods, such as the described "rippling" and mass transfer effects, of first drying the top surface of the film and trapping moisture therein. In conventional oven drying methods, the top surface changes by splitting and reforming as the trapped moisture subsequently evaporates. Such surface disruption due to continuous surface skinning and subsequent reopening of the skinned surface to evaporation results in non-uniformity and uneven thickness of the film. In addition, excessive air currents, e.g., hot air currents, can cause mass transfer, i.e., waves, in the flowable substrate before the substrate attains sufficient solidity during the drying step. Such rippling effects, whether caused by surface skinning / rupturing / reforming or by mass transfer, result in non-uniform active agent content in the film as particles are subjected to these uncontrolled mechanical and thermal forces and, as a result, move within the film. Such migration compromises the substantial uniformity of the active agent across the film which must be achieved during the mixing process and maintained in order to obtain substantially equal sized dosage units cut from the cast film, each having an amount of active agent per dosage unit that does not vary by more than 10% from the desired (labeled) amount of active agent.

[0123] These complications are avoided by the present invention, which provides a uniform film by preventing skinning / bursting / reforming or mass transfer of the film substrate before sufficient solidification of the flowable film substrate occurs so that the active agent particles do not migrate and become weakly or strongly agglomerated. The present disclosure provides several ways to control the drying process, thereby preventing the deleterious effects present in conventional drying methods and maintaining the substantial uniformity of the active agent in the substrate achieved during mixing. Drying is also desirably rapid to "lock in" the active agent by rapidly thickening to achieve a sufficiently solid substrate to prevent substantial migration. The cast and dried film can then be cut into individual dosage units of substantially equal size (length, width and thickness) and which have an active agent content that does not vary by more than 10% from the desired amount (labeled amount) of active agent.

[0124] Methods of controlling the undesirable effects of conventional drying include controlling oven airflow to prevent rippling, prevent mass transfer, and prevent premature skinning of the surface before the substrate dries below the skin. The airflow is desirably directed at the film from above, at a distance, angle, and at a velocity such that the forces generated when the airflow strikes the film do not exceed the yield value of the film substrate, i.e., below the force level that may dislodge or otherwise cause rippling and non-uniformity of the film-forming composition that forms the substrate. Controlled drying may also include directing heat to the bottom surface of the film first so that drying begins from the depth of the film upwards. This may be accomplished by applying heat to the bottom surface of the film with substantially no top airflow, or by applying heat to the bottom and top simultaneously without causing premature skinning rippling. Alternatively, drying can be accomplished by the introduction of controlled microwaves to evaporate water or other polar solvents within the film. When applying microwaves, care must be taken to ensure that the temperature of the substrate is not so high that boiling of the substrate (which would result in non-uniformity of the active agent therein) occurs.

[0125] Yet another method for drying control can include drying with a balanced fluid flow, for example, a balanced air flow, where the bottom and top air flows are controlled to provide a uniform film and avoid rippling and premature skinning as described herein. In such a case, the air flow directed to the top of the film should not create conditions that cause the movement of particles present in the wet film due to the forces generated by the air flow. In addition, the air flow directed to the bottom of the film should desirably be controlled so that the film does not lift due to the forces from the air. Uncontrolled air flow, whether at the top or bottom of the film, can create non-uniformities in the final film product. The humidity of the area surrounding the top surface can also be appropriately controlled to prevent premature blockage or skinning of the polymer substrate surface. This film drying mode offers several advantages. These include faster drying times and a more uniform film surface, as well as uniform distribution of ingredients in any given area of ​​the film. In addition, the faster drying times allow the viscosity to build up quickly within the film, further promoting uniform distribution of ingredients and reducing strong agglomeration of ingredients in the final film product. Desirably, film drying occurs within about 10 minutes, or more desirably within about 5 minutes. In the present invention, attention to reducing the strong agglomeration of the composition components results in a much more uniform film product.Furthermore, avoiding and removing excess air during the mixing process is desirable to promote uniformity of the film and dosage forms cut therefrom; in addition, selecting polymers and solvents to provide controllable viscosity while avoiding film rippling or mass transfer, and drying the film in a rapid manner as described above is desirable to maintain and provide the film and dosage forms cut therefrom with the desired uniformity of active agent content when reduced to the label amount.Thus, uniformity of the active agent content of such dosage units is achieved by attention to these parameters.

[0126] The products and processes of the present disclosure rely on the interaction between various stages of film manufacturing to provide a film that substantially reduces the self-aggregation of components within the film. Specifically, these stages include the specific method used to form the film, making the composition mixture to prevent the inclusion of air bubbles, controlling the viscosity of the film-forming composition, and the method of drying the film. More specifically, a higher viscosity of the components in the mixture is particularly useful to prevent the active agent from settling out when the active agent is not soluble in the selected polar solvent. However, the viscosity should not be so high as to impede or hinder the selected casting method, including reverse roll coating, for its ability to provide a film of substantially consistent thickness. In addition to the viscosity of the film or film-forming components or substrate, there are other considerations to obtain the desired film uniformity. For example, a stable suspension is achieved that prevents solid (such as drug particles) settling in non-colloidal applications. One approach provided by the present invention is to determine the particle density (ρ p ) and the liquid density (ρ1) and increasing the liquid viscosity (μ). For isolated particles, Stokes' law relates the critical settling velocity (Vo) of a hard sphere of radius (r) in a viscous fluid as follows: V o =(2gr r )(ρ p -ρ1) / 9μ. However, at high particle concentrations, the local particle concentration influences the local viscosity and density: the viscosity of the suspension is a strong function of the solids volume fraction, and particle-particle and particle-liquid interactions further impede the settling velocity.

[0127] Stokes analysis has shown that the incorporation of a third phase, dispersed air or nitrogen for example, increases the stability of the suspension. Furthermore, an increase in particle number leads to an impairment of the settling effect based on the solids volume fraction. For dilute particle suspensions, the settling velocity v can be expressed as: v / V o =1 / (1+κφ) where κ = constant and φ is the volume fraction of the dispersed phase. More particles suspended in the liquid phase will result in lower velocities. Particle geometry is also an important factor since particle diameter affects particle-particle flow interactions. Similarly, the viscosity of a suspension also depends on the volume fraction of dispersed solids. For a dilute suspension of non-interacting spherical particles, the expression for the suspension viscosity can be written as: μ / μ o =1+2.5φ Here, μ o is the viscosity of the continuous phase and φ is the solid volume fraction. At higher volume fractions, the viscosity of the dispersion can be expressed as: μ / μ o =1+2.5φ+C1φ 2 +C2φ 3 + where C is a constant.

[0128] The viscosity of the liquid phase is important and is preferably adjusted by customizing the liquid composition to a viscoelastic non-Newtonian fluid with low yield stress values. This corresponds to producing a high viscosity continuous phase at rest. The formation of a viscoelastic or highly structured fluid phase provides additional resistance to particle settling. Furthermore, soft particle aggregation or strong agglomeration can be controlled to minimize particle-particle interactions. The net effect will be the preservation of a homogeneous dispersed phase. The addition of hydrocolloids to the aqueous phase of a suspension can increase viscosity and provide viscoelasticity, depending on the type of hydrocolloid, its concentration and particle composition, geometry, size, and volume fraction, and can impart stability. The average particle size distribution of the dispersed phase must be controlled by selecting the smallest actual average particle size in high viscosity media, i.e., <500 μm. The presence of a slight yield stress or elastic body at low shear rates can also provide permanent stability regardless of the apparent viscosity. The separation critical particle size can be calculated from the yield stress value. For isolated spherical particles, the maximum shear stress occurring during sedimentation in a medium of a given viscosity can be shown as follows: τ max =3Vμ / 2r For pseudoplastic fluids, the viscosity in this shear stress regime may well be the zero shear rate viscosity at the Newtonian plateau.

[0129] A stable suspension is an important feature for the preparation of the premix composition that is fed to the film caster film, and to maintain this stability at the wet film stage until sufficient drying has occurred to lock in the particles and substrate in a solid enough state so that uniformity is maintained. For viscoelastic fluid systems, a rheology that results in a stable suspension for an extended period of time, such as 24 hours, must be met to meet the requirements of high speed film casting operations. A desirable film property is shear thinning or pseudoplasticity, whereby the viscosity decreases as the shear rate increases. Time-dependent shear effects such as thixotropy are also advantageous. Structural recovery and shear thinning behavior are important properties, as is the self-leveling nature of the film as it is formed. The rheological requirements of the compositions and films of the present invention are quite stringent. This is due to the need to produce a stable suspension of particles, e.g., 30-60% by weight, in a viscoelastic fluid base with acceptable viscosity values ​​over a wide shear rate range. During mixing, pumping, and film casting, 10-10 5 seconds -1 with pseudoplastic being the preferred embodiment. In film casting or coating, rheology is also a determining factor with respect to the ability to form a film with the desired uniformity. Shear viscosity, extensional viscosity, viscoelasticity, and structural recovery affect film quality. As a specific example, the leveling of a shear-thinning pseudoplastic fluid was derived as follows: 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 where α is the surface wave amplitude and α ois 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 leveling behavior is related to the viscosity and increases with increasing n and decreases with increasing K.

[0130] Desirably, the film or film-forming composition of the present disclosure exhibits extremely fast structural recovery, i.e., the film does not fall apart or become discontinuous in its structural and compositional uniformity as it is formed during processing. Such extremely fast structural recovery retards particle settling and sedimentation. Additionally, the film or film-forming composition is desirably a shear-thinning pseudoplastic fluid. Such fluids, taking into account properties such as viscosity and elasticity, promote thin film formation and uniformity. Thus, the homogeneity of the component mixture depends on many variables. As described herein, the viscosity of the components, the mixing technique, and the rheological properties of the resulting mixed composition and wet cast film are important aspects of the present invention. In addition, the control of the average particle size and particle shape is also a further consideration. Desirably, the average particle size can be 200 microns or less, 150 microns or less, or 100 microns or less. Furthermore, such particles can be spherical, substantially spherical, or non-spherical, such as irregularly shaped particles or ellipsoidal particles. Elliptical particles or ellipsoids are desirable for their ability to maintain homogeneity in the film-forming substrate, as they tend to settle less than spherical particles.

[0131] In the mixing stage, several techniques can be used to prevent the inclusion of air bubbles in the final film. Antifoaming agents or surface tension reducing agents are used to provide a composition mixture that is substantially free of air bubble formation in the final product. In addition, the speed of the mixture is desirably controlled in a manner that evacuates air from entering the mixture to prevent cavitation of the mixture. Finally, air bubble reduction can be further achieved by allowing the mixture to stand for a sufficient time to allow air bubbles to escape before drying the film. Desirably, the process of the present invention first forms a masterbatch of the film-forming ingredients that does not contain any active ingredient, such as drug particles, or volatile materials, such as fragrance oils. The active agent is added to the mixture in a smaller amount of the masterbatch just prior to casting. Thus, the masterbatch premix can stand for a longer period of time without concern for instability of the drug or other ingredients. When the substrate is formed that includes film-forming polymer and polar solvent in addition to optional additives and active ingredients, this can be done in multiple stages.For example, ingredients can be added all together, or premixing can be preferred.The advantage of premixing is that all ingredients are premixed except for active agent, which is added just before film formation.This is especially important for active agents that may decompose when exposed to water, air, or another polar solvent for a long time. Apparatus for producing the films of the present invention is disclosed, for example, in US Pat. No. 8,765,167, the entire contents of which are incorporated herein by reference.

[0132] Furthermore, the films disclosed herein may contain temperature-sensitive particles, such as flavorings that may be volatile, or drugs that may have low decomposition temperatures. In such cases, the drying temperature may be lowered while extending the drying time to adequately dry the uniform films of the present invention. Furthermore, bottom drying also tends to result in lower internal film temperatures compared to top drying. In bottom drying, the evaporating vapors can more easily transfer heat away from the film compared to top drying, thereby lowering the internal film temperature. Such lower internal film temperatures often result in reduced drug decomposition and reduced loss of certain volatile substances, such as flavorings. Additionally, particles or particulate matter may be added to the film-forming composition or substrate after the composition or substrate is cast into a film. For example, particles may be added to the film before the film is dried. The particles may be controllably metered into the film and applied by suitable techniques, such as by a doctor blade (not shown) that lightly taps the film surface and controllably applies the particles to the film surface. Other suitable techniques include, but are not limited to, the use of an additional roller to place the particles on the film surface, spraying the particles onto the film surface, and the like. The particles may be placed on one or both of opposing film surfaces, i.e., the top and / or bottom surfaces of the film. Desirably, the particles are applied to the film in a fixable manner, such as by being embedded in the film. Additionally, such particles desirably are not completely encapsulated or embedded in the film, but remain exposed to the film surface, such as when the particles are partially embedded or encapsulated. The particles may be any useful functional agent, cosmetic agent, pharmaceutical agent, or combination thereof. Desirably, the pharmaceutical agent is a taste masking agent or a sustained release pharmaceutical agent. Useful functional agents include flavoring agents and sweetening agents. Useful cosmetic agents include breath fresheners or decongestants, such as menthol, including menthol crystals.

[0133] Monitoring and control of film thickness also contributes to the production of uniform films by providing a film of uniform thickness. Film thickness can be monitored with a gauge such as a beta thickness gauge. The gauge is coupled with another gauge at the end of the drying apparatus, i.e., drying oven or tunnel, and communicates through a feedback loop to control and adjust the apertures in the coating apparatus to obtain uniform film thickness control. The film product is generally formed by combining an appropriately selected polymer and a polar solvent, and optionally any active ingredient or filler. Desirably, the solvent content of the combination is at least about 30% by weight of the total combination. The substrate formed by this combination is preferably formed into a film by roll coating, and then preferably dried by a rapid and controlled drying process to maintain the uniformity of the film, more specifically, a uniform heterogeneity that does not self-aggregate. The resulting film desirably contains less than about 10% by weight solvent, more desirably less than about 8% by weight solvent, even more desirably less than about 6% by weight solvent, and most desirably less than about 2% by weight. The solvent can be water, a polar organic solvent, such as, but not limited to, ethanol, isopropanol, acetone, methylene chloride, or any combination thereof.

[0134] Consideration of the above mentioned parameters, including but not limited to rheological properties, viscosity, mixing method, casting method and drying method, also influences the material selection of the various components of the present invention. Moreover, such considerations, together with appropriate material selection, provide the present composition including pharmaceutical and / or cosmetic dosage forms or film products in which the distribution of active agent within the cast wet film is substantially uniform, and which maintains this substantially uniform distribution during the drying process, such that equally sized dosage units can be cut from the continuously cast and dried film, and these dosage units are substantially uniform in the amount of active agent present when compared to the desired amount of active agent for each dosage unit, i.e., the labeled amount of active agent. Desirably, the uniformity of the continuously cast free-standing film is measured by the substantially equally sized individual unit doses cut from the free-standing continuously cast film, which do not vary by more than 10% of the desired amount of the at least one active agent. For clarity, assume that the desired amount of film unit dosage is, for example, 10 mg of a given drug. The films of the present invention require uniformity such that substantially equal unit doses of film cut from a continuously cast and dried film do not vary by more than 10% of the desired amount, i.e., the unit dose varies by no more than + / - 1 mg, or in other words, between 9 mg and 11 mg.

[0135] Film formation The films disclosed herein must be formed into a continuously cast wet film or wet sheet before drying. The term "continuously cast" is intended to refer to a relatively high speed manufacturing process using a conveyor substrate onto which the wet film substrate is cast and formed, followed by a drying device such as an oven, and then continuously transported to a roll-up mandrel or directly to a cutting and packaging station for storage. The term continuous is intended to distinguish processes such as those carried out in a laboratory, where the wet film substrate is cast onto a tray. After combining the desired components to form a multi-component substantially homogeneous substrate containing polymer, water, and optionally an active agent or other components, 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 of the multi-component substrate. If a multi-layer film is desired, this may be achieved by co-extrusion of two or more combinations of components, which may be the same or different. A multi-layer film may also be achieved by successive coating, spreading, or casting of the wet film substrate onto an already formed, preferably already dried, film layer. Although a variety of different continuous film-forming techniques can be used, it is desirable to select a method that provides a flexible film, such as reverse roll coating. The flexibility of the film allows for rolling and transporting the film sheet for storage or before cutting into individual dosage forms. Desirably, the films are also self-supporting, or in other words, capable of maintaining their integrity and structure in the absence of an independent support. Additionally, the films of the present invention may be selected from edible or ingestible materials.

[0136] Continuous coating or casting methods are particularly useful for forming the films of the present invention, particularly when multilayer films are desired. Specific examples include reverse roll coating, gravure coating, immersion or dip coating, metering rod or Meyer bar coating, slot die or extrusion coating, gap or knife over roll coating, air knife coating, curtain coating, or combinations thereof. Continuous roll coating, or more specifically, reverse roll coating, is particularly desirable in forming films according to the present invention. This technique provides excellent control and uniformity of the resulting film, which is desired in the present invention. In this technique, the coating material is metered onto the applicator roller by precision setting of the gap between the metering roller above and the application roller below. The coating is transferred from the application roller to the substrate as it passes through a support roller adjacent to the application roller. Both three-roll and four-roll techniques are common.

[0137] The gravure coating process involves an engraved roller that is advanced through a coating bath, with the coating material filling the engraved dots or lines on the roller. Excess coating on the roller is wiped off by a doctor blade, and the coating is then applied to the substrate as it passes between the engraved roller and a pressure roller. Offset gravure is common, in which the coating is deposited on an intermediate roller before being transferred to the substrate. In a simple method of immersion or dip coating, the substrate is immersed in a coating bath, which is usually of low viscosity so that the coating can fall back into place when the substrate emerges.

[0138] In the metering rod coating process, an excess amount of coating is deposited on the substrate as it passes over the bath rollers. A wire-wound metering rod, also known as a Mayer bar, allows the desired amount of coating to remain on the substrate. This amount is determined by the diameter of the wire used on the rod. In the slot die process, the coating is squeezed by gravity or under pressure through a slot onto the substrate. If the coating is 100% solids, the process is called "extrusion", in which case the line speed is often much faster than the extrusion rate. This allows the coating to be much thinner than the width of the slot. The gap or knife-over-roll method involves applying a coating to a substrate and then passing it through a "gap" between a "knife" and a support roller. As the coating and substrate pass, the excess is scraped off. Air knife coating is where a coating is applied to a substrate and the excess is "blown away" by a powerful jet from an air knife. This technique is useful for water-based coatings. In curtain coating, a tank with a slot in the bottom allows a continuous curtain of coating to fall into the gap between two conveyors. The item to be coated passes at a controlled speed along the conveyors, thus receiving the coating on its upper surface. The substrate may be any material known for use in the art. For example, the material may be a polyester film, such as polyethylene terephthalate, a plastic sheet, glass, or cellulosic paper, which may be optionally coated. The substrate may be polyethylene terephthalate (e.g., Mylar) or parchment paper. If the substrate is polyethylene terephthalate, it may be biaxially oriented polyethylene terephthalate, optionally corona-treated on its bottom or top surface.

[0139] Drying the film The drying step is also a contributing factor in maintaining the uniformity of the film composition. A controlled drying process is particularly important when the components in the film may have an increased tendency to strongly aggregate or agglomerate in the absence of a thickening composition or a composition whose viscosity is controlled, for example, by the selection of a polymer. Another method of forming a film of precise dosage that does not require a controlled drying process is to cast the film onto a predetermined well or to apply the desired amount of active agent to each dosage unit after cutting the dosage unit from a continuous cast film (containing no active agent) on a manufacturing line. These two alternatives do not have the same problems with maintaining the uniformity of the active agent content from the mixing step to the drying step as continuous cast films, which incorporate the active agent into the film substrate before casting. In these alternatives, there is no opportunity for migration of the active agent to adjacent dosage forms. If an ordered or rapid drying process is desired, this can be achieved by a variety of methods. A variety of methods are available, including those that require the application of heat. The liquid carrier is removed from the film in such a manner that the uniformity obtained in the wet film, or more specifically, the uniform heterogeneity without self-aggregation, is maintained.

[0140] As mentioned above, the wet continuous cast film is dried using a hot air stream that does not cause rippling of the wet flowable cast film substrate, mass transfer of the wet flowable cast film substrate, or premature surface skinning as described above. The parameters selected to achieve this include being directed at the film from above, at a distance, angle, and speed such that the force generated when striking the film does not exceed the yield value of the film substrate, i.e., below the force level that may cause the film-forming composition forming the substrate to move or otherwise cause its rippling and non-uniformity. Desirably, but not necessarily, the film is exposed to a high temperature differential when the film enters the oven so that the moisture content is rapidly removed and the flowable substrate is rapidly solidified, locking in the active agent in a more solid structure. In this regard, so long as care is taken to ensure preservation of the uniformity of the film during the drying process, the continuous cast film substrate can be dried using air emanating solely from the top or upper surface of the carrier substrate, solely from the lower surface of the carrier substrate, or solely from both the top and bottom of the carrier substrate (top and bottom surfaces of the film). Thus, in one aspect of the drying process, the film can be dried from the bottom of the film toward the top of the film. Desirably, any top air currents present should not cause the non-uniformity conditions described above. Once the initial settling period has passed and the film has solidified sufficiently, a viscoelastic structure is formed and the likelihood of ripples and premature skinning is greatly reduced, if not eliminated. This can occur within the first few minutes of the drying process, for example, approximately the first 0.5 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 a continuously cast wet film in a manufacturing situation involves casting a wet flowable film substrate onto a carrier substrate.

[0141] In some cases, it may be preferable to begin the drying process by applying airflow to the bottom of the film, and thus the bottom of the carrier substrate. Heat from the airflow in this case is applied to the bottom side of the film first to provide the energy necessary to evaporate or otherwise remove the liquid carrier. Films dried in this manner dry more quickly and uniformly than air-dried films (air-dried), or those dried by conventional drying means. In contrast to air-dried films that dry first on the top and edges, films dried by applying heat to the bottom side dry simultaneously at the center as well as the edges. This also prevents settling of components that occurs with films dried by conventional means. The exogenous air temperature at which the film is dried may be about 130°C or less, as long as the film substrate does not reach its own boiling point (e.g., 100°C) or a temperature high enough to impair its uniformity. Desirably, the exogenous air temperature may be about 100°C or less, or about 80°C or less. An alternative method of controlling the drying process, which may be used alone or in combination with the other controlled methods disclosed above, involves controlling and varying the humidity within the drying apparatus in which the film is dried. In this manner, premature drying of the top surface of the film may be avoided. In addition, it has been found that the length of drying time can be appropriately controlled, i.e. balanced with the heat sensitivity and volatility of the ingredients, especially the fragrance oils and drugs. The amount of energy, temperature and conveyor length and speed can be balanced to accommodate such active agents and minimize their loss, degradation or ineffectiveness in the final film.

[0142] An example of a suitable drying method is disclosed by U.S. Patent No. 4,631,837 to Magoon ("Magoon"), which is incorporated herein by reference, and is specifically directed to a method for drying fruit pulp. In one embodiment of the present invention, the inventors have adapted this method to make the present films. The Magoon method and apparatus are based on an interesting property of water: water transmits energy by conduction and convection in and to its surroundings, but only radiates energy in and to the water. Thus, the Magoon apparatus includes an infrared transparent surface on which the pulp is placed. The underside of the surface is in contact with a temperature controlled water bath. The temperature of the water bath is desirably controlled to just below the boiling point of water. When the hydrated pulp is placed on the surface of the apparatus, this creates a "reflectance window." This means that infrared energy can only be emitted from the surface to the area of ​​the surface occupied by the pulp, and only until the pulp is dry. The Magoon apparatus provides the films of the present invention with effective drying times that mitigate instances of strong aggregation of the film's components.

[0143] The thickness of the final dry free-standing film disclosed herein and dosage units made therefrom can vary depending on the thickness of each layer and the number of layers. Both the thickness of the layers and the number of layers (i.e., one layer or multiple layers, e.g., two, three, four or more layers) can be adjusted to alter the erosion kinetics. The film can be initially about 500 μm to about 1,500 μm, or about 508 μm (20 mils) to about 1524 μm (60 mils) thick, and when dried, it becomes about 3 μm to about 250 μm, or about 2.54 μm (0.1 mils) to about 254 μm (10 mils) thick. Desirably, the dry film can be about 50.8 μm (2 mils) to about 203.2 μm (8 mils), more desirably about 76.2 μm (3 mils) to about 152.4 μm (6 mils) thick. When the final self-supporting film product (or dosage unit made therefrom) has two layers, the total film thickness can range from about 0.005 mm to about 2 mm, about 0.01 mm to about 1 mm, or 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, greater than 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 laminated 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%, less than about 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 laminated 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.

[0144] The final film products and dosage units disclosed herein may dissolve (including dispersion and dissolution) in about 30 seconds to about 24 hours, about 30 seconds to about 30 minutes, about 1 minute to about 24 hours, about 1 minute to about 30 minutes, about 1 minute to about 20 minutes, about 3 minutes to about 40 minutes, or about 5 minutes to about 30 minutes. The final self-supporting film products and dosage units disclosed herein may dissolve in more than about 1 minute, more than about 5 minutes, more than about 7 minutes, more than about 10 minutes, more than about 12 minutes, more than about 15 minutes, more than about 20 minutes, more than about 30 minutes, more than 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 may be less than the buccal dissolution rate. More specifically, oral dissolving film dosage units (also referred to as "unit doses") fall into three main categories: fast dissolving, medium dissolving, and slow dissolving. Oral dissolving film dosage units may also include any combination of the above categories. A fast dissolving film dosage unit may dissolve in the oral cavity in about 1 second to about 30 seconds, e.g., more than about 1 second, more than about 5 seconds, more than about 10 seconds, more than about 20 seconds, and less than about 30 seconds. A medium dissolving film dosage unit may dissolve in the oral cavity in about 1 to about 30 minutes, e.g., more than about 1 minute, more than about 5 minutes, more than about 10 minutes, more than about 20 minutes, and less than about 30 minutes. A slow dissolving film dosage unit may dissolve in the oral cavity in more than about 30 minutes, e.g., 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. A fast dissolving film dosage unit may include (or consist of) a low molecular weight hydrophilic polymer (e.g., a polymer having a molecular weight of about 1,000 to about 9,000 daltons, or a polymer having a molecular weight up to about 200,000 daltons), whereas a slow dissolving film dosage unit may include a high molecular weight polymer (e.g., having a molecular weight of several million).

[0145] A medium-dissolving film dosage unit may have the particular advantage of being somewhat fast dissolving while having a good degree of mucoadhesion. Medium-dissolving film dosage units are also soft, fast hydrating, and generally non-irritating to the patient. Such medium-dissolving film dosage units may provide a sufficiently fast dissolution rate, for example, about 1 minute to about 20 minutes, while providing an acceptable degree of mucoadhesion such that the film is not easily removed once placed in the patient's oral cavity. This may ensure complete delivery of the pharmacoactive agent to the patient. Self-supporting means that the film maintains its integrity and structure in the absence of any independent support. The films of the present disclosure are formulated for absorption through the oral mucosa, i.e., for example, buccal or sublingual. Although a variety of different film-forming techniques can be used, it is desirable to select a method that provides a flexible film, such as reverse roll coating. The flexibility of the film allows for the film sheet to be rolled and transported for storage or before being cut into individual dosage forms.

[0146] Use of thin films The thin films disclosed herein are well suited for many uses. The high uniformity of the film components makes them particularly well suited for pharmaceutical formulations. Furthermore, the polymers used in the construction of the film can be selected to allow a range of disintegration times for the film. By varying or extending the time at which the film disintegrates, control of the rate at which the active agent is released can be achieved, which allows for sustained release delivery systems. In addition, the films can be used to administer active agents to any of several body surfaces, particularly mucous membranes such as the mouth, anus, vagina, eye, skin surfaces, or internal wound surfaces during surgery, and similar surfaces. The film can be used to orally administer an active agent. This is accomplished by preparing the film as described above and introducing them into the oral cavity of a mammal. The film is prepared and adhered to a second or support layer, which is removed before use, i.e., introduction into the oral cavity. An adhesive can be used to attach the film to the support or underlying material, which adhesive can be any known in the art and is preferably non-water soluble. If an adhesive is used, it is desirably an ingestible food-grade adhesive that does not change the properties of the active agent. Mucoadhesive compositions are particularly useful. The film composition often acts as a mucoadhesive, itself.

[0147] The film can be applied under the tongue or on the tongue of a mammal. If this is desired, a particular film shape that corresponds to the shape of the tongue may be preferred. Thus, the film can be cut into a shape such that the side of the film corresponding to the dorsal surface of the tongue is longer than the side corresponding to the anterior surface of the tongue. Specifically, the desired shape may be a triangular or trapezoidal shape. Desirably, the film adheres to the oral cavity so that it is not expelled from the oral cavity, and allows more active agent to be introduced into the oral cavity as the film dissolves. Another use of the films disclosed herein takes advantage of the tendency of the films to dissolve quickly when placed in a liquid. An active agent can be introduced into a liquid by making a film according to the present invention, placing it in a liquid, and allowing it to dissolve. This can be used to prepare a liquid dosage form of the active agent or to flavor a beverage. The films of the present invention are desirably packaged in a sealed, airtight and moisture-proof package to protect the active agent from exposure to oxidation, hydrolysis, volatilization and interaction with the environment. Additionally, the films of the present invention dissolve rapidly upon contact with saliva or mucosal areas, eliminating the need to wash down the dose with water. Desirably, a series of such unit doses are packaged together according to a prescribed regimen or treatment, such as, for example, a 10-90 day supply depending on the particular therapy. Individual free-standing films can be packaged without or on a substrate and peeled off for use.

[0148] How to use Also disclosed herein is a method for treating epilepsy, epileptic seizures, and other forms of seizures in humans, comprising administering to the human an oral film for delivery of a desired amount of active agent in each unit dose.The film comprises: a) a water-soluble polymeric base, a water-swellable polymeric base, or a water-soluble and water-swellable polymeric base; b) an active agent having an average particle size D90 of less than about 160 microns; and c) an additive selected from the group consisting of sweeteners, flavorings, flavor enhancers, fillers, plasticizers, dyes, pigments, permeation enhancers, buffers, preservatives, silicon dioxide, anti-tack agents, and any combination thereof.The active agent in the oral film can have any of the dissolution profiles and rates described above. The active agent may be any active agent described herein, hi certain embodiments, the active agent may be clobazam, diazepam, riluzole, or any combination thereof. Another embodiment is directed to a method of treating Lennox-Gastaut syndrome in a human comprising administering to the human an oral film disclosed herein. The terms used in relation to these embodiments (methods of use) have the same meanings and definitions as set forth above.

[0149] The features and advantages of the present invention are more fully shown by the following examples, which are presented for illustrative purposes and should not be construed as limiting the invention in any way. EXAMPLES

[0150] Example 1 - Clobazam To compare ground and micronized active agents, oral films were prepared having the following compositions shown in Table 1. [Table 1]

[0151] Figure 3 shows the average active agent dissolution plots for films (N=3) containing 5 mg clobazam milled (D90=106 microns) and micronized (D90=8.3 microns) and RLD Onfi tablets. Table 2 presents some of the graphical data points shown in Figure 3. [Table 2] Thus, oral films containing micronized clobazam performed better (ie, dissolved significantly faster) than oral films containing milled clobazam.

[0152] Example 2 - Dissolution test of oral films containing diazepam Diazepam (DBSF)-containing oral thin films were prepared containing 5 mg and 15 mg of active agent. Dissolution of 5 mg and 15 mg of DBSF under storage conditions at 25° C. for 12 months was tested using conventional dissolution and PION techniques. Conventional dissolution, as used herein, is a common approach for testing the dissolution characteristics of solid oral dosage forms such as tablets and capsules. The conventional dissolution method uses a modified USP Apparatus 5 setup with a modified sample holder required to hold the film stationary. All other aspects of the conventional 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 the samples using HPLC. The conventional dissolution method is limited in practical terms by the frequency and consistency of manual sampling and removal of sample aliquots. The PION technique uses a conventional dissolution vessel with a non-conventional setup. The vessel is set up with Apparatus 2 (paddles) on which a modified sample holder is attached. An in-line fiber optic probe is placed within the vessel. Samples are tested in-situ at predetermined intervals. Sample collection is automated and analyzed in-line, with no need for sample withdrawal, manual sampling, or offline HPLC testing. A comparison of system parameters for conventional dissolution and PION technology for DBSF testing is shown in Table 3. [Table 3]

[0153] Figure 4 is a graph showing the active agent dissolution profile of DBSF as measured by conventional dissolution. Figure 5 is a graph showing the active agent dissolution profile of DBSF as measured by PION technology. Some data points and a comparison of the results obtained by conventional dissolution and the results obtained by PION technology are shown in Tables 4 and 5. [Table 4] [Table 5]

[0154] According to the calculations shown in Tables 4 and 5 above, the active agent dissolution profiles for the 5 mg oral films are similar, but the active agent dissolution profiles for the 15 mg oral films are not similar. However, with PION technology, the active agent dissolution profile is much more rigorous and improved with more time intervals available. With conventional dissolution, the active agent dissolution profile only includes seven data points, whereas the active agent dissolution profile obtained with PION technology is five times that amount. In addition, data is obtained immediately with PION technology, whereas the first data point with conventional dissolution is five minutes. For these fast dissolving dosage forms, activity up to five minutes can be an important differentiating factor.

[0155] Example 3 - Dissolution test of oral films containing riluzole An oral thin film containing 50 mg of riluzole (ROSF) was prepared. The dissolution of 50 mg of ROSF after approximately 6 months of storage at 25° C. was tested using conventional dissolution and PION techniques in 0.1 N HCL (a medium that mimics gastric conditions). The parameters used for conventional dissolution and PION techniques to test ROSF are shown in Table 3 above. Figure 6 is a graph of the active agent dissolution profile of ROSF as measured by conventional dissolution testing. Figure 7 is a graph of the active agent dissolution profile of ROSF as measured by PION technology. Some data points and a comparison of the results obtained by conventional dissolution and the results obtained by PION technology are shown in Table 6. [Table 6] According to the calculations presented in Table 6 above, the active agent dissolution profiles for the 50 mg oral film containing riluzole are similar. However, with PION technology, the active agent dissolution profile is much more rigorous and improved with more time intervals available. With conventional dissolution, the active agent dissolution profile only includes six data points, whereas the active agent dissolution profile obtained with PION technology is five times that amount. In addition, data is obtained immediately with PION technology, whereas the first data point with conventional dissolution is five minutes. For these fast dissolving dosage forms, activity up to five minutes can be an important differentiating factor.

[0156] Example 4 - Dissolution testing of oral films containing clobazam Clobazam (COSF)-containing oral thin films were prepared having the composition shown in Table 7 and containing 5 mg, 10 mg, and 20 mg of active agent. [Table 7]

[0157] The COSF used in these examples herein contained clobazam with a mean particle size D90 of 6-8 microns. Dissolution of 5 mg and 20 mg of COSF was tested using conventional dissolution and PION techniques. The parameters used for conventional dissolution and PION techniques to test COSF are shown in Table 3 above.

[0158] FIG. 8 is a graph showing the active agent dissolution profile of 5 mg COSF measured by conventional dissolution after approximately 24 months of storage at storage and accelerated conditions at 25° C. and 40° C. and RH 60, respectively. As shown therein, the film is almost completely released at the very early sample points. There is no active agent dissolution profile information in the critical time up to 10 minutes where most of the dissolution is occurring. The lack of precision of conventional dissolution is also clearly seen in this graph as there is no detectable difference between the active agent dissolution profiles of the two samples from 0 to 10 minutes.

[0159] In contrast, Figures 9 and 10 show the active agent dissolution profiles of COSF samples measured by PION technology. As shown in these figures, there are clearly detectable differences between samples with different storage conditions as well as different doses. Figure 9 is a graph of the active agent dissolution profiles of COSF measured by PION technology at different doses and temperatures, and Figure 10 is an expanded and smoothed curve of the same test as Figure 9. Figure 10 plots the active agent dissolution profiles from 0 to 10 minutes after about 12 months of storage conditions at about 25°C and about 40°C for these COSF doses at different storage conditions. Some data points and a comparison of the results obtained at different temperatures using PION technology are shown in Tables 8 and 9. [Table 8] [Table 9]

[0160] Calculations presented in Figures 9 and 10 and Tables 8 and 9 demonstrate the precision possible using PION technology, including measurement data points less than one minute, resulting in discernible, measurable differences between oral films containing different amounts of active agent and dosage form under different storage conditions. Figures 11 and 12 plot the second derivative of the active agent dissolution profiles measured by PION technology in Figures 9 and 10. Using this, calculation of the exact inflection points (identified on the figures) can be achieved.

[0161] Example 5: COSF Dose Comparison Clobazam (COSF)-containing oral thin films were prepared containing 5 mg, 10 mg, and 20 mg of active agent with the compositions shown in Table 7. These films were stored for about 24 months at about 25° C. and RH 60 and then tested using the PION technique to determine how the active agent dissolution profile differed between COSF containing different amounts of active agent. The parameters used for the PION technique are shown in Table 3 above. Figure 13 is a graph of the actual data points obtained and Figure 14 is a smoothed curve of the data points shown in Figure 13. As can be seen in these figures, there is a detectable difference between the active agent dissolution profiles of each film. 5 mg COSF has the fast release (steepest curve, reaching 100% in 2.5 min), followed by 10 mg COSF (reaching 100% in 3.0 min), and finally 20 mg COSF has the slowest release profile, approaching 100% after 7.0 min.

[0162] Figure 15 is a first derivative graph of the active agent dissolution profile of Figure 13. This graph provides information regarding the release rate. The intensity and width of the first derivative are proportional to the release rate. As shown by the height and width of the first derivative curves in this figure, the 5mg and 10mg COSF release faster and more completely within the first minute, and the 20mg COSF releases slower, i.e., the curves are shorter and wider (less intense). For all curves, the first derivative approaches 0 when release is complete and the drug concentration in the container reaches a plateau. The first derivative curves of the 5mg and 10mg COSF are substantially equal and reach a plateau sooner than the 20mg COSF curve. Again, as noted above with respect to Figure 8, these differences shown in Figures 13, 14 and 15 are not evident when using conventional lysis. It is only with the enhanced discrimination capabilities of the PION technology that these differences can be detected and recorded.

[0163] Example 6: Comparison of COSF under different storage conditions 5 mg, 10 mg, and 20 mg of COSF made as described above were tested using PION technology either: 1) after about 24 months of storage at RH60 and about 25° C.; 2) after about 24 months of storage at RH60 and about 40° C.; or 3) upon completion of the finished product (no storage time, T=about 0 months). The parameters used for the PION technology are shown in Table 3 above. Active agent dissolution profiles were compared to determine how different storage conditions affect dissolution rates.

[0164] FIG. 16 shows the active agent dissolution profiles of 5 mg, 10 mg, and 20 mg COSF after about 24 months of storage at about 25° C., RH60, and about 24 months of storage at about 40° C., RH60. For all film strengths, the active agent in the samples stored at 40° C. dissolves faster than the active agent in the same dosage form stored at 25° C. The active agent in the 5 mg COSF stored at 40° C. dissolves faster than the 10 mg COSF stored at 40° C., while the 20 mg COSF sample had the slowest dissolution profile. Here, the enhanced discrimination ability of the PION system is seen. The active agent dissolution profiles obtained using the PION technology are tight enough to show differences based on film strength and storage conditions, both of which surprisingly affect the dissolution rate of the active agent.

[0165] Statistical analysis based on FDA guidelines further indicates the similarity or lack thereof between different samples (strength / storage conditions / storage period / etc.). Using PION technology, the similarity or lack thereof is more evident than with traditional dissolution due to the improved accuracy as well as the first derivative formation. As shown in Table 10, for example, statistical similarity is shown between 5mg and 10mg at 25°C, but not between 5mg and 10mg, 25°C and 40°C. For similarity, f2 (similarity coefficient) should not be less than 50 and f1 (dissimilarity coefficient) should not be more than 15. [Table 10]

[0166] Figure 18 shows the active agent dissolution profiles of 5 mg, 10 mg and 20 mg COSF after about 24 months of storage at RH60 and about 25°C, and without storage (T = about 0 months). For both 5 mg and 10 mg COSF, the samples tested after storage dissolve faster than the finished samples of the same strength (T = 0). With regard to statistical similarity, the active agent dissolution profiles of the finished 5 mg and 10 mg COSF are not statistically similar to the comparable stored samples. The active agent dissolution profile of the finished 20 mg COSF sample is statistically similar to the stored 20 mg COSF sample. [Table 11] Figures 17 and 19 are the first derivative curves of the graphs of Figures 16 and 18, respectively. As shown by the height and width of the first derivative curves in the figures, the 5 mg and 10 mg COSF dissolve faster and more completely within the first minute, while the 20 mg COSF dissolves slower, i.e., the curves are shorter and wider (less intense). For all curves, the first derivative approaches 0 as dissolution is complete and the drug concentration in the container reaches a plateau. The first derivative curves of the 5 mg and 10 mg COSF reach a plateau sooner than the 20 mg COSF curve.

[0167] Example 7: Vehicle Comparison To determine how the choice of medium affects the dissolution rate, 5 mg, 10 mg, and 20 mg of COSF were prepared and tested using the PION technique (no shelf life). The parameters used for the PION technique are shown in Table 3 above. Thus, dissolution of the active agent in each film is tested in baths of either 0.1 N HCL, a 0.05 molar solution of monobasic potassium phosphate adjusted to pH 6.8 with sodium hydroxide, or water. Figure 20 shows the active agent dissolution profiles of 5 mg, 10 mg, and 20 mg of COSF in various media. Figure 21 is the first derivative curve of Figure 20. Even with the high discrimination power of PION technology, the medium selected does not affect dissolution, and samples of the same strength dissolved in various media are statistically equivalent. With conventional dissolution, active agent dissolution profiles generally do not provide this high level of information unless there is a clear solubility issue.

[0168] Example 8: Comparison of release of liquid mixtures and films Experiments were designed to evaluate the effect of additional excipients on the release of the active agent. Specificity is an aspect of method development to ensure that there is no interference with the quantification of the active agent by any of the excipients contained in the drug product. Thus, the active agent dissolution profiles of the following samples were measured by PION technology and are presented in Figure 22: · 5mg COSF finished product (shown as "nominal 5mg" in Figure 22); Liquid mixture of the film composition before drying; Placebo, i.e., a film containing all excipients other than the active agent; and · 5mg COSF finished product containing twice the amount of excipients (shown as "5mg w / 2 placebo" in Figure 22). As shown in Figure 22, the placebo, i.e., film without active agent, shows some interference - about 20% response. Thus, excipients and film dosage form alone affect the active agent dissolution profile. Figure 23 is the first derivative curve of Figure 22. It was assumed that the active agent in the liquid mixture would dissolve faster than the active agent in the film, which requires hydration, swelling, and then release of the active agent.However, it was unexpectedly found that the film had a faster dissolution profile than the liquid mixture.Based on these results, it is believed that the dry film that absorbs moisture into the substrate will promote the release and dissolution of the active agent.

[0169] Example 9: Evaluation of substrate performance During manufacturing, experiments were conducted to vary the substrate used in the drying step of oral films containing 20 mg clobazam. In particular, a 40 mil gap, various substrates for comparative evaluation were used and coated with the COSF 20 mg formulation. 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. [Table 12] All of the dried film samples could be removed from the substrate after drying. However, it was noted that the edges of the film adhered strongly to the glass substrate, and that adhesion was less pronounced on the polyethylene terephthalate corona-treated substrate. The best performing substrate was polyethylene terephthalate (untreated).

[0170] Example 10: Evaluation of clobazam solubility in COSF intermediates and finished products Experiments were conducted to evaluate the solubility of clobazam in the liquid mix (before drying) and in the oral film (COSF). Thin oral films containing 10 mg and 20 mg of clobazam were made and then dissolved in 1.5 ml of water. Two other samples were also evaluated, one was the active agent in water (no excipients added to the oral film composition) and the other was the liquid mix for the film that was tested prior to film formation (i.e., drying). The results of the evaluation are shown in Table 13. [Table 13] As shown in the table above, about 1% to about 2% of the clobazam dissolved in each test sample, while more than 98% remained dispersed. The wet mass samples, i.e., the liquid mixed composition of the film, dissolved less active agent than the film samples that were subsequently hydrated with 1.5 ml of water. This is because the drying step of the film formation method enhances the solubilization of the active agent in the formulation. Solubility is a function of the drying step and the size (e.g., thickness) of the film. For example, a 10 mg film will have a higher percent dissolution than a 20 mg film because the 10 mg film is thinner and therefore has more heat exposure per unit area during the drying step. Solubility is also proportional to the taste profile of the oral film.

[0171] While there has been described what are presently believed to be certain preferred embodiments of the present invention, it will be understood that changes and modifications can be made thereto without departing from the spirit of the invention, and such changes and modifications are intended to be within the true scope of the invention.

Claims

1. 1. A self-supporting oral film for delivering a desired amount of an active agent in each unit dose, comprising: a) a water-soluble, water-swellable, or water-soluble and water-swellable polymeric substrate; b) an active agent, clobazam, having a mean particle size D90 of less than about 160 microns; and c) additives selected from the group consisting of sweeteners, flavorings, flavor enhancers, fillers, plasticizers, dyes, pigments, penetration enhancers, buffers, preservatives, silicon dioxide, anti-tack agents, and any combination thereof; Including, A film, wherein when the film is placed in a medium, after about 5 minutes, about 40% or more of the active agent dissolves in the medium.

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

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

4. 3. The film of claim 2, wherein the active agent has an average particle size D10 of less than about 10 microns.

5. 10. The film of claim 1, wherein when the film is placed in a medium, greater than about 55% of the active agent dissolves after about 5 minutes.

6. 10. The film of claim 1, wherein when the film is placed in a medium, greater than about 5% of the active agent dissolves after about 1.5 minutes.

7. 10. The film of claim 1, wherein each unit dose contains from about 2 mg to about 20 mg of clobazam.

8. 8. The film of claim 7, wherein each unit dose contains about 5 mg of clobazam.

9. 10. The film of claim 8, wherein when the film is placed in a medium, greater than about 30% of the active agent dissolves after about 1 minute.

10. 10. The film of claim 8, wherein when the film is placed in a medium, greater than about 70% of the active agent dissolves after about 2 minutes.

11. 10. The film of claim 8, wherein when the film is placed in a medium, greater than about 90% of the active agent dissolves after about 2.5 minutes.

12. 8. The film of claim 7, wherein each unit dose contains about 10 mg of clobazam.

13. 13. The film of claim 12, wherein when the film is placed in a medium, greater than about 50% of the active agent dissolves after about 1.5 minutes.

14. 13. The film of claim 12, wherein when the film is placed in a medium, greater than about 70% of the active agent dissolves after about 2.5 minutes.

15. 8. The film of claim 7, wherein each unit dose contains about 20 mg of clobazam.

16. 16. The film of claim 15, wherein when the film is placed in a medium, greater than about 2% of the active agent dissolves after about 1.5 minutes.

17. 16. The film of claim 15, wherein when the film is placed in a medium, greater than about 40% of the active agent dissolves after about 3.5 minutes.

18. The film of claim 1 for use in a method for treating epilepsy and / or seizures in a human comprising administering to the human a unit dose of the oral film of claim 1.

19. The film of claim 1, wherein when the film is placed in a medium, at least about 20% of the active agent dissolves after about 3 minutes.

20. The film of claim 1, wherein the water-soluble polymer substrate, the water-swellable polymer substrate, or the water-soluble and water-swellable polymer substrate comprises a polymer selected from polyethylene oxide (PEO), pullulan, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, 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 agent has an average particle size D90 of about 8 microns to 160 microns or less.

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