Oral film compositions and dosage forms having precise active dissolution profiles

Abstract

To solve the following problem: since oral films dissolve rapidly, improved dissolution testing is needed for these rapid dissolving products, which enables precise measurements almost immediately upon placement in a liquid and at very small time intervals.SOLUTION: An oral film in an individual unit dose for delivery of one or more actives is disclosed herein, the film having a precisely calculated and controlled active dissolution profile. A wide variety of actives may be used, including, for example, clobazam, diazepam, or riluzole. Also disclosed are methods of treating a variety of diseases and conditions, for example, epilepsy and seizures, by administering the oral film disclosed herein.SELECTED DRAWING: None

Description

Technical Field

[0001] Field of Disclosure The present disclosure relates to an oral film for each unit dose for the delivery of one or more active agents, such as clobazam, having an average particle size D90 of less than about 160 microns, the oral film having a tightly controlled active agent dissolution rate, and a method of treating various diseases, including epilepsy and seizures, by administering the same to a patient in need thereof.

Background Art

[0002] Background An active ingredient, such as a drug or medicine, can be prepared in tablet form to enable accurate and consistent administration. However, the preparation and distribution of drugs in this form have many drawbacks, including the need to add a large proportion of excipients to make them of a manageable size, the need for more storage space for larger drug forms, and inaccurate counting of tablets that tend to be distributed. In addition, it is difficult to swallow for a large number, estimated to be 28% of the population. Tablets may be broken into smaller pieces or even crushed as a means of overcoming dysphagia, but this does not result in a suitable solution for many tablet or pill forms. For example, crushing or breaking a tablet or pill form alone or mixed with food to aid oral ingestion also impairs the release control characteristics. Films may be used instead of tablets and pills to carry active ingredients such as drugs and medicines. Historically, however, methods of making films and drug delivery systems using this dosage form have presented several unique challenges in both the fields of formulation, processing, and pharmacokinetics. In particular, films and oral dosage units cut from films have suffered from several disadvantageous features that have not allowed their practical use until recent years when advances have made films a highly desirable dosage form. Similar to conventional tablets and pills, the absorption of drugs administered in the form of oral films varies depending on several factors, including the release of the active ingredient from the film, the dissolution and solubilization of the drug under physiological conditions. In one mode, in vitro dissolution serves as an appropriate predictor of in vivo performance. In vitro dissolution tests for immediate-release oral dosage forms are used to evaluate the quality of pharmaceuticals between batches; to provide guidance for the development of new formulations; and to ensure product quality, bioavailability equivalence, and performance as the product undergoes changes.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Since oral films dissolve rapidly, these rapidly dissolving products require an improved dissolution test that enables accurate measurement almost immediately and at very short time intervals when placed in a liquid.

Means for Solving the Problems

[0004] Overview Disclosed is an oral film for delivering a desired amount of an active agent having an average particle size D90 of less than about 160 microns in each unit dose. The film comprises a water-soluble polymer substrate, a water-swellable polymer substrate, or a water-soluble and water-swellable polymer substrate; and additives. 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 additives can be selected from the group consisting of sweeteners, flavoring agents, seasonings, fillers, plasticizers, dyes, pigments, penetration enhancers, buffers, preservatives, silicon dioxide, anti-adhesion 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, or about 30% of the active agent dissolves after about 3 minutes, or about 30% of the active agent dissolves after about 1 minute, or more than about 50% of the active agent dissolves after about 1 minute, or more than about 95% of the active agent dissolves after about 2.5 minutes, or more than about 40% of the active agent dissolves after about 3.5 minutes, or more than about 55% of the active agent dissolves after about 5 minutes, or more than about 75% of the active agent dissolves after about 5 minutes, or more than about 85% of the active agent dissolves after about 6.5 minutes, or more than about 95% of the active agent dissolves in the medium after about 10 minutes. Thus, in certain embodiments, the dissolution of the active agent is measured after storage of the film at 0 months to about 36 months, about 20°C to about 60°C, and / or a relative humidity (RH) of up to about 75%, or an RH of about 60%.

[0007] The oral film may contain a sweetening agent selected from the group consisting of sucralose, stevia, acesulfame potassium, saccharin, fructose, aspartame, and any combination thereof, optionally present at about 0.5 to about 5% by weight of the composition. The oral film may contain a berry flavor, optionally 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 human in need thereof an oral film containing an active agent in each unit dose.

Brief Description of the Drawings

[0008]

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Mode for Carrying Out the Invention

[0009] Detailed Description To ensure batch - to - batch consistency and to identify potential issues regarding the bioavailability of pharmaceutical active agents, dissolution profiles of oral films and pharmaceuticals containing active agents are established, more specifically, dissolution rates. A surprising new means for more accurately and precisely testing dissolution profiles has been developed using PION technology, an optical fiber UV monitoring system. Disclosed herein is an oral film for delivering a desired amount of an active agent having an average particle size D90 of less than about 160 microns in each unit dose, which has an improved accuracy, a larger number of sampling points, and a more rapid evaluation of changes in the activator dissolution profile compared to the 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 polymer substrate, a water-swellable polymer substrate, or a water-soluble and water-swellable polymer substrate; 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. A substantially uniform distribution is evaluated by each unit dose being of substantially the same size and having no more than a 10% variation from the desired amount of the active agent. Films containing an active agent can be made by, for example, the casting method 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 made as each well or strip, such as those disclosed in U.S. Patent 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" can include films and sheets of any shape, including rectangular, square, or other desired shapes. The film can be of any desired thickness and size. In certain embodiments, the film can be of a thickness and size such that it can be administered to a patient, for example, by placing it in the mouth. The film can be relatively thin, for example, from about 0.0025 mm to about 0.250 mm, or the film can be somewhat thicker, for example, from about 0.250 mm to about 1.0 mm. Depending on the film, it can be even thicker, for example, exceeding about 1.0 mm, or even thinner, for example, less than about 0.0025 mm. The film can be single-layered, or the film can be multi-layered, including laminated or multi-layer cast films. In the case of being multi-layered, the active agent can be present in one layer, in two or more layers (but not all layers), or in all layers. The active agent can be present in the mucosal contact layer. The active agent can be combined with one or more additives in a single layer, can be contained in separate layers, or otherwise can be contained in discrete regions of the same dosage form.

[0012] Active agent The film can be processed such that the active agent is substantially uniformly distributed throughout. For example, when a film such as a cast film is cut into unit dosages of substantially the same size, the amount of the active agent in the unit dosage is known to be with a certain degree of accuracy. This accuracy in dosage is particularly advantageous and is actually required by government regulatory agencies such as the US FDA when the active agent is a medicament, i.e., a drug. Active agents that can be incorporated into the film of the present invention include, but are not limited to, pharmaceutical and cosmetic active agents, drugs, medicaments, antigens or allergens such as ragweed pollen, spores, microorganisms including bacteria, seeds, oral rinse components such as chlorates or chlorites, perfumes, fragrances, enzymes, preservatives, sweeteners, colorants, spices, vitamins, and combinations thereof.

[0013] The amount of the active agent in the film varies depending on several factors including, for example, the active agent selected, the desired treatment intensity, the number of layers of the film, and the formulation selected, as will be readily understood by those skilled in the art. Pharmaceutical active agents include film compositions of 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, for example, 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, about 50% by weight, greater than about 50% by weight, less 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. The amounts of the other components can vary depending on the active agent and the other components, but generally these components are about 50% or less, about 30% or less, or about 15% or less of the total weight of the film composition.

[0014] Suitable active agents for use in the film in this specification include, but are not limited to, the following therapeutic categories: ACE inhibitors; adrenergic agents; corticosteroids; adrenocortical suppressants; aldosterone antagonists; alkaloids; amino acids; anabolic agents; central nervous system stimulants; analgesics; anesthetics; anorectics; antiacne agents; antiadrenergic agents; antiallergic agents; antiamebic agents; antianemics; antianginal agents; anxiolytics; antiarthritis agents; antiarrhythmics; antiasthmatics; antiatherosclerotic agents; antihypercholesterolemic agents; antibacterial agents; antibiotics; anticholinergic agents; anticoagulants; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antidiuretics; antidotes; antiemetics; antiepileptics; antifibrinolytics; antifungal agents; hemostatics; antihistamines; antihyperlipidemics; antihypertensives; hypotensives; anti-infectives (both systemic and non-systemic); anti-inflammatory agents; antilipid agents; antimanics; antimicrobials; antimigraine agents; antimitotics; antifungal agents; antidepressants; antineoplastics; antineutropenia agents; antiobesity agents; antiparasitic agents; antiparkinson agents; antiproliferatives; antipsychotics; antipyretics; antirheumatics; antiseborrheics; secretory suppressants; antispasmodics; antistroke agents; antithrombotic agents; antithyroid agents; antitumor agents; antitussives; antiulcer agents; antihyperuricemic agents; antivirals; anorexics; appetite stimulants; biological response modifiers; blood glucose regulators; blood modifiers; blood metabolic regulators; bone resorption inhibitors; bronchodilators; cardiovascular agents; central nervous system stimulants; cerebral dilators; contraceptives; coronary dilators; cholinergic agents; antitussives; stasis removers; inhibitors; diagnostic aids; dietary supplements; diuretics; dopaminergic agents; enzymes; estrogen receptor agonists; endometriosis management agents; expectorants; erectile dysfunction therapies; erythropoietin; fibrinolytic; ovulation stimulants; fluorescent agents; free oxygen radical scavengers; gastric acid suppressants; gastrointestinal motility promoters; gene modifiers; glucocorticoids; hair growth stimulants; hemostatics; histamine H2 receptor antagonists; homeopathic remedies; hormones; hypercalcemia management agents; hypocalcemia management agents; cholesterol lowering agents; blood glucose lowering agents; lipid lowering agents; antihypertensives; ion exchange resins; contrast agents; immunizing agents; immunomodulators; immunoregulators; immunostimulants; immunosuppressants; keratolytics; laxatives; LHRH agonists; mood regulators; motion sickness remedies; mucolytics; muscle relaxants; mydriatics; nasal decongestants; neuromuscular blockers; neuroprotective agents; 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] Analgesics include opioids and opioid derivatives, such as oxycodone (marketed as Oxycontin®); ibuprofen (marketed 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 (marketed as 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 include 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 (commercially available as Duragesic®, Onsolis®, and Fentora®), sodium hyaluronate (commercially available as Euflexxa®), adalimumab (commercially available as Humira®), sumatriptan succinate (commercially available as Imitrex®), fentanyl iontophoretic transdermal system (commercially available as Ionsys®), orphenadrine citrate (commercially available as Norgesic®), magnesium salicylate tetrahydrate (commercially available as Novasal®), oxymorphone hydrochloride (commercially available as Opana 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®) and other pain relievers can also be used in the present invention.

[0017] The films disclosed in this specification may further include drugs such as NSAIDs including etodolac (commercially available as Lodine®), ketorolac tromethamine (commercially available as Acular® or Acuvail®), sodium naproxen (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 (commercially available as Feldene®), indomethacin (commercially available as Indocin®), meloxicam (commercially available as Mobic®), mefenamic acid (commercially available as Ponstel®), sodium tolmetin (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®). Opioid 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 in this specification include antidiarrheals such as loperamide (commercially available as Imodium AD®, Imotil®, Kaodene®, Imperim®, Diamode®, QC Anti-Diarrheal®, Health Care America Anti-Diarrheal®, Leader A-D®, and Imogen®), nitazoxanide (commercially available as Alinia®), and diphenoxylate hydrochloride / atropine sulfate (commercially available as Lomotil®), antihistamines, cough suppressants, blood stasis removers, vitamins, and oral cooling agents. Common drugs used alone or in combination for colds, pain, fever, cough, blood stasis, runny nose, and allergies, such as acetaminophen, ibuprofen, chlorpheniramine 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 composition of the present invention.

[0019] Other active agents useful herein include, but are not limited to, alcohol dependence treatment agents such as acamprosate calcium (commercially available as Campral®); allergy treatment agents such as promethazine hydrochloride (commercially available as Phenergan®), bepotastine besilate (commercially available as Bepreve®), hydrocodone polistirex / chlorpheniramine polistirex (commercially available as Tussionex®), cetirizine hydrochloride (commercially available as Zyrtec®), cetirizine hydrochloride / pseudoephedrine hydrochloride (commercially available as Zyrtec-D®), promethazine hydrochloride / codeine phosphate (commercially available as codeine-containing Phenergan®), 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®), desloratadine (commercially available as Clarinex®), cromolyn sodium (commercially available as Crolom®), epinastine hydrochloride (commercially available as Elestat®), azelastine hydrochloride (commercially available as Optivar®), prednisolone sodium phosphate (commercially available as Orapred ODT®), olopatadine hydrochloride (commercially available as Patanol®), ketotifen fumarate (commercially available as Zaditor®), and montelukast sodium (commercially available as Singulair®); and antihistamines such as diphenhydramine HCl (available as Benadryl®), loratadine (available as Claritin®), astemizole (available as Hismanal®), nabumetone (available as Relafen®), diphenhydramine HCL (available as TheraFlu®) and clemastine (available as Tavist®).

[0020] The film of the present disclosure further includes Alzheimer's disease therapeutics, 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®), caprilonide (commercially available as Axona®), and memantine (commercially available as Namenda®); hematinics, such as cyanocobalamin (commercially available as Nascobal®) and ferumoxitol (commercially available as Feraheme®); anesthetics, such as antipyrine and benzocaine (commercially available as Auralgan®, 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®); antitussives, such as guaifenesin; anti - Alzheimer's disease drugs, such as nicergoline; and Ca H antagonists, such as nifedipine (commercially available as Procardia® and Adalat®), may also be included.

[0021] Also useful as active agents in the present disclosure are anti-asthmatic 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 inhaler (commercially available as Ventolin®), terbutaline sulfate (commercially available as Brethine®), formoterol (commercially available as Foradil®), cromolyn sodium (commercially available as Intal®), levalbuterol 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 inhibitor (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®) may also be included.;

[0022] The film of the present disclosure further contains one or more antibiotics, for example, amoxicillin (commercially available as Amoxil®), ampicillin (commercially available as Omnipen®, Polycillin®, and Principen®), amoxicillin / potassium clavulanate (commercially available as Augmentin®), moxifloxacin hydrochloride (commercially available as Avelox®), besifloxacin (commercially available as Besivance®), clarithromycin (commercially available as Biaxin®), cefibuten (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 T®), doxycycline hydrochloride (commercially available as Doryx®), dirithromycin (commercially available as Dynabac®), erythromycin (commercially available as E.E.S.®, E-Mycin®, Eryc®, Ery-Tab®, Erythrocin®, and PCE®), topical erythromycin (commercially available as A / T / S®, Erycette®, T-Stat®), gemifloxacin (commercially available as Factive®), ofloxacin (commercially known as Ocuflox®, Floxin®), telithromycin (commercially available as Ketek®), lomefloxacin hydrochloride (commercially available as Maxaquin®), minocycline hydrochloride (commercially available as Minocin®), fosfomycin trometamol (commercially available as Monurol®), penicillin and potassium (commercially available as Penicillin VK®, Veetids®), trimethoprim (commercially available as Primsol®), ciprofloxacin hydrochloride (ProquinCommercially available as XR (registered trademark), Rifampin, Isoniazid and Pyrazinamide (commercially available as Rifater (registered trademark)), Cefditoren (commercially available as Spectracef (registered trademark)), Cefixime (commercially available as Suprax (registered trademark)), Tetracycline (commercially available as Achromycin V (registered trademark) and Sumycin (registered trademark)), Tobramycin (commercially available as Tobrex (registered trademark)), Rifaximin (commercially available as Xifaxan (registered trademark)), Azithromycin (commercially available as Zithromax (registered trademark)), Azithromycin suspension (commercially available as Zmax (registered trademark)), Linezolid (commercially available as Zyvox (registered trademark)), Benzoyl peroxide and Clindamycin (commercially available as BenzaClin (registered trademark)), Erythromycin and Benzoyl peroxide (commercially available as Benzamycin (registered trademark)), Dexamethasone (commercially available as Ozurdex (registered trademark)), Ciprofloxacin and Dexamethasone (commercially available as Ciprodex (registered trademark)), Polymyxin B sulfate / Neomycin sulfate / Hydrocortisone (commercially available as Cortisporin (registered trademark)), Colistin sulfate / Neomycin sulfate / Hydrocortisone acetate / Tonzonium bromide (commercially available as Cortisporin-TC Otic (registered trademark)), Cephalexin hydrochloride (commercially available as Keflex (registered trademark)), Cefdinir (commercially available as Omnicef (registered trademark)), and Gatifloxacin (commercially available as Zymar (registered trademark)) may also be included.

[0023] Other useful active agents include cancer therapeutic agents 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 therapeutic agents such as ofatumumab (commercially available as Arzerra®); antithrombotic agents such as recombinant antithrombin lyophilized powder (commercially available as Atryn®), prasugrel (commercially available as Efient®); anticoagulants such as aspirin and sustained 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 (commercially available as Hep-Lock, Hep-Pak, Hep-Pak CVC, Heparin Lock Flush), tinzaparin (commercially available as Innohep®), and clopidogrel bisulfate (commercially available as Plavix®); antiemetic agents 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 therapeutic agents, 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®) are included.;

[0024] As active agents, there are further anti-inflammatory agents, for example, 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 (commercially available as Entocort EC®), anakinra (commercially available as Kineret®), diflorasone diacetate (commercially available as Psorcon®), and etanercept (commercially available as Enbrel®); antispasmodics, for example, phenobarbital / hioscyamine sulfate / atropine sulfate / scopolamine hydrobromide (commercially available as Donnatal®); antiviral therapeutic agents, for example, oseltamivir phosphate (commercially available as Tamiflu®); antiparasitic agents, for example, tinidazole (commercially available as Tindamax®); appetite treatment agents, for example, megestrol acetate (commercially available as Megace ES®), phentermine hydrochloride (commercially available as Adipex-P®), and diethylpropion hydrochloride (commercially available as Tenuate®); arthritis agents, for example, 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, for example, 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, for example, methylergonovine maleate (commercially available as Methergine®);Plasma uric acid management agents, for example, marketed as rasburicase (Elitek (registered trademark)); iron deficiency anemia agents, for example, marketed as ferumoxytol (Feraheme (registered trademark)); lymphoma agents, for example, pralatrexate (marketed as Folotyn (registered trademark)), romidepsin (marketed as Isodax (registered trademark)); malaria agents, for example, artemether / lumefantrine (marketed as Coartem (registered trademark)); hyponatremia agents, for example, tolvaptan (marketed as Samsca (registered trademark)); drugs for the treatment of von Willebrand disease (marketed as Wilate (registered trademark)); antihypertensive agents, for example, treprostinil (marketed as Tyvaso (registered trademark)), tadalafil (marketed as Adcirca (registered trademark));Cholesterol-lowering agents, such as paricalcitol (commercially available as Altocor®), pitavastatin (commercially available as Livalo®), lovastatin, niacin (commercially available as Advicor®), cholestyramine 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®), pravastatin sodium and buffered aspirin (commercially available as 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®) may also be included.;

[0025] The active agents included in this specification also include drugs for chronic kidney disease, 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 (commercially available as 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 formoterol fumarate (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®); drugs for the treatment of diabetes, such as pioglitazone hydrochloride, metformin hydrochloride (commercially available as ACTOplus met®), bromocriptine mesylate (commercially available as Cycloset®), 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®), glypidide (commercially available as Glucotrol®), glibride, metformin (commercially available as Glucovance® and Fortamet®), metformin hydrochloride (commercially available as Glumetza®), sitagliptin (commercially available as Januvia®), detemir (commercially available as Levemir®), glypidide, metformin hydrochloride (commercially available as Metaglip®), glibride (commercially available as Micronase®), repaglinide (commercially available as Prandin®), acarbose (commercially available as Precose®), nateglinide (commercially available as Starlix®), pramlintide acetate (commercially available as Symlin®), canagliflozin (commercially available as Invokana®), linagliptin (commercially available as Tradjenta®), dapagliflozin (commercially available as Farxiga®), 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®) may also be included.

[0026] Other useful active agents include digestive agents 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 (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, for example, 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®) may also be included.;

[0027] Active agents useful herein may also include therapeutic agents for emphysema, for example, tiotropium bromide (commercially available as Spiriva®); agents for fibromyalgia, for example, milnacipran hydrochloride (commercially available as Savella®); agents for the treatment of gout, for example, colchicine (commercially available as Colcrys®), and febuxostat (commercially available as Uloric®); enema therapeutic agents, for example, aminosalicylic acid (commercially available as Mesalamine® and Rowasa®); antiepileptic agents, for example, 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®) may also be included.

[0028] Also useful as active agents in this specification are ophthalmic drugs and therapeutic agents such as dipivefrin hydrochloride (commercially available as Propine®), valganciclovir (commercially available as Valcyte®), ganciclovir ophthalmic 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 (commercially available as Alphagan 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 modifiers 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® containing 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 / dichloralphenazone / acetaminophen (commercially available as Midrin®), dihydroergotamine mesylate (commercially available as Migranal®), eletriptan hydrobromide (commercially available as Relpax®), and zolmitriptan (commercially available as Zomig®); influenza medications, such as Haemophilus b conjugate vaccine; tetanus toxoid conjugate (commercially available as Hiberix®); and heart therapeutics, such as quinidine sulfate, isosorbide dinitrate / hydralazine hydrochloride (commercially available as BiDil®), digoxin (commercially available as Lanoxin®), flecainide 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®) may also be included.;

[0029] Other useful active agents include hepatitis therapeutic agents, such as entecavir (commercially available as Baraclude®), hepatitis B immunoglobulin (commercially available as HepaGam B®), and copegus / rebetaol / ribasphere / vilona / virazol (commercially available as Ribavirin®); herpes therapeutic agents, such as valacyclovir hydrochloride (commercially available as Valtrex®), penciclovir (commercially available as Denavir®), acyclovir (commercially available as Zovirax®), and famciclovir (commercially available as Famvir®); hypertension therapeutic agents, such as enalaprilat (available as Vasotec®), captopril (available as Capoten®) and lisinopril (available as Zestril®), verapamil hydrochloride (available as Calan®), ramipril (commercially 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 (AtacandCommercially available as HCT (registered trademark), irbesartan / hydrochlorothiazide (commercially available as Avalide (registered trademark)), irbesartan (commercially available as Avapro (registered trademark)), amlodipine besylate / orvalsartan medoxomil (commercially available as Azor (registered trademark)), levobunolol hydrochloride (commercially available as Betagan (registered trademark)), betaxolol hydrochloride (commercially available as Betoptic (registered trademark)), nebivolol (commercially available as Bystolic (registered trademark)), captopril / hydrochlorothiazide (commercially available as Capozide (registered trademark)), doxazosin mesylate (commercially available as Cardura (registered trademark)), clonidine hydrochloride (commercially available as Catapres (registered trademark)), carvedilol (commercially available as Coreg (registered trademark)), nadolol (commercially available as Corgard (registered trademark)), nadolol / bendroflumethiazide (commercially available as Corzide (registered trademark)), valsartan (commercially available as Diovan (registered trademark)), isradipine (commercially available as DynaCirc (registered trademark)), guanabenz acetate (commercially available as Wytensin (registered trademark)), guanfacine hydrochloride (commercially available as Tenex (registered trademark) or Intuniv (registered trademark)), losartan potassium / hydrochlorothiazide (commercially available as Hyzaar (registered trademark)), propranolol hydrochloride (commercially available as Indera (registered trademark)), propranolol hydrochloride / hydrochlorothiazide (commercially available as Inderide (registered trademark)), eplerenone (commercially available as Inspra (registered trademark)), ambrisentan (commercially available as Letairis (registered trademark)), enalapril maleate / felodipine (commercially available as Lexxel (registered trademark)), metoprolol tartrate (commercially available as Lopressor (registered trademark)), benazepril hydrochloride (commercially available as Lotensin (registered trademark)), benazepril hydrochloride / hydrochlorothiazide (LotensinCommercially available as HCT (registered trademark), amlodipine / benazepril hydrochloride (commercially available as Lotrel (registered trademark)), indapamide (commercially available as Lozol (registered trademark)),trandolapril (commercially available as Mavik (registered trademark)), telmisartan (commercially available as Micardis (registered trademark)), telmisartan / hydrochlorothiazide (commercially available as Micardis HCT (registered trademark)), prazosin hydrochloride (commercially available as Minipress (registered trademark)), amiloride, hydrochlorothiazide (commercially available as Moduretic (registered trademark)), fosinopril sodium (commercially available as ZZXT Monopril (registered trademark)), fosinopril sodium / hydrochlorothiazide (commercially available as Monopril-HCT (registered trademark)), pindolol (commercially available as Visken (registered trademark)), felodipine (commercially available as Plendil (registered trademark)), sildenafil citrate (commercially available as Revatio (registered trademark)), nisoldipine (commercially available as Sular (registered trademark)), trandolapril / verapamil hydrochloride (commercially available as Tarka (registered trademark)), aliskiren (commercially available as Tekturna (registered trademark)), eprosartan mesylate (commercially available as Teveten (registered trademark)), eprosartan mesylate / hydrochlorothiazide (commercially available as Teveten HCT (registered trademark)), moexipril hydrochloride / hydrochlorothiazide (commercially available as Uniretic (registered trademark)), moexipril hydrochloride (commercially available as Univasc (registered trademark)), enalapril maleate / hydrochlorothiazide (commercially available as Vaseretic (registered trademark)), and lisinopril / hydrochlorothiazide (commercially available as Zestoretic (registered trademark)) are included.

[0030] The films of the present disclosure are useful for drugs for the treatment of HIV / AIDS, such as agents, for example, 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 (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®); homocysteiene removers, for example, betaine anhydrous (commercially available as Cystadane®); drugs such as insulin (commercially available as Apidra®, Humalog®, Humulin®, Iletin®, Tresiba®, and Novolin®); and HPV therapeutic agents, for example, human papillomavirus vaccine (commercially available as Gardasil®) or bivalent human papillomavirus (commercially available as Cervarix®);It may contain immunosuppressive agents, for example, cyclosporine (commercially available as Gengraf®, Neoral®, Sandimmune®, and Apo-Cyclosporine®).;

[0031] Also useful as an active agent in the present disclosure are prolactin inhibitors such as bromocriptine mesylate (commercially available as Parlodel®); agents for addition to stress tests such as regadenoson (commercially available as Lexiscan®); alopecia agents such as finasteride (commercially available as Propecia® and Proscar®); pancreatitis therapeutic agents such as gemfibrozil (commercially available as Lopid®); hormonal agents such as norethindrone acetate / ethinyl estradiol (commercially available as femHRT®), goserelin acetate (commercially available as Zoladex®), 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 disorder drugs, for example, estradiol / norethindrone acetate (marketed as Activella®), drospirenone / estradiol (marketed as Angeliq®), estradiol / levonorgestrel (marketed as Climara Pro®), estradiol / norethindrone acetate (marketed as CombiPatch®), estradiol (marketed as Estrasorb®, Vagifem®, and EstroGel®), esterified estrogen and methyltestosterone (marketed as Estratest®), estrogen (marketed as Alora®, Climara®, Esclim®, Estraderm®, Vivelle®, Vivelle-Dot®), estropipate (marketed as Ogen®), conjugated estrogen (marketed as Premarin®), and medroxyprogesterone acetate (marketed as Provera®); menstrual drugs, for example, leuprolide acetate (marketed as Lupron Depot), tranexamic acid (marketed as Lysteda®), and norethindrone acetate (marketed as Aygestin®); and muscle relaxants, for example, cyclobenzaprine hydrochloride (marketed as Flexeril®), tizanidine (marketed as Zanaflex®), and hyoscyamine sulfate (marketed as Levsin®) may also be included.;

[0032] Useful active agents in this specification may also include osteoporosis drugs, such as sodium ibandronate (commercially available as Boniva®), risedronate (commercially available as Actonel®), raloxifene hydrochloride (commercially available as Evista®, Fortical®), and sodium alendronate (commercially available as Fosamax®); ovulation stimulants, such as clomiphene citrate (commercially available as Serophene®, Clomid®, Serophene®); Paget's disease therapeutic agents, such as disodium etidronate (commercially available as Didronel®); pancreatic enzyme deficiency drugs, such as pancrelipase (commercially available as Pancrease® or Zenpep®); drugs for the treatment of Parkinson's disease, such as pramipexole dihydrochloride (commercially available as Mirapex®), ropinirole hydrochloride (commercially available as Requip®), carbidopa / levodopa (commercially available as 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 β-Ib (commercially available as Extavia®); prostate drugs, 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 film of the present invention further contains psychotropic drugs, such as alprazolam (available as Niravam®, Xanax®), clozapine (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®), paroxetine hydrochloride (available as Paxil®), aripiprazole (commercially available as Abilify®), guanfacine (commercially available as Intuniv®), amphetamine and methamphetamine (commercially available as Adderall® and Desoxyn®), clomipramine hydrochloride (commercially available as Anafranil®), buspirone hydrochloride (commercially available as BuSpar®), citalopram hydrobromide (commercially available as Celexa®), duloxetine hydrochloride (commercially available as Cymbalta®), methylphenidate (commercially available as Ritalin, 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 (commercially available as Eskalith®), fluvoxamine maleate / dexmethylphenidate hydrochloride (commercially available as Focalin®), ziprasidone hydrochloride (commercially available as Geodon®), ergoloid mesylate (commercially available as Hydergine®), escitalopram oxalate (commercially available as Lexapro®), chlordiazepoxide (commercially available as Librium®), molindone hydrochloride (commercially available as Moban®), phenelzine sulfate (commercially available as Nardil®),Thiotixene (commercially available as Navane®), desipramine hydrochloride (commercially available as Norpramin®), benzodiazepine (e.g., those available as Oxazepam®), nortriptyline hydrochloride (commercially available as Pamelor®), tranylcypromine sulfate (commercially available as Parnate®), prochlorperazine, mirtazapine (commercially available as Remeron®), risperidone (commercially available as Risperdal®), quetiapine fumarate (commercially available as 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®) may also be included.

[0034] Also useful as active agents in this specification are uric acid lowering agents such as allopurinol (commercially available as Zyloprim®); anticonvulsants such as gabapentin (commercially available as Neurontin®), ethotoin (commercially available as Peganone®), vigabatrin (commercially available as Sabril®), and topiramate (commercially available as Topamax®); agents for treating herpes zoster such as live herpes zoster 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 (commercially available as Cetacort®, 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 / 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®) may also be included.;

[0035] Other active agents useful in the present specification include sleep disorder drugs, 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®);and may include steroids such as alclometasone dipropionate (commercially available as Aclovate®), betamethasone dipropionate ester (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 ester (commercially available as Lotrisone®), prednisolone acetate (commercially available as Pred Forte®, Prednisone®, Budesonide Pulmicort®, Rhinocort Aqua®), prednisolone sodium phosphate (commercially available as Pediapred®), desonide (commercially available as Tridesilon®), and halobetasol propionate ester (commercially available as Ultravate®).;

[0036] The film of the present invention may further contain active agents useful for the treatment of thyroid diseases, such as hormones TC and TD (commercially available as Armour Thyroid®); agents for treating potassium deficiency, such as potassium chloride (commercially available as Micro-K®); triglyceride regulators, such as omega-3-acid ethyl esters (commercially available as Omacor®); urinary agents, such as phenazopyridine hydrochloride (commercially available as Pyridium®) and methenamine, methylene blue / phenyl salicylate / benzoic acid / atropine sulfate / hioscyamine (commercially available as Urised®); vitamins for pregnant women (commercially available as Advanced Natalcare®, Materna®, Natalins®, Prenate Advance®); weight management 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 acexatidine.

[0038] Effective antacid components include, but are not limited to, the following: aluminum hydroxide, dihydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate, sodium aluminum carbonate dihydroxide, bicarbonates, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth subsalicylate, calcium carbonate, calcium phosphate, citrate ions (acid or salt), aminoacetic acid, magnesium aluminum silicate hydrate, magaldrate, magnesium aluminum silicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, monobasic or dibasic calcium aluminum phosphate, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminum silicate, tartaric acid, and salts.

[0039] Examples of the active agent used in the present invention include allergens or antigens, such as, but not limited to, plant pollen derived from Gramineae, trees, or ragweed; animal dander, that is, fine flakes from the skin and hair of animals covered with cat and other hair; insects such as dust mites, honeybees, and wasps; and drugs such as penicillin.

[0040] Examples of specific activators include, but are not limited to, the following: 16-α fluorocstradiol, 16-α gitokine, 16-epiestriol, 17α-dihydroekirenin, 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, abanol, abecarnil, abiraterone, ablcast, ablcast sodium, acadestin, acamprosate, acarbose, acebutolol, acecainide hydrochloride, aceclidine, aceclofenae, acedapsone, aceglutamide aluminum, acemanan, acetaminophen, acetazolamide, acethexamide, acetohydroxamic acid, acetomepregenol, acetophenazine maleate, acetosulfone sodium, acetylcholine chloride, acetylcysteine, acetyl-L-carnitine, acetylmethadol, acifran, acipimox, acitemate, acitretin, acivicin, aclarubicin, acratonium, acodazole hydrochloride, aconiazide, acrisorcin, acrivastine, acronine, actisomide, actodigin, acyclovir, acylfulvene, adaphenoxate, adapalene, adapalene, adatanserin, adatanserin hydrochloride, adesipenol, adesipenol, adefovir, adelmidrol, ademetionine, adenosine, adinazolam, Adipheinine Hydrochloride, adiposin, adozelesin, adrafinil, adrenalone, airbutamine, alacepril, alamethicin, alanine, alaproclate, alapide, albendazole, albolabrin, albuterol, albutoin, Alclofenae, alclometasone dipropionate, alcloxa, aldecalmycin, aldesleukin, aldioxa,Alendronate Sodium, Alendronic Acid, Alentamol, Alentamol Hydrobromide, Arethamine Hydrochloride, Aleuronium Chloride, Alexidine, Alpha Calcidol, Alfentanil Hydrochloride, Alfuzosin, Algestone Acetonide, Alglucerase, Alifurane, Arinastine, Aripamide, Allantoin, Allobarbital, Allopurinol, ALL-TK Antagonist, Alogliptin, Arolonium, Allosetron, Allosetron Hydrochloride, Allopurinol, Alprazolam, Alprenolol Hydrochloride, Alprenoxime Hydrochloride, Alprostadil, Arlestatin Sodium, Altanserin Tartrate, Alteplase, Altiaride, Altretamine, Altromycin B, Alverinc Citrate, Albilseptosdtox, Amadinone Acetate, Amantadine Hydrochloride, Ambamustine, Amphomycin, Ambucycline, Ambufylline, Ambucide, Amcinafal, Amcinonide, Amdinocillin, Amdinocillin pivoxyl, Amedalin Hydrochloride, Amelometasone, Amelotride, Amesergide, Ametantrone Acetate, Amedinium Methyl Sulfate, Amphibromethamon, Amphiphenac Sodium, Amphifluazole, Amicicillin, Amidefrine 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, Amikicin Hydrochloride, Amisulpride, Amitraz, Amitriptyline Hydrochloride, Unreloxanox, Amlodipine, Amobarbital Sodium, Amodiaquine, Amodiaquine Hydrochloride, Amorolfine, Amoxapine, Amoxicillin, Amphicloral, Amphetamine Sulfate, Amphomycin, Amphotericin B, Ampicillin, Ampiroxicam, Ampicillin Sulfate, Amquinate, Amrinone, Amrinone, Amrubicin, Amsacrine, Amylin, Amithiamycin,Anagestone acetate, Anagrelide, Anakinra, Ananine, Analitide, Analitide acetate, Anastrozole, Anazolene sodium, Ancrod, Andrographolide, Androstenedione, Angiogenesis inhibitor, Angiotensin amide, Anidoxime, Anileridine, Anilopam hydrochloride, Anilacetam, Anilorac, Methylanisotropine bromide, Anistreplase, Anitrazafen, Anordrin, Antagonist D, Antagonist G, Antarellex, Antazoline phosphate, Antelmicin, Anthralin, Anthramycin, Antiandrogen agent, Aceclidine, Felbamate, Antiestrogen agent, Antineoplaston, Antipyrine, Antisense oligonucleotide, Apadoline, Apafant, Aparcilin sodium, Apaxifylline, Apazone, Affidicolin glycinate, Apixifylline, Apomorphine hydrochloride, Apraclonidine, Apraclonidine hydrochloride, Apramycin, Aprindine, Aprindine hydrochloride, Aprosartan sodium, Aprotinin, Aptazapine maleate, Aptiganel, Aprinic acid, Aprinic acid, Aranidipine, Alanosine, Albaprostil, Arbekicin, Arbidol, Albuterol hydrochloride, Alclofenine, Aldeparin sodium, Argatroban, Arginine, Argipressin tannate, Allyldone, Aripiprazole, Allopurinol, Arpinocid, Arteflene, Altiride fumarate, Acetimidrin, Asparatone, Asparaginase, Aspartic Acid, Aspartocin, Asperfuran, Aspirin, Aspoxicillin, Asprelin, Astemizole, Astromycin sulfate, Aslacrin, Atamestane, Atenolol, Atevirdine, Atipamezole, Atiprosin maleate, Ator, Atorvastatin calcium, Atosiban, Atracurium besylate, Attrimustine, Atri nositol, Atropine, Auranofin, Aureobasidin A, Aurothioglucose, Avilamycin, Aboparcin, Abridin, Axid, Axinasatatin 1,Axinasatine 2, Axinasatine 3, Azabon, Azacitidine, Azachloridine Hydrochloride, Azaconazole, Azadirachtine, Azalastat Dihydrochloride, Azaloxan Fumarate, Azanatol Maleate, Azanidazole, Azaperone, Azaribine, Azaserine, Azaseron, Azatadine Maleate, Azathioprine, Azathioprine Sodium, Azatoxin, Azatyrosine, Azelaic Acid, Azelastine, Azelnidipine, Azepindole, Azetepa, Adimirdol, Adisromycin, Azurosirine, Azolimine, Azosemide, Azotomycin, Azotreonam, Azomolene Sodium, Bacampicillin Hydrochloride, Baccatin III, Bacitracin, Baclofen, Bacoside A, Bacoside B, Bactobolin, Baranol, Barasipone, Balhimycin, Balofloxacin, balsalazide, Bambellomycin, Bambuterol, Bamethan Sulfate, Bamifylline Hydrochloride, Bamidazole, Baofuoside 1, Balmastine, Balnidipine, Basifungin, Batopradil Hydrochloride, Batebrolast, Baterapine Maleate, Batimastat, Beaucubecin, Becantone Hydrochloride, Becapreermin, Biclotymazole, Beclomethasone Dipropionate, Befloxatone, Beinserazide, Berofosdil, Belladonna, Beroxamide, Bemcentron, Bemithradine, Bemoradan, Benapridin Hydrochloride, Benazepril Hydrochloride, Benazeprilat, Bendacarol Mesylate, Bendazac, Bendroflumethiazide, Benflumetol, Benidipine, Benorterone, Benoxaprofen, Benoxaprofen, Benoxinate Hydrochloride, Benperidol, Bentazepam, Bentiromide, Benurestat, Benzbromarone, Benzethonium Chloride, Benzethimide Hydrochloride, Benzilonium Bromide, Benzindopyrine Hydrochloride, Benzisoxazole, Benzocaine, Benzoclorin, Benzocumine Hydrochloride, Benzodepa, Benzoisodaxoxan, Benzonatard, Benzoyl Peroxide, Benzoyl Pascalsium, Benzoyl Staurosporine, Benzquinamide, Benzthiazide, Benztropine, Benztropine Mesylate, Benzydamine Hydrochloride, Benzylpenicilloyl Polylysine, Beplidyl,Bepridil hydrochloride, Beractant, Beraprost, Bephrine, Bellarophenone, Beltazamil, Verisomycin, Besipirdine, β-Aletin, Betaclamycin B, Betamethasone, Betamipron, Betaxolol, Betaxolol hydrochloride, Bethanechol chloride, Betanidine sulfate, Betulinic acid, Bebantrol, Bebantrol hydrochloride, Bezafibrate, bFGF inhibitor, Bialamicol hydrochloride, Biapenem, Bicalutamide, Bischophazin hydrochloride, Bicrotizide hydrochloride, Bisdiamide, Bifemelane, Bifonazole, Bimakalim, Bimithil, Bindarit, Viniramycin, Vinospirone, Biocxalomycin α2, Bipenamol hydrochloride, Bisperidine, Biphenamine hydrochloride, Biriperone, Bisantrene, Bisaramide, Bisaziridinyl spermine, Bis-benzimidazole A, Bis-benzimidazole B, Bisnafide, Bisopurinol lactate, Bisoprolol, Bispirithione magsulfex, Bistramide D, Bistramide K, Bistratene A, Sodium bitethenolate, Vitortrol mesylate, Bivaldine, Bizelesin, Bleomycin sulfate, Bolandiol dipropionate, Bolasterone, Boldenone undecylenate, Boldine, Bolenol, Bolmantarate, Popindolol, Bosentan, Boxidine, Brefeldin, Brefolate, Brequinal sodium, Bretazenil, Bretylium tosylate, Briventanyl hydrochloride, Brimonidine, Brinolase, Brocresine, Brocrinat, Broxofin, Bromadoline maleate, Bromazepam, Bromochlorenone, Bromelain, Bromfenac, Brominidione, Bromocriptine, Brompheniramine hydrochloride, Bromoxamide, Bromperidol, Bromperidol decanoate, Brompheniramine maleate, Broperamol, Broprimine, Brotizolam, Bucainide maleate, Bucindolol, Bucridine hydrochloride, Bucromarone, Budesonide, Buzidipine, Budotitane, Buformin, Bumetanide, Bunaprolast, Bunazosin, Bunolol hydrochloride, Bupicomide, Bupivacaine hydrochloride, Buprenorphine hydrochloride, Bupropion hydrochloride, Bramart, Buserelin acetate, Buspirone hydrochloride, Busulfan, Butabarbital, Butacetin,Butaclamol hydrochloride, butalbital, butamben, butamirate citrate, butaperazine, butaprost, butedronate tetrasodium, butenafine,

[0041] Buterizine, buthionine sulfoximine, buticacin, butylphenine, butirosine sulfate, butyxylate, butixocort propionate, butoconazole nitrate, butonate, butopamine, butoprozine hydrochloride, butorphanol, butoxamine hydrochloride, butriptyline hydrochloride, actinomycin, cadexomer iodine, caffeine, calanolide A, calcifediol, calcipotriene, calcipotriol, calcitonin, calcitriol, calcium undecylenate, calphostin C, calusterone, 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, caprylyl, caracemide, carbachol, carbadox, carbamazepine, urea peroxide, carbantel lauryl sulfate, calcium carbaspirin, carbazeran, carbazomycin C, carbenicillin potassium, carbenoxolone sodium, carbetimer, carbetocin, carbidopa, carbidopa·levodopa, carbinoxamine maleate, carbinoxamine hydrochloride, carbochloral, carbocysteine, fuchsin phenol, carboplatin, carboprost, carbovir, carboxamide-amino-triazo-le, carboxamide triazole, carboxymethylated β-1,3-glucan, carbuterol hydrochloride, calrest M3, carfentanil citrate, carisoprodol, carmantadine, carmustine, CARN 700, Camidazole, caroxazone, carpeting, carfenazine maleate, carprofen, calfactonin succinate, cartazolate, carteolol, carteolol hydrochloride, cartilage-derived inhibitor, carvisine hydrochloride, carmonam sodium, carvedilol, carbortolin, carbortolin hydrochloride, carzelesin, casein kinase inhibitor (ICOS), castanospermine, carmonam, sevalacetam, cecropin B, sedefingol,Cefaclor, Cefadroxil, Cefamandole, Cefaparole, Cefatrizine, Cefazafuril Sodium, Cefazolin, Cefbuperazone, Cefcapene Pivoxil, Cefdaloxime Pentexil Tosilate, Cefdinir, Cefditoren Pivoxil, Cefepime, Cefetamet, Cefetecol, Cefixime, Cefluprenam, Cefmenoxime Hydrochloride, Cefinetazole, Cefminlox, Cefodizime, Cefonicid Sodium, Cefoperazone Sodium, Ceforamide, Cefoselis, Cefotaxime Sodium, Cefotetan, Cefothiam, Cefoxitin, Cefozopran, Cefpimizole, Cefpiramide, Cefpironium, Cefpodoxime Proxetil, Cefprozil, Cefroxadine, Cefurosine, Cefotazidime, Cefteram, Cefibuten, Ceftezoxime Sodium, Cefotriaxone, Cefuroxime, Celastrol, Sericarium, Seriprorol, Cepacidiine A, Cefacetril Sodium, Cephalexin, Cefaloglycin, Cefaloridine, Cefalothin Sodium, Cefapirin Sodium, Cefradine, Sericlamine, Serbastatin, Seronapril, Certoparin Sodium, Certred, Cetaben Sodium, Cetalkonium Chloride, Cetamolol Hydrochloride, Cethiedyl, Cethridine, Cetophenicol, Cetraxate Hydrochloride, Cetrorelix, Cetylpyridinium Chloride, Kenodiol, Clophenesianoil Hydrochloride, Chloral Betaine, Chlorambucil, Chloramphenicol, Clodantoin, Chlordiazepoxide, Chlorhexidine Gluconate, Chlorine, Chloromadinone Acetate, Chlorolienticin A, Chloroprocaine Hydrochloride, Chlorpropamide, Chloroquine, Chlorquinoxaline Sulfonamide, Chlorothiazide, Chlorotrianisene, Chloroxine, Chloroxylenol, Chlorphenesin Carbamate, Chlorpheniramine Maleate, Chlorpromazine, Chlorpropamide, Chlorprothixene, Chlorotetracycline Bisulfate, Chlorthalidone, Chlorzoxazone, Cholestyramine Resin, Cromonarol Hydrochloride, Sibenzoline, Cicaprost,Cyclafrine hydrochloride, cyclazindol, ciclesonide, cycletanine, ciclopirox, cycloprofen, cycloprolol, cidofovir, cidoxepin hydrochloride, cifenline, ciglitazone, siradopam hydrochloride, silansetron, cilastatin sodium, cilazapril, nilidipine, silobamine mesylate, silobramine, silofungin, cilostazol, cimaterol, cimetidine, methoctramine bromide, sinalcust, cinanserine hydrochloride, cinepazet maleate, cinflumide, singestol, cinitapride, cinamedrine, cinarizine, sinorazepam, sinoxazine, simpelen, sinromide, sintazone, sintriamide, sioteronel, sipamfilin, ciproheptadol succinate, ciprosinonide, ciprofibrate, ciprofloxacin, ciplostene, silamadol, sirolomycin, cisapride, cisatracurium besylate, cisconazole, cisplatin, cis - porphyrin, cistinexine, citalopram, citename, citicholine, citreamicin α, cladribine, clomoxyquine hydrochloride, clarithromycin, clausenamide, potassium clavulanate, clonazepam, clonazoline, clebopride, clemastine, clemizole maleate, criadinium bromide, clinafloxacin, clindamycin, clioquinol, clioxamide, cliprofen, clobazam, clobetasol propionate, clobetasone butyrate, crocortolone acetate, clodarenone, clodazone hydrochloride, clodronic acid, clofazimine, clofibrate, clofilium phosphate, clogestone acetate acetate, chromacuran phosphate, chromegestone acetate, chrometerone, chlormethiazole, clomiphene analog, chrominorex, clomiphene, clomipramine hydrochloride, clonazepam, clonidine, clonitrate, clonixylyl, clonixin, clopamide, clopentixol, cloperidone hydrochloride, clopidogrel, clopimidol, clopirac, cloprednol, cloprostenol sodium, dipotassium clorazepate, chloretate, chlorexolone, chlorperone hydrochloride, clorprenaline hydrochloride, chlorthalidone, chlorteramine hydrochloride, chrysanthemin,Clocillamine acetate, Clotiapine, Clotiazamide maleate, Clobetasone propionate, Clotrimazole, Cloxacillin benzathine, Cloxikin, Clozapine, Cocaine, Cocoxydine, Codeine, Codoxime, Colchicine, Colestimide, Colestipol hydrochloride, Cholestrone, Corformycin, Colfosceril palmitate, Colistin methanesulfonate sodium, Colistin sulfate, Colistimethate A, Colistimethate B, Cortol mesylate, Combretastatin A4, Combretastatin analogs, Combretastatin, Conagenin, Conorphone hydrochloride, Contignasterol, Contortrostatin, Cormetasone acetate, Corticoliberin ouabain trifluoroacetate, Corticotropin, Cortisone acetate, Cortivazol, Cortodoxone, Cosalan, Costatride, Cosyntropin, Cotinine, Cumadin, Cumermycin, Clavicipitacin 816, Crilubastatin, Crisnatol, Cromitril sodium, Cromolyn sodium, Clotamiton, Cryptophycin 8, Cucumarioside, Cuprimixine, Curcusin A, Cardlan sulfate, Curiosin, Cyclacillin, Cyclazocine, Cyclazosin, Cyclic HPMPC, Cyclindole, Cycliramine maleate, Cyclizine, Cyclobenzaprine, Cyclobut A, Cyclobut G, Cyclocapron, Cycloguanil pamoate, Cycloheximide, Cyclopentanthraquinone, Cyclopenthiazide, Cyclopentolate hydrochloride, Cyclophenazine hydrochloride, Cyclophosphamide, Cycloplatam, Cyclopropane, Cycloserine, Cyclocin, Cyclosporin, Cyclothiazide, Cyclothiazide, Cyclothiazomycin, Sheptamide, Sipelomycin, Sipenamine hydrochloride, Ciprazepam, Cyproheptadine hydrochloride, Cyprolidol hydrochloride, Cyproterone, Cyproxamide, Cysteamine, Cysteine hydrochloride, Cystine, Cytarabine, Cytarabine hydrochloride, Cytarabine ocfosfate, Cytokinesis B, Cytolytic factor, Cytostatin, Dacarbazine, Daclizumab, Dactinomycin, Dactinomycin, Daidzein,Tosilic acid daredarine, dalfopristin, dalteparin sodium, daltroban, dalvastatin, danaparoid, danazol, dantrolene, dapagliflozin, daphlnodorin A, dapiplazole, dapitant, dapoxetine hydrochloride, dapsone, daptomycin, dalglitazone sodium, dariphenacin, darulcin A, darozipin, darsidomine, daunorubicin hydrochloride, dazadrol maleate, dazepinyl hydrochloride, dazmegrel, dazopride fumarate, dazoxiben hydrochloride, debrisoquine sulfate, decitabine, deferiprone, deflazacort, dehydrocholic acid, dehydrodidemnin B, dehydroepiandrosterone, delapril, delapril hydrochloride, delavirdine mesylate, derecamine, delfaprazine, dermazinone acetate, dermopinol, delphinidin, demecarium bromide, demeclocycline, desmethacycline, demoxepam, denofungin, deoxypyridinoline, depakote, deprodone, deprostil, depsidomycin, delamciclane, dermatan sulfate, dessiclovir, descinolone acetonide, desflurane, desipramine hydrochloride, desildine, deslanoside, deslorelin, desmopressin, desogestrel, desonide, desoxymethasone, desoxoamiodarone, desoxycorticosterone acetate, detajmium tartrate, deterenol hydrochloride, detirelix acetate, dexbazepide, dexamethasone, dexamisole, dexchlorpheniramine maleate, dexchlorphenylamine maleate, dexclamol hydrochloride, dexetimide, dexfenfluramine hydrochloride, dexifosfamide, dexamafene, dexibucaine, dexketoprofen, dexloxiglumide, dexmedetomidine, dexormaplatin, dexoxadrol hydrochloride, dexapanthenol, dexpepemedrol, dexpropranolol hydrochloride, dexrazoxane, dexosotalol, dextrin 2-sulphate, dextroamphetamine, dextromethorphan, dextrorphan hydrochloride, dextrothyroxine sodium, dexverapamil,Desguanine, desinamide, desosine, diacetol hydrochloride, diamocaine cyclamate, diapamide, meglumine diatrizoate, diatrizoic acid, diabelidin, diazepam, diadicon, diazoxide, dibenzepin hydrochloride, dibenzothiophene, dibucaine, Dichliorvos, dichloralphenazone, dichlorphenamide, disilenone, diclofenac sodium, dicloxacillin, dichranine, dicumarol, dicyclomine hydrochloride, didanosine, demninin B, didox, dienestrol, dienogest, diethylcarbamazine citrate, diethylhomospermine, diethylnorspermine, diethylpropion hydrochloride, diethylstilbestrol, diphenoximide hydrochloride, , diphenoxin, diflurazon acetate, difloxacin hydrochloride, difluanine hydrochloride, diflucortolone, diflumidone sodium, diflunisal, difluprednate, diphthalon, digitalis,

[0042] Digitoxin, digoxin, dihexyverine hydrochloride, dihydroxyzin, dihydro-5-azacytidine, dihydrocodeine hydrogen tartrate, dihydroergotamine mesylate, dihydroestosterone, dihydrostreptomycin sulfate, dihydrotachysterol, dihydrotaxol, 9-, dilantin, levalbuterol hydrochloride, diltiazem hydrochloride, dimefadane, dimefline hydrochloride, dimenhydrinate, dimercaprol, dimethadione, dimethindene maleate, dimestrol, dimethyl prostaglandin Al, dimethyl sulfoxide, dimethylhomospermine, dimyracetam, dimoxamine hydrochloride, dinoprost, dinoprostone, dioxadrol hydrochloride, dioxamycin, diphenhydramine citrate, diphenidol, diphenoxylate hydrochloride, diphenyl spiromustine, Dipivefin Hydrochloride, dipivefrin, Dipliencyprone, diprafenone, dipropylnorspermine, dipyridamole, dipyrithione, dipyrone, dirlithromycin, discodermolide, disobutamide, disophenin, disopyramide, disoxaril, disulfiram, ditepine, divalproex sodium, dizocilpine maleate, dobutamine, docarpamine, dosebenone, docetaxel, doconazole, docosanol, dofetilide, drotrecogin alfa, ebastine, ebiratide, ebrotidine, ebselen, eptacog alfa, eptacog beta, eptacog delta, ecdisteron, echicetin, exastatin, ecothiopate iodide, eclamnazine maleate, eclazolast, ecomustine, econazole, eptainasib 722, edarabone, edatrexate, edelfosine, edrophonium chloride, edroxyprogesterone acetate, efegatran, eflornithine, efonidipine, egualcen, elantrine, eleatonin, elemen, eletriptan, ergodipine, eliprodil,Elsamiltoxin, Eltenae, Elcain, Emalkalim, Emedastine, Emetine Hydrochloride, Emigrate, Emilium Tosylate, Emitelflur, Emoctakin, Empagliflozin, Enadoline Hydrochloride, Enalapril, Enalaprilate, Enalkylene, Enazadrem, Enciplate, Endralazine Mesylate, Endrisone, Enflurane, Englitazone, Enilconazole, Enisoprost, Enlimomab, Enroplatin, Enopherast, Enolicam Sodium, Enoxacin, Enoxacin, Enoxaparin Sodium, Enoxaparin Sodium, Enoximon, Empyrollin Phosphate, Enprofylline, Enpromate, Entacapone, Enterostatin, Enviradene, Enviroxime, Ephedrine, Epicillin, Epimestrol, Epinephrine, Epinephrine Borate, Epipropidine, Epirizole, Epirubicin, Epitetracycline Hydrochloride, Epithiazide, Epoetin Alpha, Epoetin Beta, Epoprostenol, Epoprostenol Sodium, Epoxymexrenone, Epristeride, Eprosartan, Eptastigmine, Exirenin, Exirin, Elbrozole, Erdosteine, Ergoloid Mesylate, Ergometrine Maleate, Ergotamine Tartrate, Elsentirolide, Elsofermin, Erythritol, Erythrityl Tetranitrate, Erythromycin, Esmolol Hydrochloride, Esorubicin Hydrochloride, Esproquine Hydrochloride, Estazolam, Estradiol, Estramustine, Estramustine Analog, Estradiol Hydrobromide, Estriol, Estrone Sulfate, Estrogen Agonist, Estrogen Antagonist, Estrogen, Conjugated Estrogen, Esterified Estrone, Estropipate, Estroprone, Ethamfetamine Hydrochloride, Ethanidazole, Etanterol, Etaloten, Etazolamate Hydrochloride, Eterobarb, Etacizine, Ethacrynic Acid Sodium, Ethacrynic Acid, Ethanbutol Hydrochloride, Etamivan, Monoethanolamine Oleate, Ethchlorvynol, Ether, Ethinyl Estradiol, Ethiodized Oil, Ethionamide, Etomoxir Nitrate, Etopropazine Hydrochloride, Ethosuximide, Ethotoin,Etoxazene hydrochloride, etibenzotropine, ethyl chloride, diethyl dibunate, ethyl estrenol, ethynodiol (Ethyndiol), ethinelon, ethynodiol diacetate, etibendazole, etidocaine, disodium etidronate, etidronic acid, etiphenin, etintidine hydrochloride, etizolam, etodolac, etofenamate, ethoformine hydrochloride, etomidate, etonogestrel, etoperidone hydrochloride, etoposide, etoprine, etoxadrol hydrochloride, etozolin, etrabamine, etretinate, etriptamine acetate, homatropine hydrochloride, eugenol, euprocin hydrochloride, eveminomicin, exametazime, examorelin, exaprool hydrochloride, exemestane, fadrozole, feriefungin, famciclovir, famotidine, fanpridine, fantofarone, fantridone hydrochloride, faropenem, fasidotril, fasudil, fazarabine, fedotozine, felbamate, felbinac, felodipine, felipressin, phenamide, phenamol, fenbendazole, fenbufen, fensibutrol, fenclofenac, fenclonine, fenclorac, fendosal, fenestrel, phenethylamine hydrochloride, fenfluramine hydrochloride, fengabine, phenimid, phenisorex, fenmetozole hydrochloride, fenmetramide, phenobarbital, phenoctimine sulfate, fenofibrate, phenoloxazepam, fenoprofen, phenoterol, fenpiparon, fenprinast hydrochloride, fenprostalene, fenquone, fenretinide, fenspiride, fentanyl citrate, fentiazac, fenticlor, fenticonazole, phenylipol hydrochloride, fepralidinol, ferpiphosate sodium, ferristene, ferrixan, dried iron sulfate, ferric oxide, ferromoxyl, fetoxylate hydrochloride, phenoxephedrine, phenozolamine fumarate, fiacitabine, fiarridine, fibrinogen 1 125, filgrastim, Philippines, finasteride, flavodilol maleate, flavopiridol, flavoxate hydrochloride, flazarone,Flecainide, fenoterol, fleroxacin, flosinoxacin, flestolol sulfate, fletazepam, fexelastine, flobufen, floctafenine, flomoxef, flordipine, florfenicol, florifenine, florsatidyl, flosequinan, flouxasillin, floxuridine, fluasterone, fluazacort, fluvastatin hydrochloride, flubendazole, flucindol, flucronidil, fluconazole, flucytosine, fludarabine, fludarabine phosphate, fludazonium chloride, fludeoxyglucose F 18, fludrex, fluocortolone acetate, flufenamic acid, flufenisal, flumazenil, flumethinol, flumethin, flumethide, flumetasone, flumetramide, flumethazapine, fluminorex, flumizole, flumoxonide, flunaridine, flunidazole, flunisolide, flunitrazepam, flunixin, fluocalcitriol, fluocinonide acetonide, fluocinonide, fluocortin butyl, flucortolone, fluorescein, fluorodaunorunicin hydrochloride, fluorodopa F 18, fluorometholone, fluorouracil, fluorotracene hydrochloride, fluoxetine, fluoxymesterone, fluparoxan, fluperamide, fluperolone acetate, fluphenazine decanoate, flupyrazine, fluprednisolone, fluproquazone, fluprostenol sodium, flucourazone, fluradoline hydrochloride, flurandrenolide, flurazepam hydrochloride, flurbiprofen, fluretofen, flurithromycin, flurocitabine, flurofamide, flugestone acetate, flurotyl, fluoxetine, fluspirone, fluspirilen, fluticasone propionate, flutrimazole, flutroline, fluvastatin, fluvastatin sodium, fluvoxamine, fludinamid, folic acid, Follicle regulatory protein, Folliculostatin, homopiperizole, dimethothiazine mesylate, horasartan, holfenimex, forfenirmex, formestane, hormocortalFormoterol, Hosarylate, Hosazepam, Hoskarnet Sodium, Fosfomycin, Phosphonat Sodium, Fosinopril, Fosinoprilat, Fosphenyloin, Hosquidone, Hostedyl, Hostriesin, Hostemicin, Fuchsin, Alkaline, Fumoxicillin, Fungimycin, Flaprofen, Furazolidone, Furazolinium Chloride, Freglerat Sodium, Frobufen, Flodazole, Furosemide, Sodium Fusidate, Fusidic Acid, Gabapentin, Meglumine Gadobenate, Gadobenic Acid, Gadobutrol, Gadodiamide, Gadolinium Texaphyrin, Dimethylglucamine Gadopentetate, Gadoteric Acid, Gadoteridol, Gadobesetamide, Galantamine, Galantacetron, Galantacetron Hydrochloride, Galamine Triethiodide, Gallium Nitrate, Galopamil, Galocitabine, Gamfexine, Gamolenic Acid, Ganciclovir, Ganirelix, Gelatinase Inhibitor, Gemcadiol, Gemcitabine, Gemeprost, Gemfibrozil, Gentamicin Sulfate, Gentian Violet, Gepirone, Gestaclone, Gestoden, Gestonorone Caproate, Gestrinone, Gebotrolin Hydrochloride, Gilyzopam, Glaspimod, Glaucocalyxin A, Gremanserin, Gliamilide, Glibornuride, Glycetanyl Sodium, Glyflumide, Glimepiride, Glypidide, Glocximonam, Glucagon, Glutapyrone, Glutathione Inhibitor, Glutetimide, Gliblide, Glycopine, Glycopril, Glycopyrrolate, Glyhexamide, Sodium Glymidine, Glyoctamide, Glyparamide, Gold Au 198, Gonadoctrinins, Gonadorelin, Gonadotropin, Goserelin, Gramicidin, Granisetron, Grepafloxacin, Glyceofulvin, Guaiapate, Guaitrilin, Guanabenz, Guanabenz Acetate, Guanadrel Sulfate, Guanidine, Guanethidine Sulfate, Guanfacine Hydrochloride, Guanisoxine Sulfate, Guanoclor Sulfate, Guanocutin Hydrochloride, Guanoxabenz, Guanoxan Sulfate, Guanoxyfen Sulfate, Gusperimus Hydrochloride, Halazepam, Halcinonide, Halicondrin B, Halobetasol Propionate,Halofantrine, halofantrine hydrochloride, halofenate, haloguinone hydrobromide, halomon, halopemide, haloperidol, halopredone, haloprogesterone, haloprozine, halothane, halquinol, hamycin, Han menopausal gonadotropins, hatomamycin, hatomargin A, hatomargin B

[0043] Columbianadin C, Columbianadin D, Heparin Sodium, Hepsulfam, Heregulin, Hetacillin, Heteronium Bromide, Hexachlorophene, Hydrogen Peroxide, Hexafluoreniun Bromide, Hexamethylenebisacetamide, Hexetidine, Hexobenzene, Hexoprenaline Sulfate, Hexylresorcinol, Histamine Phosphate, Histidine, Histoplasmin, Histrelin, Homatropine Hydrobromide, Hokydil Hydrochloride, Human Chorionic Gonadotropin, Hicantone, Hydralazine Hydrochloride, Hydralazine Polystyrene, Hydrochlorothiazide, Hydrocodone Bitartrate, Hydrocortisone, Hydroflumethiazide, Hydromorphone Hydrochloride, Hydroxyamphetamine Hydrobromide, Hydroxychloroquine Sulfate, Hydroxyphenamate, Hydroxyprogesterone Caproate, Hydroxycarbamide (Hydroxyurca), Hydroxyzine Hydrochloride, Himechromone, Hyostiamine, Hypericin, Ibafloxacin, Ibandronic Acid, Ibogaine, Ibopamine, Ibudilast, Ibufenac, Ibuprofen, Ibutilide Fumarate, Icatibant Acetate, Ictamol, Ichthyodin, Idarubicin, Idoxifen, Idoxuridine, Idramantone, Iemefloxacin (Iemefloxacin), Iesopitron (Iesopitron), Ifetroban, Ifosfamide, Ilepeimide (Ilepeimide), Irimaqinone, Ilmofosine, Iromustat, Ironidap, Iloperidone, Iloprost, Imafen Hydrochloride, Imazodan Hydrochloride, Imidapril, Imidazenyl, Imidazoacridone, Imidacil Iodine, Imidocarb Hydrochloride, Imidrine Hydrochloride, Imidurea, Imiloxan Hydrochloride, Imipenem, Imipramine Hydrochloride, Imiquimod, Immunostimulating Peptide, Impromidine Hydrochloride, Indacrinone, Indapamide, Indecainide Hydrochloride, Indeloxazine Hydrochloride, Indigo Carmine Sodium Sulfate, Indinavir, Indocyanine Green, Indalapril Hydrochloride, Indridan, Indomethacin, Indomethacin Sodium, Indoprofen, Indolamine, Indorenate Hydrochloride, Indoxole, Indoline Hydrochloride, Inocoterone, Inogatran, Inolimomab (inolimomab), Inositol Nicotinate, Insulin, Interferon, Interleukin,Intrazole, Intriptyline Hydrochloride, Iobenzguan, Iobenzamic Acid, Iobitridol, Iocarmate Meglumine, Yocarmic Acid, Iosefamic Acid, Iodamide, Iodine, Iodipamide Meglumine, Iodixanol, Iodamide, Iodoantipyrine I 131, Iodocholesterol I 131, Iododoxorubicin, Sodium Iodohippurate I 131, Iodopyracet I 125, Iodoquinol, Iodoxamic Acid Meglumine, Iodoxamic Acid (Iodoxamie Acid), Ioglycic Acid, Iofetamine Hydrochloride I 123, Iofratol, Ioglucol, Ioglucamide, Ioglicamic Acid, Ioglamide, Iohexol, Iomeprol, Iomethin I 125, Iopamidol, Iopanoic Acid, Iopentol, Iofendylate, Yoprocemic Acid, Iopromide, Iopronic Acid, Iopidol, Iopidon, Iopyrol (iopyrol), Yosefamic Acid, Ioselatic Acid, Ioslamide Meglumine, Yosmetinic Acid, Yotalsul, Yotetoric Acid, Sodium Iotalamate, Iotalamic Acid, Iotriside (iotriside), Iotrolan, Iotroxate, Yothyrosine I 131, Ioversol, Ioxaglate Sodium (Ioxagiate Sodium), Ioxaglate Meglumine, Ioxagluic Acid, Ioxilan, Ioxotrizic Acid, Ipadilide, Ipenoxazone, Ipidacrine, Ipodate Calcium, Ipomethanol, 4-, Ipratropium Bromide, Ipriflavone, Iprindole, Iprofenin, Ipronidazole, Iproplatin, Iproxamine Hydrochloride, Ipsapiron, Irbesartan, Irinotecan, Irloxacin, Iroplact, Ilosogladine, Iltemazole, Isalsetin, Isamoxole, Isbogrel, Isepamicin, Isobenzgazole, Isobutane Benz, Isocarboxazid, Isoconazole, Isoetharine, Isoflupredone Acetate, Isoflurane, Isoflurophate, Isohomohalicondrin B, Isoleucine, Isomazole Hydrochloride, Isomiramide Hydrochloride, Isoniazid, Isopropylamide Iodide, Isopropyl Alcohol, Isopropyl Unoprostone, Isoproterenol Hydrochloride, Isosorbide, Isosorbide Mononitrate, Isothiximide, Isotretinoin,Isoxepac, Isoxicam, Isoxsuprine Hydrochloride, Isradipine, Itamelin, Itacetron, Itazigrel, Itopride, Itraconazole, Ivermectin, Jaspraquinolide, Josamycin, Kahalalide F, Calafungin, Kanamycin Sulfate, Ketamine Hydrochloride, Ketanserin, Ketazolosin, Ketazolam, Ketoxal, Ketipramine Fumarate, Ketoconazole, Ketoprofen, Ketorfanol, Ketorolac, Ketotifen Fumarate, Kitasamycin, Labetalol Hydrochloride, Lacidipine, Lactitol, Lactivicin, Laennec, Lafutidine, Lamelarin-N Triacetate, Lamifiban, Lamivudine, Lamotrigine, Lanoconazole, Lanoxin, Lampreison, Lanreotide, Lansoprazole, Latanoprost, Lateralitin, Laurocapram, Lauryl Isoquinolinium Bromide, Labotrigine Succinate, Lazabemide, Resimvid, Reinamycin, Remirdipine, Reminoprazole, Renalcept, Renicinsin, Lenograstim, Risperidone, Lentianan Sulfate, Leptin, Leptostatin, Relcanidipine, Rergotrile, Relisertion, Retimid Hydrochloride, Retrazuril, Retrozole, Leucine, Leucomycin, Leuprorelin Acetate, Leuprorelin + Estrogen + Progesterone, Leuprorelin, Levamfetamine Succinate, Levamisole, Levodopbutamine Lactobionate, Levcromakalim, Levetiracetam, Leveycloserine, Levobetaxolol, Levobunolol, Levobupivacaine, Levocabastine, Levocarnitine, Levodopa, Levodropropizine, Levofloxacin, Levoflaltadone, Levoleucovorin Calcium, Levomethadyl Acetate, Levomethadyl Acetate Hydrochloride, Levomoprolol, Levonantradol Hydrochloride, Levonordefrin, Levonorgestrel, Levopropoxyphene Naproxenate, Levopropylcillin Potassium, Levormeloxifene, Levorphanol Tartrate, Levosimendan, Levosulpride, Levothyroxine Sodium, Levoxadrol Hydrochloride, Lexipafant, Lexithromycin, Riarozole, Lisinopril, Ridamidine Hydrochloride, Lidocaine, Lidofenine, Lidoflazine, Rifalazidine, Rfibricate, Rfibrol, Linalool, Lincomycin,Linear polyamine analogs, linogliride, linopirdine, linitroban, linsidomine, lintriptol, lintopride, liothyronine I 125, liothyronine sodium, liotrix, lirexapride, lisinopril, lissoclinamide 7, lixazinone sulfate, lobaplatin, lobenzarit sodium, lobucavir, loderaben, lodoxamide, lofemizole hydrochloride, lofentanyl oxalate, lofepramine hydrochloride, lofexidine hydrochloride, lonbricin, lomefloxacin, lomeridine, lometraline hydrochloride, lometrexol, lomofungin, lornoxicam, lomustine, lonaparen, lonazolac, lonidamine, loperamide hydrochloride, loracarbef, lorazumin hydrochloride, loratadine, lorazepam, lorbamate, lorcainide hydrochloride, lorecreosol, loreinadol, lorglumide, lormetazepam, lornoxicam, lornoxicam, lortalamic, lorazafone, losartan, losigamon, losoxantrone, losulazine hydrochloride, loteprednol, lovastatin, lobivudine, loxapine, loxoribine, luberzole, lucanthone hydrochloride, lufironyl, lurasidone mesylate, lurtotecan, luteinizing hormone, lurasidone, lutetium, leuprolide acetate, ludindole, liaporternatrium, lisetamine, lysicamycin, lysimycin, linestrenol, repressin, lysine, lysophilin, lysostaphin, lytic peptide, maduramycin, mafenide, magainin 2 amide, magnesium salicylate, magnesium sulfate, magnolol, maytansine, maletamer, marlotocromen, marlotojaponin, marlotilate, marlotilate, mangafodipir, manidipine, maniwanamycin A, mannitol, mannostatin A, manumycin E, manumycin F, mapinastine, maprotiline, marimastat, Martek 8708, Martek 92211, masoprocol, maspin, massetolide, matrix metalloproteinase inhibitor, maytansine, mazapertine succinate, mazindol, mebendazole, mebeverine hydrochloride, mebrofenin, mebutamate, mecamylamine hydrochloride, mechlorethamine hydrochloride, meclocycline, meclofenamic acid sodium,Mecrocolon, Mecrolisone Dibutyrate, Medazepam Hydrochloride, Medroxyprogesterone, Medrogestone, Medroxalol, Medroxyprogesterone, Medrysone, Meclizine Hydrochloride, Mefenamic Acid, Mephenidyl, Mephentermine Hydrochloride, Mefexamide, Mefloquine Hydrochloride, Meflursid, Megalomycin Potassium Phosphate, Megestrol Acetate, Meglumine, Miglitol, Melenegestrol Acetate, Melitracen Hydrochloride, Melphalan, Memotine Hydrochloride, Menabitan Hydrochloride, Menoctone, Menogaril, Menotropin, Mephentermine Sulfate, Mepartricin, Mepenzolate Bromide, Meperidine Hydrochloride, Mephentermine Sulfate, Mephenyloin, Mephobarbital, Mepivacaine Hydrochloride, Meprobamate, Meptazinol Hydrochloride, Mecodox, Melarain Sodium, Melvalone, Mercaptopurine, Merck Phenol Chloride, Mercury, Ammoniated, Merisoprol Hg 197, Meropenem, Mesalamine, Mesecrazone, Mesoridazine, Mestosterone, Mestranol, Mesopramine Hydrochloride, Metalol Hydrochloride, Metaproterenol Polystyrex, Metaramino Hydrochloride Hydrogen Tartrate, Metaxalone, Meteplenost, Meteclirine, Metformin, Metacholine Chloride, Metacycline, Methadone Hydrochloride, Metazide, Metolazone, Methamphetamine Hydrochloride, Metacolon, Metazolamide, Methdilazine, Methenamine, Mestenolone Acetate, Mephenytoin, Methicillin Sodium, Methimazole, Methioninase, Methionine, Methisazone, Methixene Hydrochloride, Methocarbamol, Methohexital Sodium, Methopterin, Methotrexate, Methotrimeprazine, Methoxatone, Methoxyflurane, Methsuximide, Methyclothiazide, Methyl Palmoxylate, Methylatropine Nitrate, Methylbenzethonium Chloride, Methyldopa, Methyldopate Hydrochloride, Methylene Blue, Methylergometrine Maleate, Methylhistamine, R-α, Methylinosine Monophosphate, Methylphenidate Hydrochloride, Methylprednisolone, Methyltestosterone, Methynodiol Diacelate, Methylceled, Methylceled Maleate, Methiamide,Methiapin, Methioprim, Methypamide, Methypranolol, Methylzoline Hydrochloride, Metokeclamide Acetate, Metoclopramide, Methocrin Iodide, Metogest, Metrazone, Metopimazine, Methoprin, Metoprolol, Methoxidine, Metrifonate, Metrizamide, Sodium Metrizonate, Metronidazole, Metsuredepa, Methylapone, Methylosin, Mexiletine Hydrochloride, Potassium Mexirenate, Mezlocillin, Mfonelic Acid, Mianserin Hydrochloride, Mibefradil, Mibefradil Dihydrochloride, Mibolerone, Miceramin B, Miconazole, Microcortin A, Midafuryl, Midazolam Hydrochloride, Midodrine, , Mifepristone, Mifovert, Miglitol, Milasemide, Milameline, Mildronate, Mireperone, Milpertine, Milnacipran, Milrinone, Miltefosine, Minaprine Hydrochloride, Minaprine, Minaxolone, Minocromil, Minocycline, Minoxidil, Mioxifradil Hydrochloride, Myocamycin, Mipragoside, Mifentanyl, Millimostim, Milinkamycin Hydrochloride, Milsetron Maleate, Mirtazapine, Mismatch Double-Stranded RNA, Misonidazole, Misoprostol, Mitindomide, Mitocarcin, Mitochromin, Mitodilene, Mitoguazone, Mitolactol, Mitomarcin, Mitomycin, Mitonafide, Mitosper, Mitotan, Mitoxantrone, Mivacurium Chloride, Mivazerol, Mixampril, Mixidine, Mizolastine, Mizoribine, Moclobemide, Modafinil, Modarin Sulfate, Modecainide, Moexipril, Mofarotene, Mofegiline Hydrochloride, Mofezolac, Molgramostim, Molinazone, Molindone Hydrochloride, Molcimindomide, Mometasone, Monatepril Maleate, Monensin, Monocaprylin, Montelukast Sodium, Montirelin, Mopidamol, Moracizine, Morantel Tartrate, Moricizine, Moliniflumart, Morphine Sulfate, Sodium Morinate, Mosapramine, Mosapride, Motolide, Motretinide, Moxalactam Disodium, Moxazosin, Moxirapril, Moxnidazole, Moxonidine, Mumps Skin Test Antigen, Mustard Anticancer Agent, Muzolimine, Micaperoxide B, Mycophenolic Acid, Miliapolone, Nabazenil, Navilone,

[0044] Navitane hydrochloride, Naboctate hydrochloride, Nabumetone, N-acetyl dinarine, Nadide, Nadifloxacin, Nadolol, Nadroparin calcium, Nafadotride, Nafamostat, Nafarelin, Nafcillin sodium, Nafenopin, Nafimidone hydrochloride, Naphrocort, Nafomin malate, Nafoxidine hydrochloride, Nafronyl oxalate, Naftifine hydrochloride, Naphthopyridyl, Naglivan, Nagrestip, Nalbuphine hydrochloride, Naldemedine, Sodium nalidixate, Nalidixic acid, Nalmefene, Nalmexone hydrochloride, Naloxone + Pentazocine, Naltrexone, Namoxyrate, Nandrolone phenylpropionate, Nantradol hydrochloride, Napactadine hydrochloride, Napadisylate, Napamezol hydrochloride, Napaviin, Naphazoline hydrochloride, Napterpin, Naproxen, Naproxol, Napsagatran, Naranol hydrochloride, Narasin, Naratriptan, Nartograstim, Nasalplase, Natamycin, Nateplase, Naxagolide hydrochloride, Nebivolol, Nebramycin, Nedaplatin, Nedocromil, Nefazodone hydrochloride, Neflumodide hydrochloride, Nefopam hydrochloride, Nelezaprine maleate, Nemazoline hydrochloride, Nemorvicine, Neomycin palmitate, Neostigmine bromide, Neridronic acid, Netilmicin sulfate, Neutral endopeptidase, Neutramycin, Nevirapine, Nexeridine hydrochloride, Niacin, Nibroxan, Nicardipine hydrochloride, Nicergoline, Niclosamide, Nicorandil, Nicotinyl alcohol, Nifedipine, Nifirmerone, Niflumide, Nifradene, Nifraldazone, Nifrate, Nifratrone, Nifurdazil, Nifrimide, Niflumipyrinol, Niflumiknazole, Niflumithiazole, Nilutamide, Nilvadipine, Nimazon, Nimodipine, Nipelotidine, Nirabolin, Niridazole, Nisamycin, Nisbuterol mesylate, Niacin, Nisobamate, Nisoldipine, Nisoxetine, Nisterime acetate, Nitarson, Nitazoxamide, Nitecapone, Nitrafudam hydrochloride, Nitralamine hydrochloride, Nitramisol hydrochloride, Nitrazepam,Nitrendipine, Nitrosycline, Nitrodan, Nitrofurantoin, Nitrofurazone, Nitroglycerin, Nitromersol, Nitromide, Nitromifene citrate, Nitrogen dioxide, Nitroxide antioxidant, Nitrulin, Nibazole, Nibemedone sodium, Nizatidine, Novestamine, Nocodazole, Nogalamycin, Norinium bromide, Nomifensine maleate, Noracymethadol hydrochloride, Norethandrolone, Norepinephrine bitartrate, Norethindrone, Norethynodrel, Norfloxacin, Norfurantoin, Norgestimate, Norgestomet, Norgestrel, Nortriptyline hydrochloride, Noscapine, Novobiocin sodium, N-Substituted benzamides (benzaimides), Nufencoxol, Nilestriol, Nystatin, O6-Benzylguanine, Obidoxime chloride, Ocapeldone, Octaphenyl hydrochloride, Oxanaplon, Octanoic acid, Octazamide, Octenidine hydrochloride, Octodrine, Octreotide, Octriptyline phosphate, Ofloxacin, Ofloxacin, Oxenone, Olanzapine, Oligonucleotide, Oropatadine, Orprinone, Olsalazine, Olsalazine sodium, Orvanil, Omeprazole, Onapristone, Ondansetron, Ontazolast, Oocyte maturation inhibitor, Opipramol hydrochloride, Orasin, Orconazole nitrate, Ornithine, Orlistat, Ormaplatin, Ormetoprim, Ornidazole, Orpanoxin, Orphenadrine citrate, Osaterone, Otenzepad, Oxacillin sodium, Oxagrelate, Oxaliplatin, Oxamarin hydrochloride, Oxamisole, Oxamniquine, Oxandrolone, Oxantel pamoate, Oxaprotiline hydrochloride, Oxaprozin, Oxalazole, Oxatomide, Oxauromycin, Oxazepam, Oxcarbazepine, Oxendolone, Oxesazine, Oxetorone fumarate, Oxfendazole, Oxyphenisine, Oxibendazole, Oxiconazole, Oxidopamine, Oxidronic acid, Oxifungin hydrochloride, Oxolorphan, Oxymonam, Oxymonam sodium, Oxyphenamide, Oxirace tam, Oxylamide, Oxysuran, Oxymethidine hydrochloride, Oxodipine, Oxogestone phenpropionate,Oxolinic acid, Oxprenolol hydrochloride, Oxotriphylline, Oxybutynin chloride, Oxychlorosene, Oxycodone, Oxymetazoline hydrochloride, Oxymetholone, Oxymorphone hydrochloride, Oxypertine, Oxyphenbutazone, Oxypurinol, Oxytetracycline, Oxytocin, Ozagrel, Ozolinone, Paclitaxel, Para-aminou, Pardimicin, Parinavir, Palmitoyl lysophosphatidylcholine, Palmoxirate Sodium, Pamaqueside, Pamatolol sulfate, Pamicogrel, Pamidronate disodium, Pamidronate, Panadiplon, Panamesine, Panaxytriol, Pancopride, Pancuronium bromide, Panipenem, Panomycin, Panomifene, Pantethine, Pantoprazole, Papaverine hydrochloride, Parabactin, Parachlorophenol, Paraldehyde, Paramethasone acetate, Paraaniline hydrochloride, Parapenzoate bromide, Pararosaniline Pamoate, Parbendazole, Parconazole hydrochloride, Paregoric, Pareptide sulfate, Pargyline hydrochloride, Paranaparin sodium, Paromomycin sulfate, Paroxetine, Parthenolide, Partricin, Paulomycin, Pazelliptine, Padinacrone, Pazoxide, Pazufloxacin, Perfloxacin, Pegaspargase, Pegorgotein, Pelanserin hydrochloride, Perdesin, Periomycin, Pelretin, Perlinone hydrochloride, Pemedolac, Pemethide nitrate, Pemirolast, Pemoline, Penamesillin, 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, Pentafoside, Pentamidine, Pentamorphone, Pentamustine, Pentapiperium methyl sulfate, Pentazocine, Pentetate, Pentiapine maleate, Pentigetide, Pentisomicin,Pentizidone sodium, pentobarbital, pentomone, pentopril, pentosan, pentostatin, pentoxifylline, pentrinitrol, pentolozole, pepromycin sulfate, pepstatin, perflubron, perfofamide, perfosfamide, pergolide, perhexiline maleate, perillyl alcohol, perindopril, perindoprilat, perlapine, permethrin, perospirone, perphenazine, phenacylamide, phenalidine, phenazinomycin, phenazopyridine hydrochloride, phenylbutazone sodium glycerophosphate, phencarbamide, fenciclamine hydrochloride, phentermine tartrate, fenethazine sulfate, fenmetrazine hydrochloride, phenobarbital, phenoxybenzamine hydrochloride, fenprocumone, fenfluramine, phensuccinal, phensuccinimide, phentermine, phentermine hydrochloride, phentolamine mesylate, pentoxifylline, phenyl salicylate, phenyl acetate, phenylalanine, phenylalanyl ketoconazole, phenylbutazone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenylpropanolamine polistirex, phenyramidol hydrochloride, Phenyloin, phosphatase inhibitor, physostigmine, picenadol, picibanil, picotrin dydrochloride, picroliv, picrotropine, pidotimod, Pifamine, pilocarpine, pircainide, pimagedine, pimetidine hydrochloride, pimoprostone, pimobendan, pimozide, pinacidil, pinadoline, pindolol, pinnenol, pinoceline, pinoxepin hydrochloride, pioglitazone, pipamperone, pipazetate, pipethonium bromide, piperacetazine, piperacillin sodium, piperamide maleate, piperazine, pipobroman, piposulfan, pipothiazine palmitate, pipoxolan hydrochloride, piprozoline, picindone hydrochloride, picizide hydrochloride, piracetam, pyrandamine hydrochloride, pirarubicin, Pirazmonam sodium, Pirazolac, pirbenicillin sodium, pirbuterol acetate, pyrenperone,Pirenzepine hydrochloride, piretamide, pirfenidone, pyridoxylidene sodium, pyridronate sodium, piproxim, pirithioxime, pirrimycin hydrochloride, pirindole, pirmagrel, pirenol hydrochloride, pirnabin, piroctone, pirodabir, pirodast, pirogliride tartrate, pirolate, pyrazamide, pyroxantrone hydrochloride, piroxicam, pyroximon, pirprofen, pirquinozol, pircidimine, prenylamine, pituitary, posterior, pivampicillin hydrochloride, pivopril, pizotiline, placetin A, platinum compound, platinum triamine complex, precamycin, promestane, pobilcasto edamine, podophyllox, American ginseng extract, porzine methyl sulfate, poliglusam, polignate sodium, polymyxin B sulfate, polythiazide, ponalrestat, porfimer sodium, porfiromycin, potassium chloride, potassium iodide, potassium permanganate, povidone-iodine, plactol, pralidoxime chloride, pramiracetam hydrochloride, pramoxine hydrochloride, pronolium hydrochloride, pravadoline maleate, pravastatin (pravacol), prazepam, prazosin, prazosin hydrochloride, prednazate, prednicarbate, prednimustine, prednisolone, prednisone, prednival, pregnenolone succinate, prenalterol hydrochloride, predelfin hydrochloride, prefiron, procaine hydrochloride, primakin phosphate, primidol, primidone, prinivil, priminod tromethamine, prinoxodan, pridilol hydrochloride, proadifen hydrochloride, probenecid, probicromil calcium, probucol, procainamide hydrochloride, procaine hydrochloride, procarbazine hydrochloride, procaterol hydrochloride, prochlorperazine, procionide, procronol, procyclidine hydrochloride, prodilidine hydrochloride, prodol acid, profadol hydrochloride, progabide, progesterone, proglymid, proinsulin inh,Proline, proline hydrochloride, promazine hydrochloride, promethazine hydrochloride, propafenone hydrochloride, propagermanium, propanidid, propantheline bromide, proxymetacaine hydrochloride, propatyl nitrate, propentophylline, propenzolate hydrochloride, propicain, propiomazine, propionic acid, propionyl carnitine, L-propiram, propiram + paracetamol, propiverine, propofol, propoxycaine hydrochloride, propoxyphene hydrochloride, propranolol hydrochloride, proprussid, propylbis-acridone, propylhexedrine, propyliodone, propylthiouracil, procazone, prolenoate potassium, proxolane hydrochloride, proscillaridin

[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, Rifamexil, Rifamide, Rifampin, Rifapentine, Rifaximin, RII Retinamide, Rilopirox, Riluzole, Rimantadine, Rimcazole Hydrochloride, Remexolone, Rimitrol Hydrobromide, Remopragine, Riomidipine, Rioprostil, Lipazepam, Lipasartan, Risedronate Sodium, Risedronic Acid, Risocaine, Lisotridine Hydrochloride, Lispenedepine, Risperdal, Risperidone, Ritanserin, Litempepenem, Litodrine, Litolukast, Litonavir, Rizatriptan Benzoate, Locastine Hydrochloride, Roclonium Bromide, Rodocaine, Rofluran, Logretimide, Rohitukin, Roxithromycin, Roletamicide, Rogamidine, Loliciprin, Lolipram, Lolitetracycline, Lologin, Romazarit, Romurtide, Ronidazole, Ropinirole, Ropitoin Hydrochloride, Ropivacaine, Ropidine, Rokinimex, Rosaramicin, Rosiglitazone, Roxoxacin, Rotoxamine, Roxatidine, Roxarsone, Roxindole, Roxithromycin, Rubiginone B1, Ruboxyl, Rufloxacin, Rupatadine, Rutilamycin, Ruzadran, Saberzol, Safingol, Saffironyl, Saintopin, Salbutamol, R-Sarcoleks, Saletamide Maleate, Salicylic Alcohol, Salicylamide, Meglumine Salicylate, Salicylic Acid, Salmeterol, Salnacediin, Salsalate, Sameridine, Sampatrilat, Sancycline, Sanfetrineum, Sanguiarin Chloride, Saperconazole, Supprasartan, Supproptelin, Saquinavir, Sarafloxacin Hydrochloride, Saralasin Acetate, SarCNU, Sarco phytol A, Sargramostim, Salmoxisylyne, Salpisyline, Sarpoagrelate, Sarplase, Saterinone, Satigrel, Satsuma MAb Pentide, Chick Test Control, Scopafungin, Scopolamine Hydrobromide, Scrazaipine Hydrochloride, Sdi 1 Mimetic, Secalciferol, Secobarbital, Seal Zone, Seglitide Acetate, Selegiline Hydrochloride, Selenium Sulfide, Selenomethionine Se 75,Cell hotel, Sematiride, Senduramycin, Semotiadil, Semustine, Sense oligonucleotide, Sepazonium chloride, Seperidol hydrochloride, Seprilose, Ciproxetine hydrochloride, Seractide acetate, Selgorexol maleate, Serine, Selmetacin, Sermorelin acetate, Celtoconazole, Certindole, Sertraline, Cetiprilin, Cetroperone, Sevirumab, Sevoflurane, Sezolamide, Sibopirdine, Sibutramine hydrochloride, Signal transduction inhibitor, Silandron, Siripide, Silteplase, Silver nitrate, Simendan, Simtrazene, Simvastatin, Cinacalcet, Cinefungin, Cinitrozil, Sinnabidol, Sipatridin, Sirolimus, Sisomicin, Citoglucide, Schizophyllan, Sobuzoxan, Sodium amylosulfate, Sodium iodide I 123, Sodium nitroprusside, Sodium oxybate, Sodium phenylacetate, Sodium salicylate, Solverol, Solperthin tartrate, Somalapor, Somatandine hydrochloride, Somatomedin B, Somatomedin C, Somatrem, Somatropin, Somenopor, Somidbob, Sonermin, Solvinyl, Solibudine, Sotolol, Soteranol hydrochloride, Sparfloxacin, Sparfosate sodium, Sparfosic acid, Sparsomycin, Sparteine sulfate, Spectinomycin hydrochloride, Spicamycin D, Spipperone, Spirapril mesylate, Spiramycin, Spirapril hydrochloride, Spiraprilat, Spirogermanium hydrochloride, Spirothromycin, Spironolactone, Spiroplatin, Spiroxasone, Spreponpentine, Spongistatin 1, Sprodiamide, Squalamine, Starimycin hydrochloride, Stannous pyrophosphate, Stannous sulfur colloid, Stanozolol, Statron, Staurosporine, Stabudin, Stefimycin, Stenbolone acetate, Stepronine, Stilbazium iodide, Stilonium iodide, Stipiamide, Stilpentol, Stovadin, Streptomycin sulfate, Streptonicodide, Streptomycin, Streptozocin, Stromelysin inhibitor, Strontium chloride Sr89, Succibun, Sacximer, Succinylcholine chloride, Scralfurat, Scralfurat potassium, Sudoxicam, Sufentanil, Sphotidine,Slazepam, Sulbactam pivoxil, Sulconazole nitrate, Sulfabenz, Sulfabenzamide, Sulfacetamide, Sulfacitine, Sulfadiazine, Sulfadoxine, Sulfalen, Sulfamerazine, Sulfamethizole, Sulfamethazine, Sulfamethoxazole, Sulfamethoxazole, Sulfamonomethoxine, Sulfamoxole, Zinc sulfanilate, Sulfanitran, Sulfasalazine, Sulfisomizole, Sulfazamet, Sulfinpyrazone hydrochloride, Sulfinosine, Sulfinpyrazone, Sulfisoxazole, Sulfomixine, Sulfonterol hydrochloride, Sulfoxamine, Sulinldac, Sulfamarin, Sulfonidazole, Sroctidyl, Srofenurol, Sropenem, Sulfoxyphen oxalate, Sulpiride, Sulprostone, Sulfatamicillin, Sulthiam, Sultopride, Sulcaste, Sumaroten, Sumatriptan, Sunsirine sodium, Sproclon, Sprofen, Sladista, Slamine, Sulfomar, Sulcainide maleate, Sritozole, Sronacrine maleate, Suxemilide sulfate, Swainsonine, Symakalim, Simcroscen, Cimetidine hydrochloride, Synthetic glycosaminoglycan, Taciamine hydrochloride, Tacrine hydrochloride, Tacrolimus, Tarampicillin hydrochloride, Talerenol, Talithromycin, Talimstin, Talmetacin, Luniflumart, Talopram hydrochloride, Talosalate, Tametralin hydrochloride, Tamoxifen, Tampramine fumarate, Tamsulosin hydrochloride, Tandamine hydrochloride, Tandospirone, Tapgen, Taprostene, Tazosartan, Taurostin, Taxane, Taxoid, Tazadrene succinate, Tazanolast, Tazarotene, Tajifillin hydrochloride, Tazobactam, Tazopheron, Tazolol hydrochloride, Tebufenron, Tebukin, Technetium Tc99m bicisate, Tecrozan, Tecogalan sodium, Teecleukin, Tefluran, Tegafur, Tegretol, Teicoplanin, Terenzepine, Terlapirillium, Termestain, Telmisartan, Telomerase inhibitor, Teloxantrone hydrochloride, Terodipine hydrochloride, Temafloxacin hydrochloride, Tematropium methyl sulfate, Temazepam, Temerastine, Temocapril,Temocillin, temoporphyrin, temozolomide, tenidap, teniposide, tenosal, tenoxicam, tepirindole, tepoxalin, teprotide, terazosin, terbinafine, terbutaline sulfate, terconazole, terfenadine, terflavoxate, terguride, terliparatide acetate, terlakiren, terlipressin, terodiline, teroxalene hydrochloride, teroxylon, tertatrol, tesicam, tesimide, testolactone, testosterone, tetracaine, tetrachlorodecaoxide, tetracycline, tetrahydrozoline hydrochloride, tetramizole hydrochloride, tetrazolast meglumine, tetrazomine, tetrophosmin, tetroquinone, tetroxoprim, tetridamine, taliblastine, thalidomide, theofibrate, theophylline, thiabendazole, thiamiprine, thiamphenicol, thiamylal, thiazecim hydrochloride, thiazinamium chloride, thietylperazine, thimerfonate sodium, thimerosal, thiocolchicine, thiophenedrine, thioguanine, thiomarinol, thiopental sodium, thioperamide, thioridazine, thiotepa, thiothixene, tifennamil hydrochloride, tifensillin potassium, thiram, tozarinone, threonine, thrombin, thrombopoietin, thrombopoietin mimetic, timalphasin, timopoeitin receptor agonist, timotrinan, thyromedan hydrochloride, thyroxine 1 125, thyroxine 1 131, tiacrilast, tiacrilast sodium, tiagabine, thiamenidine, tianeptine, thiapapant, thiapamil hydrochloride, thiaramide hydrochloride, thiazofurin, tibelast sodium, tibolone, tiburic acid, ticabesone propionate, ticarbodine, ticarsilin cresyl sodium, ticlatone, ticlopidine, ticrinaphen, thienoxolol, tifurac sodium, tigemonam dicoline, tigestol, tiretanine hydrochloride, tilidine hydrochloride, tilisolol, tilnoprofen albamel, tilorone hydrochloride, tiludronic acid disodium, tiludronic acid, timelfrone, timobenzon acetate, timolol, ethyl ethiopurpurin tin, tinabinol, timidazole, tinzaparin sodium, tioconazole, thiodazosin, thiodonium chloride, thioperidone hydrochloride, thiopinac, thiospirone hydrochloride,Thiotidine, tiotropium bromide, thioxydazole, tiopentosin hydrochloride, tiperdan, tiprenolol hydrochloride, tiprinast meglumine, tiopropidyl hydrochloride, tiquezide, tichinamide hydrochloride, tilandridine, tirapazamine, tilazad, tirofiban, tiplamide, titanocene dichloride, tixanox, tixocortol pivalate, tizanidine hydrochloride, tobramycin, tocainide, tocanfil, tofenacin hydrochloride, tramolol, trazamide, trazoline hydrochloride, tolbutamide, tolcapone, tolcyclate, tolfaamide, tolgabide, lamotrigine, toluidimide, trindate(, Tolindate), tolmetin, tolnaftate, tropovidone 1131, tropiramide, torelestat, tomelukast, tomoxetine hydrochloride, terazosin mesylate, topiramate, topotecan, topotecan hydrochloride, topsentin, topterone, toxyzine, tracethamide, tamoxifen, torsemide, tosilfen, tosufloxacin, totipotent stem cell factor, tracazolate, trafermin, traloridine, tramadol hydrochloride, tramazoline hydrochloride,trandolapril, tranexamic acid, tranilast, transcinamide, translation inhibitor, traxanox, trazodone hydrochloride, trazodone-HCL, trebenzomine hydrochloride, trepipan maleate, tretinoin, triacetin, triacetyluridine, triafungin, triamcinolone, triampicillin sulfate, triamterene, triazolam, tribenoside, tricaprylin, tricetamide, trichlormethiazide, trichoherin, trisciribine, tricitrate, trichlorophenol piperazine, trichlorophosphate sodium, triclonide, trientine, trifenaagrel, triflavin, triflurosine, triflubazam, triflumidate, trifluoperazine hydrochloride, trifluperidol, trifluoperazine, triflupromazine hydrochloride, trifluridine, trihexyphenidyl hydrochloride, trilostane, trimazosin hydrochloride, trimegestone, trimipramine tartrate, trimethadione, trimethaphan camsylate, trimethobenzamide hydrochloride, trimethoprim, trimethidine, trimethrexate, trimipramine, trimoprostil, trimoxamine hydrochloride, triolein 1125, triolein 1131, trioxifen mesylate, tripamide, tripelennamine hydrochloride,

[0046] It should be noted that some of the terms in the original text may be incorrect or very rare drug names. It is recommended to double-check the accuracy of the source text for more reliable translation.Triprolidine hydrochloride, tryptoline, trisulfapyrimidine, troxerutin potassium, troglitazone, tromethamine, troleandomycin, thromboxane dipyridamole, trometamol, tropacocaine hydrochloride, tropicamide, tropine ester, tropisetron, trospecomycin, trovafloxacin, trovirdine, tryptophan, tuberculin, tubocurarine chloride, tubrolzol hydrochloride, tucarcsol, tulobuterol, turos teride, tibamate, thyroglobulin, sodium tiopronate, tyrosine, thyrotriiodothyronine, tilostatin, ubenimex, urdazepam, undecylenic acid, uracil mustard, urapidil, urea, ure depa, uridine triphosphate, urofolitropin, urokinase, ursodiol, valaciclovir, valine, barnoctamide, sodium valproate, valproic acid, valsartan, bamikamide, vanadeine, vancomycin, vaninorele, bapiprostone hydrochloride, vapreotide, variolin B, vasopressin, vecuronium bromide, veraresol, bernacrine maleate, venlafaxine, veradoline hydrochloride, veramine, verapamil hydrochloride, vergin, verilopam hydrochloride, zafirlukast, theophylline, veroxan, verteporfin, besnarinone, bexibinol, vidarabine, vigabatrin, viloxazine hydrochloride, vincristine sulfate, vinblastine sulfate, vinburnine citrate, vincophos, vincanate, vindesine, vindesine sulfate, vinleurosine sulfate, vinorelbine, vinpocetine, vintoperol, vinsalazine, vinzolidine sulfate, biprostol, virginiamycin, viridofluvin, viroxime, vitaxin, terazosin, voriconazole, vorozole, boxelgolide, warfarin sodium, xamoterol, xanomeline, sodium xanoxate, xanthinol nicotinate, xemilofiban, xenalipin, xenbutine, xylobam, ximoprofen, xipamide, zolmitriptan mesylate, xylamidine tosylateTosylate, xylazine hydrochloride, xylometazoline hydrochloride, xylose, yangambin, zabisopril, zacopride, zafirlukast, zalcitabine, zaleplon, zolospiron, zalcitabine hydrochloride, zaltoprofen, zanamivir, zankiren, zanoterone, zantac, zarirlukast, zatebradine, zatosetron, zatosetron maleate, zenerestat, terazosin mesylate, cisplatin, zeralanol, didomethacin, didobutine, diflucortolone, dilanter, dilascob, dirotone, dimelazine hydrochloride, zinc undecylenate, zindotrine, diniconazole hydrochloride, dinostatin, dinterol hydrochloride, dinviroxime, diplasidone, zobolt, zofenopril calcium, zofenoprilat, zolamine hydrochloride, zolazepam hydrochloride, zoledronic acid, zolertine hydrochloride, sumatriptan, zolpidem, zomepirac sodium, zomepizole, zoniclezole hydrochloride, zonisamide, zopiclone, zopolrestat, zorbamyciin, zorbicin hydrochloride, zotepine, zucapsaicin.

[0047] Another pharmaceutically active agent acceptable for use herein is lumateperone as disclosed in U.S. Patent 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, 9,168,258, RE039680E1, 9,616,061, 9,586,960, and U.S. Patent Application Publication Nos. 2017 / 114037, 2017 / 183350, 2015 / 072964, 2004 / 034015, 2017 / 189398, 2016 / 310502, 2015 / 080404, the entire contents of which are incorporated herein by reference in their entirety.

[0048] Further examples of anti-diabetic agents include, but are not limited to, JTT-501 (PNU-182716) (pioglitazone), AR-H039242, MCC-555 (netoglitazone), AR-H049020 (tesaglitazar), CS-011 (CI-1037), GW-409544X, 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] Useful erectile dysfunction therapeutic agents herein include, but are not limited to, agents for promoting blood flow to the penis, or agents for affecting the activity of the autonomic nervous system such as increasing the activity of the parasympathetic (cholinergic) nervous system and decreasing the activity of the sympathetic (adrenergic) nervous system. Useful active agents for the treatment of erectile dysfunction include, for example, but are not limited to, alprostadil, tadalafil, vardenafil, apomorphine, yohimbine hydrochloride, sildenafil citrate, and any combination thereof. In certain embodiments, the active agent is tadalafil. Active agents or drugs for the treatment of headache and / or migraine are also usable herein. Examples of specific active agents include, but are not limited to, triptans such as eletriptan, naratriptan, rizatriptan (rizatriptan benzoate), sumatriptan, and zolmitriptan. In certain embodiments, the active agent is rizatriptan optionally combined 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 can be diazepam. When the active agent is diazepam, 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 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 certain 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 agent used in the oral films disclosed herein may be micronized. The active agent may be micronized by any means known in the art. The active agent can 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 about 8 microns. The active agent can 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 about 3 microns. The active agent can 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 about 1 micron. The active agent can 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 can have an average particle size D90 of about 8 microns, a D50 of about 3 microns, and a D10 of about 1 micron.

[0052] For particles in the range of 0.02 - 2000 μm / 0.01 - 3500 μm, the particle size is most commonly measured using laser diffraction light scattering. In this technique, the particles pass through the laser beam path and diffract the light. Next, the angle of this diffracted light is correlated with the particle size using the difference in refractive index between the particle and the medium. The output of this measurement is a volume distribution, often represented as D x where x is the representation of the distribution. For example, D 90 represents the volume distribution of the analyzed particles such that 90% of the observed diffraction falls within this size, and thus 90% of the particles are smaller than this particle size. Since larger particles can disproportionately load the volume, other descriptions of particle size such as the "number distribution" that correlates the number of particles of this size are also in common use. However, these alternative statistical descriptions of particle size based on laser diffraction light scattering are mathematical calculations based on the volume distribution, and thus, unless otherwise specifically stated, the particle size description of D x is the volume distribution. It has been known that an average particle size of less than 200 microns is preferred to obtain a smooth oral film. However, further development has shown that a smaller average particle size, i.e., fine powder particles, can improve the aesthetics and dissolution of the film. Furthermore, the results of dissolution tests of lower-dose films (e.g., 5 mg and 10 mg) have been found to show better performance for the micronized active agent than for films containing a pulverized active agent (e.g., about 100 microns at average particle size D90).

[0053] Dissolution profile PION devices such as the PION Rainbow Dynamic Dissolution Monitor (RDDM (registered trademark)) ("PION technology") are powerful analytical instruments that accurately and effectively measure the dissolution percentage in real time. PION technology utilizes high-fiber optics for in situ kinetic solubility and supersaturated UV monitoring in dissolution tests to determine the release rate of the drug substance and its dissolution over time. PION technology uses individual diode array spectrophotometers and is equipped with 6 - 8 acquisition channels, an immersion probe, and interchangeable optical path length chips. PION technology has a real-time data display, thereby providing rapid and reproducible results for the testing of active agents, formulations, and pharmaceuticals. These measurements are accurate even for small volumes and complex substrates.

[0054] Optical fiber-based dissolution systems, such as PION technology, have been used in dosage forms other than oral films. However, these systems could not be used appropriately for oral films due to the size and density of the oral films, for example, the film had already dissolved and released the active agent before measurement could be performed. To overcome this, a custom film introduction system / holder had to be designed and developed. This custom film introduction system / holder prevents the film from floating in the dissolution vessel and being agitated. It also allows for the simultaneous introduction of multiple films. This is important for rapid data collection. Furthermore, both the sample holder, its distance from the paddle, and the distance and angle from the optical fiber probe play important roles in ensuring consistent and accurate data collection while meeting the hydrodynamic requirements of the USP. A non-limiting example of the configuration of the apparatus used in PION technology is shown in FIG. 1. As shown in this figure, the system is composed of multiple systems configured to perform tests simultaneously in parallel on different samples. The system includes a probe, a dissolution paddle, and a custom sample holder. There are options for the placement of this custom sample holder (height and angle with respect to the flow). Also, the size of the holder can be changed to fit the film. In addition, as will be readily understood by those skilled in the art, the optical path length of the probe can also be changed. If the optical path length is too wide, the signal will be overloaded. If the optical path length is too narrow, the signal will be too weak.

[0055] Figure 2 is another exemplary configuration of a paddle, a holder, and means for adjusting the height of the probe and the holder used in obtaining a dissolution profile by PION technology. When sufficient paddle stirring is performed, the height of the probe is not thought to affect the results, but the orientation of the sample holder affects the disintegration of the film and can affect the dissolution rate of the active agent. As shown in FIGS. 1 and 2, for example, the sample holder is arranged perpendicular to the wall of the dissolution vessel to maximize exposure. The angle of the holder with respect to the dissolution vessel can be changed by changing the holder orientation (twisting the holder from vertical to the desired angle). The holder can be made larger to accommodate larger films, but there are limitations to the acceptable angle range. For example, when the holder is made larger to fit a larger film, the degree of freedom of adjustment is reduced. If the twist is too large, the holder or film may contact the side wall of the vessel or 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. By using PION technology, there are several advantages as follows. 1. Off-line analysis is not required. 2. There are many available sampling points. 3. Multiple wavelengths can be evaluated. 4. The rate of change (e.g., inflection point acceptance criteria) can be evaluated. 5. Comparison of profiles shows potential discriminative ability between intensity and storage conditions. The dissolution profiles and rates of the oral films disclosed herein measured by PION technology generally matched those measured by conventional dissolution, except that the curves were more precise and accurate, and thus the inflection points were determinable. Using an optical fiber UV monitoring system such as PION technology enables a more accurate and precise dissolution profile of the oral film. The dissolution profile is an average collection of data points showing the percent dissolution of the dosage form or active agent over time from t = 0 until after 100% of the dosage form or active agent has dissolved. The "active agent dissolution profile" refers to the dissolution profile of the active agent after it has been released from the film. The film itself and the carriers therein have some effect on the dissolution rate of the active agent as it dissolves after being released from the oral film dosage form. For example, FIGS. 9 and 10 show the active agent dissolution profiles, and FIGS. 13 - 23 show the improved and more precise data and differentials possible with PION technology. In contrast, FIG. 8 shows the active agent dissolution profile measured by conventional dissolution that lacks discriminability at very early time points for rapidly 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 FIGS. 19, 21, and 23. The first derivative graph provides insight into the release rate of the active agent from the film. The intensity and width of the first derivative are proportional to the release rate. For example, by plotting these differentials, it can be learned that oral films containing 5 mg and 10 mg of the active agent release more quickly and more fully within 1 minute than an equivalent oral film containing 20 mg of the active agent, as indicated by the height and width of the first derivative curve. In such a display, the oral film containing 20 mg of the active agent has a broader curve and shows a slower release. For all curves, as release is completed, the first derivative approaches 0 and the concentration of the drug in the container reaches a plateau. When different dosage forms of an active agent have the same particle size distribution, it is thought that the active agent dissolution profiles will be the same. However, this is not always the case. By using PION technology, distinguishable differences between dosage forms can be seen, indicating 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 the first derivative curve and the second derivative curve give maximum, minimum, 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 more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, more than about 50%, or more than about 55% in about 2 minutes when measured by the PION technology. The active agent may optionally exhibit an average dissolution of more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, more than about 50%, more than about 55%, more than about 60%, more than about 65%, or more than about 70% in about 3 minutes when measured by the PION technology. The active agent may optionally exhibit an average dissolution of more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, more than about 50%, more than about 55%, more than about 60%, more than about 65%, or more than about 70% in about 5 minutes when measured by the PION technology. The active agent may optionally exhibit an average dissolution of more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, more than about 50%, more than about 55%, more than about 60%, more than about 65%, more than about 70%, more than about 75%, more than about 80%, more than about 85%, or more than about 90% in about 10 minutes when measured by the PION technology. The active agent may optionally exhibit an average dissolution of more than about 30%, more than about 35%, more than about 40%, more than about 45%, more than about 50%, more than about 55%, more than about 60%, more than about 65%, more than about 70%, more than about 75%, more than about 80%, more than about 85%, more than about 90%, more than about 95%, or more than about 98% in about 15 minutes when measured by the PION technology. The active agent may optionally exhibit an average dissolution of more than about 60%, more than about 65%, more than about 70%, more than about 75%, more than about 80%, more than about 85%, more than about 90%, more than about 95%, more than about 98%, or more than about 99% in about 20 minutes when measured by the PION technology.As measured herein, dissolution of the active agent occurs after the film is placed in the medium. When placed in the medium, the film dissolves and releases the active agent into the medium.

[0059] Dissolution rate is the rate at which the oral film or the active agent dissolves and is calculated as a percentage of the amount released at a given point in time. The dissolution rate is obtained by performing a dissolution test with a selected apparatus and measured according to specific dissolution parameters. Dissolution parameters include storage conditions such as time, temperature, and relative humidity, as well as 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 calculated as a percentage of the amount released at a given point in time. In the case of an oral film dosage form 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). Dissolution of the active agent can also be expressed as the %(average) of the active agent dissolved at a given point in time. Unless stated otherwise, dissolution of the active agent is measured under storage conditions of the oral film at about 0 months to about 36 months, up to about 36 months beyond 0 months, about 6 to about 36 months, about 6 to about 24 months, about 9 months to about 18 months, or about 12 months, about 20°C to about 60°C, about 25°C to about 40°C, or about 25°C, and a relative humidity (RH) of up to about 75%, for example, at an RH of about 60%.

[0061] The dissolution test can be carried out under the "immersion" conditions defined by USP <1092> as "at least three times the volume of the medium required to form a saturated solution of the active ingredient. If immersion conditions exist, the dissolution results are more likely to represent the characteristics of the dosage form". Different media may be required for different pharmaceuticals based on characteristics of the active agent such as solubility and route of administration. As can be readily understood by those skilled in the art, the above factors can be considered in developing the dissolution method. Using that, USP <1092> also defines the range of media to be evaluated. "Typical media for dissolution may include the following (listed not in preferred order): dilute hydrochloric acid, buffers (phosphate or acetate) in the physiological pH range of 1.2 - 7.5, artificial gastrointestinal fluids (with or without enzymes), water, and surfactants (with or without acids or buffers)". Surfactants can be, but are not limited to, polysorbate 80, sodium lauryl sulfate, and bile salts. For some drugs, incompatibility of the drug with a particular buffer or salt can affect the choice of buffer. The molar concentration of the buffer and acid used may affect the solubilization effect, and this factor can be evaluated. An aqueous solution (acidic or buffer solution) may contain a percentage of surfactant, such as sodium dodecyl sulfate (SDS), polysorbate, or lauryl dimethylamine oxide, to increase the solubility of the drug.

[0062] In one embodiment, dissolution of the active ingredient is measured in dilute hydrochloric acid, buffers (phosphate or acetate) in the physiological pH range of 1.2 - 7.5 (including, but not limited to, 0.05 molar potassium primary phosphate buffer pH 6.8), artificial 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 ingredient is measured in dilute hydrochloric acid, 0.05 molar potassium primary phosphate buffer pH 6.8, 0.1N HCL), water, or 0.5% sodium lauryl sulfate.

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

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

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

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

[0067] In an oral film containing about 50 mg of riluzole, can more than about 2% of riluzole dissolve after about 3 minutes, can more than 10% of riluzole dissolve after about 5 minutes, can more than 20% of riluzole dissolve after about 5 minutes, can more than 30% of riluzole dissolve after about 5 minutes, can less than about 45% of riluzole dissolve after about 5 minutes, or can about 40% of riluzole dissolve after about 5 minutes, optionally measured by the PION technology? In a film containing about 50 mg of riluzole, can more than 30%, more than 40%, more than 50%, less than about 75%, or about 71% of riluzole dissolve after about 10 minutes, optionally measured by the PION technology? In a film containing about 50 mg of riluzole, can more than 85%, less than 93%, less than about 91%, or about 89% to about 90% of riluzole dissolve after about 15 minutes, optionally measured by the PION technology? Any combination of the above dissolutions at different time points is within the scope of the present invention.

[0068] In an oral film containing clobazam, optionally when measured by the PION technology, more than about 3%, more than about 5%, more than about 10%, or more than about 15% of clobazam may dissolve after about 1 minute. Optionally when measured by the PION technology, more than about 5%, more than about 10%, more than about 30%, or more than about 40% of clobazam may dissolve after about 1.5 minutes. Optionally when measured by the PION technology, more than about 15%, more than about 20%, more than about 40%, or more than about 60% of clobazam may dissolve after about 2.5 minutes. Optionally when measured by the PION technology, more than about 20%, more than about 30%, more than about 35%, more than about 40%, or more than about 45% of clobazam may dissolve after about 3 minutes. Optionally when measured by the PION technology, more than about 55%, more than about 65%, more than about 70%, or more than about 75% of clobazam may dissolve after about 5 minutes. Optionally when measured by the PION technology, more than about 85%, more than about 90%, or more than about 91% of clobazam may dissolve after about 6.5 minutes. Optionally when measured by the PION technology, more than about 95% or more than about 99% of clobazam may dissolve after about 10 minutes. Any combination of the above dissolutions at different time points is within the scope of the present invention.

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

[0070] In an oral film containing about 10 mg of clobazam, when measured optionally by the PION technology, after storage of the film at about 25°C and then measured, more than about 15%, or more than about 20% of clobazam dissolves after about 1 minute, and when measured optionally by the PION technology, after storage of the film at about 40°C and then measured, more than about 35%, or more than about 40% of clobazam may dissolve after about 1 minute. In a film containing about 10 mg of clobazam, when measured optionally by the PION technology, after storage of the film at about 25°C and then measured, more than about 50%, or more than about 55% of clobazam dissolves after about 1.5 minutes, and when measured optionally by the PION technology, after storage of the film at about 40°C and then measured, more than about 65%, or more than about 70% of clobazam may dissolve after about 1.5 minutes. In a film containing about 10 mg of clobazam, when measured optionally by the PION technology, after storage of the film at about 25°C and then measured, more than about 70%, or more than about 75% of clobazam dissolves after about 2 minutes, and when measured optionally by the PION technology, after storage of the film at about 40°C and then measured, more than about 80%, or more than about 85% of clobazam may dissolve after about 2 minutes. Any combination of the above dissolutions at different time points is within the scope of the present invention.

[0071] In an oral film containing about 20 mg of clobazam, when measured optionally by the PION technology, after storage of the film at about 25°C and then measured, more than about 2% or about 4% of clobazam dissolves after about 1.5 minutes; when measured optionally by the PION technology, after storage of the film at about 40°C and then measured, more than about 5% or about 6% of clobazam may dissolve after about 1.5 minutes. In a film containing about 20 mg of clobazam, when measured optionally by the PION technology, after storage of the film at about 25°C and then measured, more than about 10% or more than about 15% of clobazam dissolves after about 2.5 minutes; when measured optionally by the PION technology, after storage of the film at about 40°C and then measured, more than about 25% or more than about 30% of clobazam may dissolve after about 2.5 minutes. In a film containing about 20 mg of clobazam, when measured optionally by the PION technology, after storage of the film at about 25°C and then measured, more than about 40% or about 46% of clobazam dissolves after about 3.5 minutes; when measured optionally by the PION technology, after storage of the film at about 40°C and then measured, more than about 65% or about 68% of clobazam may dissolve after about 3.5 minutes. In a film containing about 20 mg of clobazam, when measured optionally by the PION technology, after storage of the film at about 25°C and then measured, more than about 80% or about 83% of clobazam dissolves after about 5.5 minutes; when measured optionally by the PION technology, after storage of the film at about 40°C and then measured, more than about 90% or about 94% of clobazam may dissolve after about 5.5 minutes. 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 the active agent dispersed in the film and the amount dissolved in the film. If the amount dissolved is too much compared to the amount dispersed in the film, when the film is placed in the oral cavity, the patient will feel the taste of the active agent, and the active agent often has a very unpleasant flavor. In certain 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 As a more significant change in the pharmaceutical product, comparison of the dissolution profiles conducted under the same conditions for the reference product and the changed product 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)). The dissolution profiles can be considered similar based on (1) the similarity of the overall profiles and (2) the similarity at each time point of the dissolution samples.

[0074] One means of comparing dissolution profiles is by use of a model-independent method using a similarity coefficient. A simple model-independent approach uses a dissimilarity coefficient (f1) and a similarity coefficient (f2) to compare dissolution profiles (Moore, J. W. and H. H. Flanner, 1996, “Mathematical Comparison of Dissolution Profiles,” Pharmaceutical Technology, 20 (6):64-74). The dissimilarity coefficient (f1) calculates the percent (%) of the difference between 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 obtaining the dissimilarity coefficient and the similarity coefficient is as follows: a. Determine the dissolution profiles of two products, the test article (before change) and the reference article (after change). b. Using the average dissolution values from both curves at each time interval, calculate the dissimilarity coefficient (f1) and the similarity coefficient (f2) using the above equation. c. These curves are considered similar if the f1 value is 15 or less (0 - 15) and the f2 value is greater than 50 (i.e., 50 - 100), and thus the identity of these two products is guaranteed. With the improved accuracy and enhanced PION technology, it is possible to compare the dissolution profiles of active agents with higher precision and for variables not previously understood to obtain computable differences in dissolution.

[0076] Polymer The film and / or its components can be water-soluble, water-swellable, water-insoluble, or a combination of one or more of these. The term "water-soluble" can refer to a substance that is at least partially soluble in an aqueous solvent containing water, although not limited thereto. The term "water-soluble" does not necessarily mean that the substance is 100% soluble in the aqueous solvent. The term "water-insoluble" refers to a substance that is not soluble in an aqueous solvent containing water, although not limited thereto. The solvent can contain water or, alternatively, can contain another solvent (preferably a polar solvent) alone or in combination with water.

[0077] The film can be made by a combination of at least one polymer and a solvent, optionally including other components. The solvent can be water or a polar organic solvent including, although not limited to, 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 vapor 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 radiant energy to a wet film substrate to form a viscoelastic structure, thereby controlling the uniformity of the film content. This controlled drying process can include contacting air alone, heat alone, or heat and air together with the upper surface of the film, the lower surface of the film, or the substrate supporting the cast, vapor deposited, or extruded film, or contacting two or more surfaces simultaneously or at different times during the drying process. Some such processes are described in more detail in U.S. Patent Nos. 8,765,167 and 8,652,378, which are incorporated herein by reference. Alternatively, the film can be extruded as described in U.S. Patent Application Publication No. 2005 / 0037055, which is incorporated herein by reference.

[0078] The polymer substrate contained in the film can be water-soluble, water-swellable, or a combination thereof. The polymer substrate contains a polymer. The polymer can be polyethylene oxide. The polymer can include cellulose, a cellulose derivative, or a gum. The polymer can include polyethylene oxide, cellulose, a cellulose derivative, such as a cellulose ether, or a combination thereof. The polymer can be a cellulose-based polymer. In certain embodiments, the cellulose-based polymer can be hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, and / or sodium carboxymethyl cellulose. In certain embodiments, the polymer can include hydroxypropyl methylcellulose. In certain embodiments, the polymer can include polyethylene oxide and a cellulose ether, such as hydroxypropyl methylcellulose. In certain embodiments, the polymer can include polyethylene oxide and / or polyvinylpyrrolidone. In certain embodiments, the polymer substrate can include polyethylene oxide and / or a polysaccharide. In certain embodiments, the polymer substrate can include polyethylene oxide, hydroxypropyl methylcellulose, and / or a polysaccharide. In certain embodiments, the polymer substrate can include polyethylene oxide, a cellulose-based polymer, a polysaccharide, and / or polyvinylpyrrolidone. In certain embodiments, the polymer substrate can include at least one polymer selected from the group consisting of pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide, propylene oxide copolymer, collagen, albumin, polyamino acid, polyphosphazene, polysaccharide, chitin, chitosan, and derivatives thereof.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 copolymer, carboxyvinyl copolymer, starch, gelatin, polysaccharides, and combinations thereof.

[0079] As used herein, the term "water-soluble polymer" and variations thereof refer to polymers that are at least partially soluble in water, desirably completely or mostly soluble in water, or absorb water. Polymers that absorb water are often referred to as water-swellable polymers. The 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. Further, these materials can be water-soluble or water-swellable at pressures lower than atmospheric pressure. Desirably, the water-soluble polymer is water-soluble or water-swellable with at least 20% by mass water uptake. Water-swellable polymers with 25% by mass or more water uptake are also useful. In some embodiments, films formed from such water-soluble polymers can be water-soluble enough to be soluble when contacted with body fluids.

[0080] Other polymers useful for incorporation into the film include biodegradable polymers, copolymers, block polymers or combinations thereof. The term "biodegradable" is understood to include materials that decompose chemically, rather than materials that physically disintegrate (i.e., materials that are biodegradable). The polymers incorporated into the film may also include combinations of biodegradable materials or biodegradable materials. Known useful polymers or polymer species that meet the above criteria include poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxane, polyoxalate, poly(α-ester), polyanhydride, polyacetate, polycaprolactone, poly(orthoester), polyamino acid, polyaminocarbonate, polyurethane, polycarbonate, polyamide, poly(alkyl cyanoacrylate), 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), polyphosphazene, polyhydroxy-alkanoate or mixtures thereof. Binary and ternary systems are also contemplated. The polymer substrate may include one, two, three, four or more components.

[0081] Other specific polymers of interest include those commercially available 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 - polymer and hydroxy - polymer and hydroxyacetic acid". Four such polymers include lactide / glycolide 100L, which is thought to be 100% lactide and has a melting point in the range of 338 - 347°F (170 - 175°C); lactide / glycolide 100G, which is thought to be 100% glycolide and has a melting point in the range of 437 - 455°F (225 - 235°C); lactide / glycolide 85 / 15, which is thought to be 85% lactide and 15% glycolide and has a melting point in the range of 338 - 347°F (170 - 175°C); and lactide / glycolide 50 / 50, which is thought to be a copolymer of 50% lactide and 50% glycolide and has a melting point in the range of 338 - 347°F (170 - 175°C). The Biodel materials correspond to a series of chemically different polyanhydrides.

[0082] A variety of different polymers can be used, but it is desirable to select a polymer that gives the film mucoadhesive properties and the desired dissolution and / or disintegration rate. In particular, the time for which it is desirable to maintain the film in contact with the mucosal tissue varies depending on the type of pharmaceutical active agent contained in the composition. Some pharmaceutical active agents may require only a few minutes for delivery via 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 as described above to form the film. 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. Inclusion of one or more water - swellable, water - insoluble and / or biodegradable polymers can provide a slower dissolution or disintegration rate of the film than a film formed from a water - soluble polymer alone. Thus, the film can adhere to the mucosa for a longer time, such as up to several hours, which may be desirable for the delivery of certain pharmaceutical active agents.

[0083] The polymer substrate may include a dendritic polymer that may include a highly branched polymer having various structural configurations. The dendritic polymer may include a dendrimer, a dendronized polymer (dendrigraft polymer), a linear dendritic hybrid, a multi-arm star polymer, or a hyperbranched polymer. The polymer substrate may include a hyperbranched polymer, which is a highly branched polymer having structural imperfections. However, they can be synthesized in a one-step reaction, which may be more advantageous than other dendritic structures, and are thus suitable for applications with a bulky volume. In addition to a spherical structure, the properties of these polymers are an abundance of functional groups, intramolecular cavities, low viscosity, and high solubility. Dendritic polymers have been used in some 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 in its entirety.

[0084] The dendritic polymer may have a lumen capable of encapsulating a drug. The steric hindrance caused by the high density of polymer chains may prevent the crystallization of the drug. Thus, the branched polymer may provide an additional advantage when formulating a crystalline drug in the polymer substrate. 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(arylalkylene ether)-based dendrons, dendrimers, and hyperbranched polymers, poly(alkyleneimine)-based dendrons, dendrimers, and hyperbranched polymers, and poly(amidoamine)-based dendrons, dendrimers, or hyperbranched polymers. Other examples of hyperbranched polymers include poly(amine), polycarbonate, poly(ether ketone), polyurethane, polycarbosilane, polysiloxane, poly(ester amine), poly(sulfone amine), poly(urea urethane), 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 can be another water-soluble polymer, water-swellable polymer, water-insoluble polymer, biodegradable polymer, or any combination thereof. Suitable water-soluble polymers include, but are not limited to, any of those shown above. In one embodiment, the water-soluble polymer can be a hydrophilic cellulose-based polymer such as hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose. In another embodiment, the polyethylene oxide-based film may also contain one or more water-swellable, water-insoluble, and / or biodegradable polymers. Any of the water-swellable, water-insoluble, or biodegradable polymers shown above can be used. The second polymer can 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, 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, 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 a liquid that controls the stability of an active agent in an emulsion, colloid, or suspension. Generally, the viscosity of the base material 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 for the viscosity of the film-forming base material to increase rapidly at the start of the drying process.

[0087] Viscosity can be adjusted based on the selected active agent according to other components in the base material. For example, if the component is not soluble in the selected solvent, an appropriate viscosity should be selected so that the component does not adversely affect the uniformity of the resulting film. Viscosity can be adjusted in various ways. To increase the viscosity of the film base material, a polymer with a higher molecular weight may be selected, or a cross-linking agent such as salts of calcium, sodium, and potassium may be added. Viscosity can also be adjusted by adjusting the temperature or by adding a thickening component. Components that increase viscosity or stabilize the emulsion / suspension include, but are not limited to, higher molecular weight polymers and polysaccharides and gums, including alginates, carrageenans, hydroxypropylmethylcellulose, locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gum, and combinations thereof. Also, certain polymers that typically require a plasticizer to achieve a soft film when used alone have also been found to achieve a soft film without combining a plasticizer. For example, HPMC and HPC, when used in combination, result in a flexible and strong film with appropriate plasticity and elasticity for manufacturing and storage. There is no need for an additional plasticizer or polyalcohol for flexibility.

[0088] Additive Additives may be added to the films disclosed in this specification. The various additives that can be incorporated into the films of the present invention can provide various different functions. Examples of additive types include excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, extenders, sweeteners, flavoring agents, fragrances, release regulators, adjuvants, plasticizers, flow promoters, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, lubricants, adhesives, anti-caking agents, acidulants, softeners, resins, mucilages, solvents, surfactants, emulsifiers, elastomers, and mixtures thereof. These additives can be added before or together with the active agent. The amount of additives in the film can range from about 0.005% to about 50%, about 1% to about 20%, or about 3% to about 20% based on the mass of the film composition (the total mass of all components therein), up to about 80% maximum, 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%, about 3%, or less than about 1%. The additive can be selected from the group consisting of sweeteners, flavoring agents, seasonings, fillers, plasticizers, colorants, such as dyes or pigments, penetration enhancers, buffers, preservatives, silicon dioxide, anti-tack agents, and any combination thereof.

[0089] The flavoring agent can be selected from natural and synthetic flavoring liquids. An exemplary list of such agents includes volatile oils, synthetic flavor oils, flavor aromatic oils, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. A representative list, without limitation 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 flavoring agents. Useful perfumes or flavoring agents include natural and artificial perfumes. These fragrances can be selected from synthetic flavor oils and fragrant essential oils, and / or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, etc., and combinations thereof. Non-limiting flavor oils include spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, hinoki oil, nutmeg oil, sage oil, and bitter almond oil. Also useful are artificial, natural or synthetic fruit perfumes 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 fragrances can be used individually or in combination. Commonly used perfumes, whether used individually or in combination, include mints such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit perfumes. Fragrances such as aldehydes and esters including cinnamyl acetate, cinnamaldehyde, citral, diethyl acetal, dihydrocarbyl acetate, eugenyl formate, p-methyl anisole, etc. can also be used.Further examples of aldehyde fragrances include, but are not limited to, acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamic aldehyde (cinnamon); citral, i.e., α-citral (lemon, lime); neral, i.e., β-citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropin, i.e., piperonal (vanilla, cream); vanillin (vanilla, cream); α-amyl cinnamaldehyde (spice fruit flavoring); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronellal (modified, various); decanal (citrus fruit); aldehyde C-8 (citrus fruit); aldehyde C-9 (citrus fruit); aldehyde C-12 (citrus fruit); 2-ethyl butyraldehyde (berry fruit); hexanal, i.e., trans-2 (berry fruit); tolualdehyde (cherry, almond); veratraldehyde (vanilla); 12,6-dimethyl-5-heptenal, i.e., melonal (melon); 2,6-dimethyloctanal (unripe fruit); and 2-dodecenal (citrus, mandarin); cherry; grape; and mixtures thereof, etc. are included.

[0090] Other useful fragrances include aldehydes and esters such as benzaldehyde (cherry, almond), citral, i.e., α-citral (lemon, lime), neral, i.e., β-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruit), aldehyde C-9 (citrus fruit), aldehyde C-12 (citrus fruit), tolualdehyde (cherry, almond), 2,6-dimethyloctanol (unripe fruit), and 2-dodecenal (citrus, mandarin), and combinations thereof.

[0091] The amount of fragrance used is usually a matter of preference according to factors such as the type of flavoring agent, the individual flavoring agent, and the desired intensity. This amount can be varied to obtain the desired result in the final product. Such variations are within the ability of those skilled in the art without undue experimentation. Generally, an amount of about 0.1 to about 30% by mass is useful for the practice of the present invention. In certain embodiments, the film comprises a berry flavor. The berry flavor can be raspberry, strawberry, blueberry, boysenberry, blackberry, or combinations thereof. In another embodiment, the film comprises a raspberry flavor. The berry, raspberry, strawberry, blueberry, boysenberry, or blackberry flavor can be natural or artificial, can be purchased, and / or can be produced by any means known in the art. For example, a raspberry flavoring containing 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 content of which is incorporated herein by reference. When used, the berry flavor can be present in the composition from about 0.1 to about 15 wt%. In certain embodiments thereof, the berry flavor is present in the composition from about 0.5 to about 10 wt%, from about 1 to about 8 wt%, from about 2 to about 7 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, or about 7 wt%.

[0092] Suitable sweeteners include both natural and artificial sweeteners. Non-limiting examples of suitable sweeteners include, for example, water-soluble sweeteners such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (table 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, namely sodium or calcium saccharin salts, cyclamate, sodium, ammonium or calcium salts of 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, potassium salts of 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide (acesulfame-K), the free acid form of saccharin, etc.; 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-alanine amide hydrate, L-aspartyl-L-phenylglycerin and L-aspartyl-L-2,5-dihydroxyphenylglycine, L-aspartyl-2,5-dihydro-L-phenylalanine, methyl ester of L-aspartyl-L-(1-cyclohexene)-alanine, etc.; water-soluble sweeteners derived from natural water-soluble sweeteners such as chlorinated derivatives of ordinary sugar (sucrose) (e.g., known as sucralose); and protein-based sweeteners such as thaurnatoccous danielli (thaumatin I and II). Natural high-intensity sweeteners such as lakanka, stevia, stevioside, monellin, and glycyrrhizin can also be used.

[0093] Generally, an effective amount of a sweetening agent is used to provide a desired level of sweetness to a particular composition, and this amount varies depending on the sweetening agent selected. This amount is typically considered to be from 0.01 to about 10% by weight of the composition. These amounts can be used to achieve the desired level of sweetness independently of the level of flavoring achieved from any optional flavoring oils used. In certain embodiments, the sweetening agent 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. The sweetening agent can 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 certain embodiments, about 3 to about 4%, about 3%, or about 3.5% by weight of sucralose, saccharin, aspartame, and any combination thereof are present in the film.

[0094] Coloring additives useful in the present invention include food, drug, and cosmetic colorants (FD&C), drug and cosmetic colorants (D&C), or external drug and cosmetic colorants (Ext.D&C). These colorants are dyes, their corresponding lakes, and contain certain natural and derived colorants. A lake is a dye absorbed onto aluminum hydroxide. Other examples of coloring agents include known azo dyes, organic or inorganic pigments, or colorants of natural origin. Inorganic pigments such as oxides of iron or titanium, these oxides, are preferred and are added at a concentration in the range of about 0.001 to about 10%, preferably about 0.5 to about 3%, based on the weight of the total composition. The film can be any color including, but not limited to, white, transparent, blue, green, red, pink, purple, orange, or yellow. In certain embodiments, the film is transparent and translucent.

[0095] The film more preferably contains a buffering agent to control the pH. Any desired level of buffer tray may be incorporated into the polymeric substrate to provide the desired pH level encountered when the pharmaceutically active agent is 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 include a polyalkylene oxide (e.g., polyethylene glycol, polypropylene glycol, polyethylene - propylene glycol), a low molecular weight organic plasticizer (e.g., glycerol, mono - acetic, di - acetic or tri - acetic glycerol, triacetin, polysorbate, cetyl alcohol, propylene glycol, sugar alcohol sorbitol, sodium diethyl sulfosuccinate, triethyl citrate, tributyl citrate, plant extracts, fatty acid esters, fatty acids, oils, etc.). The plasticizer may be added at a concentration of about 0.1% to about 40%, or about 0.5% to about 20% based on the mass of the film composition, e.g., 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%, 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%. Further, to improve the texture properties of the film material, an animal or vegetable fat, preferably in its hydrogenated form, especially one that is solid at room temperature, may be added to the compound. These fats preferably have a melting point of 50°C or higher. C 12 -, C 14 -, C 16 -, C 18 -, C 20 - and C 22Triglycerides having - fatty acids are preferred. These fats can be added alone without adding extenders or plasticizers and advantageously can be added alone or together with monoglycerides and / or diglycerides or phosphatides, especially lecithin. The monoglycerides and diglycerides are preferably of the type of fats described above, i.e., C 12 -, C 14 -, C 16 -, C 18 -, C 20 - and C 22 - fatty acids. The total amount of fat, monoglyceride, diglyceride and / or lecithin used is up to about 5% or in the range of about 0.5% to about 2% relative to the mass of the film composition.

[0097] A variety of other components and fillers can also be added to the films disclosed herein. These include, but are not limited to, surfactants; other defoaming agents; simethicone which provides a smoother film surface by releasing oxygen from the film; thermosetting gels such as pectin, carrageenan, and gelatin which assist in maintaining the dispersion of the components; and inclusion compounds such as cyclodextrins and caged molecules which improve the solubility and / or stability of certain active agent components.

[0098] Further additives can desirably be inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium, etc. in a concentration range of about 0.02% to about 3% by weight, desirably about 0.02% to about 1% relative to the mass 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 conditioning agents. These additives should be used in an amount sufficient to achieve their intended purpose. In general, specific combinations of these additives can alter the overall release profile of the active ingredient and can be used to modify the release, i.e., inhibit or promote it.

[0099] An anti-adhesive agent may be incorporated into the oral film of the present disclosure. The anti-adhesive agent may be selected from the group consisting of lubricants, antiadherants, slip agents, and combinations thereof. The anti-adhesive agent aids in the flow properties of the material, for example, by reducing adhesion to the die during the extrusion process and reducing adhesion to the palate during administration of the dosage form. During consumption of the film, particles tend to adhere to the palate. This is undesirable for films containing bitter drugs, such as dextromethorphan, as the adhered particles elude the drug and increase the amount of bitterness perceived by the user. Addition of an anti-adhesive agent to the film reduces adhesion to the palate and thereby effectively reduces the bitterness that may be perceived by the user during consumption.

[0100] The anti-adhesive agent may also impart a low coefficient of friction between films, thereby reducing the problem of film dosage units, i.e., strips, adhering to each other. More specifically, in many types of film packaging, the strips are laminated to each other. Incorporation of an anti-adhesive agent allows the individual strips to slide smoothly past each other when each unit is removed from the package. Examples of lubricants suitable for use as anti-adhesive agents 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 of molecular weight 4000 (commercially available as Carbowax 4000); polyethylene glycol of 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; corn starch; synthetic amorphous silicon dioxide cristalline 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; corn starch; synthetic amorphous silicon dioxide cristalline free (commercially available as Cab-O-Sil); Syloid; aerosol; and combinations thereof.

[0101] Vitamin E is another suitable anti-sticking agent for use in some embodiments of the present invention. Vitamin E can act as both an anti-sticking agent and an active ingredient in the film. Desirably, vitamin E TPGS (d-α 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. Further, vitamin E TPGS does not substantially impart taste to the film. Vitamin E TPGS can be used in a solution such as, for example, a 10% or 20% aqueous solution. Vitamin E TPGS is particularly useful for reducing film thickness and the tendency to adhere 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-sticking agent can be included in an amount of about 0.01 to about 20% by weight of the film composition. More specifically, the anti-sticking agent can be present in an amount of about 0.01 to about 10% by weight of the film composition, and even more specifically in an amount of about 0.25 to about 5% by weight of the film composition.

[0102] Combinations of anti - sticking agents can also be used. For example, combinations of stearates 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 provides improved lubricating properties, i.e., it can assist the film strips to slide smoothly past each other during packaging. Thus, magnesium stearate may be present in the film composition at about 0.1 to about 2.5% by weight, and silica may be present in the film composition at about 0.1 to about 1.5% by weight. Such combinations of anti - sticking agents can be useful in various films containing various flavoring agents and / or active agents. The anti - sticking agent may be included in the film composition itself. For example, a single - layer or multi - layer film containing an anti - sticking agent can be formed. The multi - layer film can include, for example, films of 2, 3 or more layers substantially in contact with each other. These film layers may be laminated to each other. The anti - sticking agent may be present in one or more of the layers of the multi - layer film. For example, some embodiments may include a two - layer film in which the anti - sticking agent is present in one of the two film layers. Some embodiments may include a three - layer film in which the anti - sticking agent is present in each outer layer but not in the inner or intermediate layer. Accordingly, various different combinations of layers can be formed.

[0103] Alternatively, an anti - sticking agent used to coat the outer surface of the film may be included in the composition. For example, the anti - sticking agent can be applied to the film in the form of a wet or dry coating, such as a sugar coating or a sugar - free coating. The film can be coated with the anti - sticking agent in any conventional manner, such as, but not limited to, dip coating, spray coating, dusting, or fluidized bed. One or more film surfaces can be coated. In some embodiments, the anti - sticking coating may be applied to a substrate such as a backing of the film rather than directly to the film itself. When the film is removed from the backing, the anti - sticking coating can adhere to the film. Some embodiments may include fat and / or wax as an anti-sticking agent. Any other optional components described in U.S. Patent Nos. 7,425,292 and 8,765,167 by the same applicant as shown above may also be included in the films described herein.

[0104] Penetration enhancer The films disclosed herein may contain a penetration enhancer. The active agent may be combined with the penetration enhancer in a single layer of the film, contained in separate layers, or otherwise contained in discrete regions of the same dosage form. In certain embodiments, the active agent contained in the polymeric substrate can be dispersed within the matrix. In certain embodiments, the penetration enhancer contained in the polymeric substrate can be dispersed within the matrix. Any penetration enhancer known for use in the art can be incorporated into the films of the present disclosure. The term "penetration enhancer" is interchangeable with absorption enhancer and permeation enhancer. When delivered into the oral cavity through the film, the penetration enhancer is a component that can improve the permeability of the pharmaceutically active agent from the subject's mucosa into the bloodstream.

[0105] The penetration enhancer can be a nonionic alkyl glucoside having a hydrophobic alkyl group linked by crosslinking to a hydrophilic saccharide. The penetration enhancer can be selected from the group consisting of maltosides or maltoside derivatives, sucrose esters or sucrose ester derivatives, and essential oils or essential oil components. The penetration enhancer can be selected from the group consisting of alkylthiomaltoside, maltoside, maltotrioside, maltopyranoside, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, tetradecyl-β-D-maltoside, dodecyl-β-D-maltoside, tridecyl-β-D-maltoside, sucrose ester, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, and combinations thereof. The penetration enhancer can improve the absorption rate and absorption amount of the pharmaceutically 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% by other components in the composition, or in combinations of these ranges.

[0106] In certain embodiments, the film comprises a pharmaceutically acceptable non-toxic nonionic alkyl glucoside having a hydrophobic alkyl group linked by crosslinking to a hydrophilic saccharide, in combination with (a) an aggregation inhibitor; (b) a charge modifier; (c) a pH controller; (d) a degrading enzyme inhibitor; (e) a mucolytic or mucus removing agent; (f) a ciliostatic 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) a NO-donating compound; (vi) a long-chain amphiphilic 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 β-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or its salt; (xiv) an N-acetyl amino acid or its salt; (xv) a degrading enzyme for a selected membrane component; (ix) a fatty acid synthesis inhibitor; (x) a cholesterol synthesis inhibitor; and (xi) any combination of the membrane permeation enhancers listed in (i)-(x); (h) an epithelial binding physiology regulator; (i) a vasodilatory agent; (j) a selective transport enhancer; and (k) a mucosal delivery enhancer selected from a stabilizing delivery vehicle, carrier, mucoadhesive, support, or complex-forming species in which the compound is effectively formulated, associated, contained, encapsulated, or bound and which provides for the stabilization of the compound for enhanced trans mucosal delivery. The formulation of the compound with these trans mucosal delivery enhancers provides for an increase in the bioavailability of the compound in the plasma of the subject. The permeation enhancers are described in J. Nicolazzo, et al., J. of Controlled Disease, 105 (2005) 1-15, which is incorporated herein by reference in its entirety.

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

[0108] In vitro studies on the enhancement of the 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 paper also describes recent studies on the effect of dihydroxy bile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC), and trihydroxy bile salts, sodium glycochenodeoxycholate (GC) and sodium taurocholate (TC), at a concentration of about 100 mM on the oral epithelial permeability, including permeability changes correlated with histological effects. Fluorescein isothiocyanate (FITC) and morphine sulfate were used as model compounds, respectively. 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 its enhancing effect on the permeation of compounds across the intestinal mucosa and cultured Caco-2 cells.

[0109] The penetration enhancer may be a plant extract. The plant extract can be an essential oil or a composition containing essential oil extracted by distillation of plant material. In certain situations, the plant extract can contain synthetic analogs of compounds extracted from plant material (i.e., compounds produced by organic synthesis). The plant extract can contain phenylpropanoids, such as phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid esters, cinnamic aldehydes, hydrocinnamic acids, cabicol, or safrole, or combinations thereof. The plant extract can be an essential oil extract from clove plants, for example, from the leaves, stems or flower buds of clove plants. The clove plant can be Syzygium aromaticum. The plant extract can contain about 20% to about 95% eugenol, for example, about 40% to about 95% eugenol, for example, about 60% to about 95% eugenol, for example, about 80% - 95% eugenol. This extract can also contain about 5% to about 15% eugenol acetate. This extract can also contain caryophyllene. This extract can also contain up to about 2.1% α-humulene. Other volatile compounds contained in clove essential oil at low concentrations can be β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone or ethyl hexanoate. Other penetration enhancers can be added to the composition to improve drug absorption. Suitable penetration enhancers include natural or synthetic bile salts, such as sodium fusidate; glycocholic acid 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, atone, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynol-9, laureth-9, polysorbate, sterols, or glycerides, such as caprylocaprylyl polyoxyl glyceride, such as labrasol. The penetration enhancer can contain plant extract derivatives and / or monolignols. The penetration enhancer can also be a fungal extract.

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

[0111] Fatty acids can be used as inactive ingredients in pharmaceutical 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 fuels (storing and transporting energy), which are essential components of all membranes and gene regulators, either free of complex lipids or as part of complex lipids. For a review, see Rustan A. C. and Drevon, C. A., Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences (2005), which is incorporated herein by reference. There are two families of polyunsaturated fatty acids (PUFAs), omega-3 and omega-6, which are metabolized in the human body. They are called omega-3 fatty acids if the first double bond is found between the third and fourth carbon atoms from the omega carbon. They are called omega-6 fatty acids if the first double bond is between the sixth and seventh carbon atoms. PUFAs are further metabolized in the body by addition and unsaturation (extraction of hydrogen) of carbon atoms. Linoleic acid, an omega-6 fatty acid, is metabolized to gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, and docosapentaenoic acid. Alpha-linolenic acid, an omega-3 fatty acid, is metabolized to octadecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and docosahexaenoic acid (DHA).

[0112] Fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid are Na + K +-It has been reported that fatty acids with increased cis unsaturation induced relaxation and hyperpolarization of porcine coronary smooth muscle cells via a mechanism involving activation of APTase pumps, and had a higher ability. See Pomposiello, S. I. et al., Hypertension 31:615-20 (1998), which is incorporated herein by reference. Interestingly, the response of the pulmonary vasculature to arachidonic acid, a metabolite of linoleic acid, can be either vasoconstrictive or vasodilatory depending on the dose, animal species, mode of arachidonic acid administration, and the state of the pulmonary circulation. For example, arachidonic acid has been reported to cause cyclooxygenase-dependent and -independent pulmonary vasodilation. See Peddersen, C. O. et al., J. Appl. Physiol. 68(5):1799-808 (1990), which is incorporated herein by reference, or Sparwhake, E. W., et al., J. Appl. Physiol. 44:397-495 (1978) and Wicks, T. C. et al., Circ. Res, 38:167-71 (1976), each of which is incorporated herein by reference.

[0113] Numerous studies have reported the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on vascular reactivity after administration in ingestible forms. In some studies, EPA-DHA or EPA alone has been found to suppress the vasoconstrictive effect of norepinephrine or enhance the vasodilatory response to acetylcholine in the forearm microcirculation. See Chin, J. P. F., et al., Hypertension 21:22-8 (1993) and Tagawa, H, et al., J Cardiovasc Pharmacol 33:633-40 (1999), each incorporated herein by reference. In another study, both EPA and DHA have been found to tend to increase systemic arterial compliance and decrease pulse pressure and total vascular resistance. See Nestel, P. et al., Am J. Clin. Nutr. 76:326-30 (2002), incorporated herein by reference. On the other hand, in one study, in the forearm microcirculation of overweight individuals with hyperlipidemia, DHA was found to promote the vasodilatory mechanism and attenuate the contractile response, while EPA did not. See Mori, T. A., et al., Circulation 102:1264-69 (2000), incorporated herein by reference. In another study, the vasodilatory effect of DHA on the rhythmic contraction of isolated human coronary arteries in vitro has been found. 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 are targets of catecholamines, particularly norepinephrine (noradrenaline) and epinephrine (adrenaline). Epinephrine (adrenaline) interacts with both α-adrenoceptors and β-adrenoceptors, causing vasoconstriction and vasodilation, respectively. α-Receptors have a low sensitivity to epinephrine, but when activated, there are more peripheral α1-receptors than β-adrenoceptors, so vasoconstriction mediated by α-receptors takes precedence over vasodilation mediated by β-adrenoceptors. As a result, high levels of circulating epinephrine cause vasoconstriction. At low levels of circulating epinephrine, β-adrenoceptor stimulation predominates, resulting in vasodilation and subsequent decrease in peripheral vascular resistance. α1-Adrenoceptors are known for smooth muscle contraction in the skin, mucosa, and abdominal organs, mydriasis, vasoconstriction, and sphincter contraction in the gastrointestinal (GI) tract and bladder. The α1-adrenergic receptor is a member of the G q protein-coupled receptor superfamily. When activated, the heterotrimeric G protein G q activates phospholipase C (PLC). This mechanism of action involves interaction with calcium channels and changes in intracellular calcium content. For a review, see Smith R. S. et al., Journal of Neurophysiology, 102(2): 1103-14 (2009), which is incorporated herein by reference in its entirety. Many cells have these receptors.

[0115] The α1 - adrenergic receptor may be a major receptor for fatty acids. For example, saw palmetto is an extract (SPE) widely used in the treatment of benign prostatic hyperplasia (BPH), and it has been reported to bind to α1 - adrenergic, muscarinic and 1,4 - dihydropyridine (1,4 - DHP) calcium channel antagonist receptors. See Abe M., et al., Biol. Pharm. Bull. 32(4) 646 - 650 (2009), and Suzuki M. et al., Acta Pharmacologica Sinica 30:271 - 81 (2009), each of which is incorporated herein by reference in its entirety. SPE contains various fatty acids such as lauric acid, oleic acid, myristic acid, palmitic acid and linoleic acid. Lauric acid and oleic acid can bind non - competitively to α1 - adrenergic, muscarinic and 1,4 - DHP calcium channel antagonist receptors.

[0116] In certain embodiments, the penetration enhancer can be an adrenergic receptor interacting factor. An adrenergic receptor interacting factor refers to a compound or substance that modifies and / or otherwise alters the action of an adrenergic receptor. For example, an adrenergic receptor interacting factor can interfere with receptor stimulation by enhancing or reducing their binding ability. Such interacting factors can be provided either as short-acting or long-acting types. Certain short-acting interacting factors can act rapidly, but their effects only last for a few hours. Certain long-acting interacting factors take time to act, but their effects can last longer. The interacting factors can be selected and / or designed, for example, based on one or more of the desired delivery and dosage, active pharmaceutical ingredient, penetration modifier, penetration enhancer, matrix, and the condition being treated. The adrenergic receptor interacting factor can be an adrenergic receptor blocker. The adrenergic receptor interacting factor can be a terpene (e.g., a volatile unsaturated hydrocarbon found in essential oils of plants derived from isoprene units) or a C3-C22 alcohol or acid, preferably a C7-C18 alcohol or acid. In certain embodiments, the adrenergic receptor interacting factor can include farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, and / or docosapentaenoic acid. This acid can be a carboxylic acid, phosphoric acid, sulfuric acid, hydroxamic acid, or derivatives thereof. The derivative can be an ester or an amide. For example, the adrenergic receptor interacting factor can be a fatty acid or a fatty alcohol. The C3-C22 alcohol or acid can be an alcohol or acid having a straight-chain 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 is optionally 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- to 5-membered heterocycloalkyl, monocyclic aryl, 5- to 6-membered heteroaryl, C 1-4 Alkylcarbonyloxy, C 1-4 Alkylsiloxycarbonyl, C 1-4 May be substituted with alkylcarbonyl, or formyl; further, optionally --O--, --N(R 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. R a And R b Are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.

[0117] Fatty acids with higher degrees of unsaturation are effective candidates for promoting drug penetration. Unsaturated fatty acids showed higher promotion than saturated fatty acids, and the promotion 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, which is incorporated herein by reference. Also, the position of the double bond also affects the promotion activity of the fatty acid. Differences in the physicochemical properties of fatty acids resulting from differences in the position of the double bond probably determine the effectiveness of these compounds as skin penetration enhancers. Skin distribution increases as the position of the double bond moves towards the hydrophilic end. Fatty acids having double bonds at even positions have also been reported to more rapidly perturb the structures of both the stratum corneum and the dermis than fatty acids having double bonds at odd positions. Cis unsaturation within the chain may tend to enhance activity.

[0118] The adrenergic receptor interacting factor can be a terpene. The antihypertensive activity of terpenes in essential oils has been reported. See Menezes I. A. et al., Z. Naturforsch. 65c:652-66 (2010), which is incorporated herein by reference. In certain embodiments, the penetration enhancer can be a sesquiterpene. Sesquiterpenes consist of three isoprene units and are a type of terpene with the empirical formula C 15 H 24 . Similar to monoterpenes, sesquiterpenes can be acyclic or can contain rings with many unique combinations. Biochemical modifications such as oxidation or rearrangement give rise to related sesquiterpenoids. The adrenergic receptor interacting factor can be an unsaturated fatty acid such as linoleic acid. In certain embodiments, the penetration enhancer can be farnesol. Farnesol is a 15-carbon organic compound that is an acyclic sesquiterpene alcohol and is the natural dephosphorylated form of farnesyl pyrophosphate. Under standard conditions, farnesol is a colorless liquid. Farnesol is hydrophobic and thus insoluble in water but miscible with oils. Farnesol can be extracted from the fats of plants such as citronella, neroli, cyclamen, and gecko oil. 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 fragrances and flavorings. Farnesol has been reported to selectively kill acute myeloid leukemia blast cells and leukemia cell lines rather than primary hematopoietic cells. See Rioja A. et al., FEBS Lett 467 (2-3): 291-5 (2000), which is incorporated herein by reference. The vascular action properties of farnesyl analogs have been reported. See Roullet, J.-B., et al., J. Clin. Invest., 1996, 97:2384-2390, which is incorporated herein by reference. Both farnesol and N-acetyl-S-trans,trans-famesyl-L-cysteine (AFC), a synthetic mimic of the carboxyl terminus of farnesylated proteins, inhibit blood contraction in rat aortic rings.

[0119] In certain embodiments, the film comprises a penetration enhancer comprising one or more of phenylpropanoids, farnesol, labrasol, and linoleic acid. In certain embodiments, the penetration enhancer is a phenylpropanoid selected from the group consisting of eugenol; eugenol acetate; cinnamic acid; cinnamic acid esters; cinnamic aldehydes; hydrocinnamic acid; carvacrol; safrole; or combinations thereof. In certain embodiments, the film comprises a penetration enhancer that is a plant extract. The plant extract can be an essential oil extract of cloves, an essential oil extract of clove leaves, an essential oil extract of clove flower buds, an essential oil extract of clove stems, or combinations thereof. In certain embodiments, the plant extract can be a synthetic product. The plant extract can contain 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] Homogeneity and manufacturing For the purposes of the present invention, the term non-self-aggregating uniform heterogeneity refers to the ability of the films of the present invention, formed from one or more components in addition to a polar solvent, to substantially reduce (i.e., have little or no) the occurrence of strong or weak aggregation of the components within the film as typically experienced when the film is formed by conventional drying methods such as hot air baths using a drying oven, drying tunnel, vacuum dryer, or other such drying apparatus. The term heterogeneity, as used in the present invention, includes films formulated with a single component such as a polymer, as well as combinations of components such as a polymer and an active agent. Uniform heterogeneity includes the substantial absence of strong or weak aggregation that is common to conventional mixing and thermal drying used to form films. Furthermore, 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 a uniform thickness can adversely affect the uniformity of the component distribution over a given area or extent of the film.

[0121] The films disclosed herein are produced by a combination of a polymer and a polar solvent, optionally including an active ingredient and other fillers known in the art, selected as appropriate. These films provide a non-self-aggregating uniformity of components within the film by using a selected casting or vapor deposition method and a controlled drying process. 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 all of which are incorporated herein by reference in their entirety. Another drying technique for obtaining the films is controlled radiant drying in the absence of uncontrolled air currents such as infrared and radio frequency irradiation (i.e., microwaves).

[0122] The purpose of this drying process is to provide a film drying method that avoids the complex problems associated with conventional drying methods, such as the described "rippling" and the effects of mass transfer, by first drying the upper surface of the film to trap moisture inside. In conventional oven drying methods, when the moisture trapped inside subsequently evaporates, the upper surface changes due to cracking and reformation. Such surface disruption due to continuous surface skinning and subsequent reopening of the skinned surface for evaporation results in film non-uniformity and uneven thickness. In addition, excessive air flow, e.g., hot air flow, can cause mass transfer, i.e., waves, in the fluidized substrate before the substrate gains sufficient integrity during the drying process. Such a rippling effect, whether caused by surface skinning / cracking / reformation or by mass transfer, causes particles to be subjected to these uncontrolled mechanical and thermal forces and as a result move within the film, leading to non-uniformity in the active agent content in the film. Such movement occurs during the mixing process and impairs the substantial uniformity of the active agent across the film that is required to obtain dosage units of substantially the same size cut from the cast film (each having an amount of active agent per dosage unit with a variation of no more than 10% from the desired amount (stated amount) of the active agent).

[0123] These complex problems are avoided by the present invention, which provides a uniform film by preventing skinning / cracking / reformation or mass transfer of the film substrate before sufficient solidification of the fluidized film substrate occurs so that the active agent particles do not move and do not weakly or strongly aggregate. The present disclosure provides several ways to control the drying process, thereby preventing the detrimental effects present in conventional drying methods and maintaining the substantial uniformity of the active agent in the substrate achieved during mixing. Drying is also preferably carried out rapidly so as to "lock in" the active agent by rapidly increasing the viscosity to achieve a sufficient solid substrate to prevent substantial movement. Next, the cast and dried film can be cut into individual dosage units of substantially equal size (length, width, and thickness), and these dosage units have an active agent content with no more than 10% variation from the desired amount (stated amount) of the active agent.

[0124] As a method of controlling the undesirable effects of conventional drying, it includes controlling the oven air flow to prevent lip ringing, prevent mass transfer, and prevent early skinning of the surface before the substrate dries under the skin. The air flow preferably is directed at the film from above, at a distance, at an angle, and at a speed such that the force generated when the air flow hits the film does not exceed the yield value of the film substrate, i.e., the film-forming composition forming the substrate can move or, otherwise, the level of force that can cause such lip ringing and non-uniformity is below. Controlled drying may also include first directing heat to the bottom surface of the film so that drying starts from above the depth of the film. This can be achieved by applying heat to the bottom surface of the film substantially without using the upper air flow or by applying heat simultaneously to the bottom and the top without causing lip ringing of early skinning. Alternatively, drying can be achieved by introducing controlled microwaves to evaporate water or other polar solvents in the film. When applying microwaves, care must be taken that the temperature of the substrate does not reach a high temperature such that boiling of the substrate (where non-uniformity of the active agent in it occurs) occurs.

[0125] Yet another method for drying control involves drying with a balanced fluid flow, such as a balanced air flow, where the bottom and top air flows are controlled to provide a uniform film and avoid lip ringing and early skinning as described herein. In such cases, the air flow directed towards 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. Additionally, the air flow directed towards the bottom of the film should preferably be controlled so that the film is not lifted due to the forces from that air. Whether at the top or bottom of the film, an uncontrolled air flow can potentially create non-uniformities in the final film product. Also, the humidity in the area surrounding the upper surface can be appropriately adjusted to prevent premature blocking 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, and the components may be uniformly distributed in any given area of the film. Additionally, the faster drying time allows for a rapid increase in viscosity within the film, further promoting a uniform distribution of components, and reducing strong aggregation of the components in the final film product. Desirably, the drying of the film occurs within about 10 minutes, or more desirably within about 5 minutes. In the present invention, it is noted that by reducing the strong aggregation of the composition components, a significantly more uniform film product is obtained. Further, preventing the entry of excess air and removing excess air in the mixing process is desirable in promoting the uniformity of the film and the dosage forms cut therefrom; additionally, selecting the polymer and solvent to provide a controllable viscosity while avoiding lip ringing or mass transfer in the film, and drying the film in a rapid manner as described above are desirable in maintaining and providing dosage forms cut from a film having the desired uniformity of active agent content when reduced to the film and the indicated amount. Thus, the 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 are due to interactions between various stages of film manufacture to provide a film that substantially reduces self-aggregation of components within the film. Specifically, these stages include creating a composition mixture to prevent entrapment of air bubbles, controlling the viscosity of the film-forming composition, a particular method used to form the film, and a method of drying the film. More specifically, a higher viscosity of the components in the mixture is particularly useful for preventing 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 prevent 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 component or substrate, there are other considerations for achieving the desired film uniformity. For example, a stable suspension is achieved that prevents solid (such as drug particle) deposition in non-colloid applications. One approach provided by the present invention is to balance the particle density (ρ p ) and the liquid phase density (ρ1) and increase the liquid phase viscosity (μ). For isolated particles, Stokes' law relates to the limiting settling velocity (Vo) of a rigid 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 affects the local viscosity and density. The viscosity of the suspension is a strong function of the solid volume fraction, and particle-particle and particle-liquid interactions further impede the settling velocity.

[0127] Stokes analysis has shown that the incorporation of a dispersed air or nitrogen, a third phase, for example increases the stability of the suspension. Further, an increase in the number of particles results in an impediment to the sedimentation effect based on the solid volume fraction. In a dilute particle suspension, the sedimentation rate v can be expressed as follows. v / V o =1 / (1+κφ) Here, κ = constant, and φ is the volume fraction of the dispersed phase. When there are many particles suspended in the liquid phase, the velocity decreases. The particle diameter affects the particle-particle flow interaction, so the particle geometry is also an important factor. Similarly, the viscosity of the suspension also depends on the volume fraction of the dispersed solid. In a dilute suspension of non-interacting spherical particles, the expression for the suspension viscosity can be represented as follows. 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 follows. μ / μ o =1 + 2.5φ + C1φ 2 + C2φ 3 + Here, C is a constant.

[0128] The viscosity of the liquid phase is important and is preferably adjusted by customizing the liquid composition into a viscoelastic non-Newtonian fluid with a low yield stress value. This corresponds to producing a high-viscosity continuous phase in a stationary state. The formation of a viscoelastic or highly structured fluid phase provides additional resistance to particle sedimentation. Furthermore, soft particle aggregates or strong agglomerates can be controlled to minimize particle-particle interactions. This net effect would be the preservation of a homogeneous dispersed phase. The addition of a hydrocolloid to the aqueous phase of the suspension can increase the viscosity, impart viscoelasticity, and provide stability, depending on the type of hydrocolloid, its concentration, and the particle composition, geometry, size, and volume fraction. The average particle size distribution of the dispersed phase needs to be controlled by selecting the minimum practical average particle size in a high-viscosity medium, i.e., <500 μm. The presence of a slight yield stress or an elastic body at low shear rates can also result in permanent stability regardless of the apparent viscosity. The critical separation particle size can be calculated from the yield stress value. In the case of isolated spherical particles, the maximum shear stress that occurs during sedimentation in a medium of a given viscosity can be shown as follows. τ max = 3Vμ / 2r In the case of a pseudoplastic fluid, the viscosity in this shear stress regime can be the zero shear rate viscosity sufficiently at Newton Plateau.

[0129] A stable suspension is an important feature for maintaining this stability at the wet film stage for the production of the premix composition supplied to the film casting machine film and until sufficient drying is done to lock in the particles and the substrate sufficiently solidly so that uniformity is maintained. In a viscoelastic flow system, the rheology resulting in a stable suspension, for a long time such as 24 hours, must meet the requirements of the high-speed film casting operation. Desirable film properties are shear thinning or pseudoplasticity, whereby the viscosity decreases as the shear rate increases. Time-dependent shear effects such as thixotropy are also advantageous. Structure recovery and shear thinning behavior are important properties as well as the self-leveling property of the film when it is formed. The rheology requirements for the compositions and films of the present invention are extremely stringent. This is due to the need to produce a stable suspension of particles and has a viscosity value acceptable in a wide shear rate range in a viscoelastic fluid substrate, for example, 30 to 60% by mass. During mixing, pumping, and film casting, it may be subject to a shear rate of 10 to 10 5 seconds -1 and pseudoplasticity is a preferred embodiment. In film casting or coating, rheology is also a determining factor regarding the ability to form a film having the desired uniformity. Shear viscosity, extensional viscosity, viscoelasticity, and structure recovery affect the quality of the film. 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, 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, increasing as n increases and decreasing as K increases.

[0130] Desirably, the film or film-forming composition of the present disclosure exhibits extremely rapid structure recovery, i.e., when the film is formed during processing, it does not fall apart or its structural and compositional uniformity does not become intermittent. Such extremely rapid structure recovery delays particle sedimentation and resulting deposition. Further, the film or film-forming composition is desirably a shear-thinning viscoplastic fluid. Such fluids, considering properties such as viscosity and elasticity, promote thin film formation and uniformity. Thus, the uniformity 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, control of the average particle size and particle shape is a further consideration. Desirably, the average particle size can be 200 microns or less, 150 microns or less, or 100 microns or less. Further, such particles can be spherical, substantially spherical, or non-spherical, e.g., irregularly shaped particles or ellipsoidal particles. Ellipsoidal particles or ellipsoids are desirable for their ability to maintain uniformity in the film-forming substrate as they tend to have a lower degree of sedimentation compared to spherical particles.

[0131] In the mixing stage, several techniques can be used to prevent the inclusion of air bubbles into 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. Additionally, the velocity of the mixture is preferably controlled to prevent cavitation of the mixture in a manner that vents air entering the mixture. Finally, bubble reduction can be further achieved by allowing the mixture to stand for a time sufficient to allow the bubbles to escape before drying the film. Preferably, the process of the present invention first forms a masterbatch of film-forming components that do not contain active ingredients such as drug particles or volatile materials such as aromatic oils. The active agent is added to a smaller amount of the masterbatch mixture immediately prior to casting. Thus, the masterbatch premix can be allowed to stand for longer periods without concern for the instability of drugs or other components. When a substrate comprising a film-forming polymer and a polar solvent is formed in addition to any additives and active ingredients, this can be done in multiple steps. For example, all of the components may be added together or a premix may be preferred. The advantage of a premix is that all components other than the active agent are premixed and the active agent is added immediately prior to film formation. This is particularly important for active agents that may decompose when exposed to water, air or another polar solvent for extended periods of time. An apparatus for making the films of the present invention is disclosed, for example, in U.S. Patent No. 8,765,167, the entire contents of which are incorporated herein by reference.

[0132] Furthermore, the films disclosed herein may contain temperature-sensitive particles such as flavoring agents that may be volatile or drugs that may have a low decomposition temperature. In such cases, the drying temperature may be lowered while extending the drying time to sufficiently dry the uniform films of the present invention. Additionally, bottom drying also tends to result in a lower internal film temperature compared to top drying. In bottom drying, the vapor being vaporized escapes heat from the film more readily than in top drying, thereby lowering the internal film temperature. Such a lower internal film temperature often results in a reduction in drug degradation and a reduction in the loss of certain volatile substances such as flavoring agents. Furthermore, the particles or particulate matter may be added to the film-forming composition or substrate after casting the composition or substrate into a film. For example, the particles may be added to the film before drying of the film. The particles may be controllably metered onto the film and applied to the film surface by suitable techniques such as by a doctor blade (not shown) that lightly touches 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 dispose the particles on the film surface, spraying of the particles onto the film surface, etc. The particles may be disposed on one or both of the opposing film surfaces, i.e., the top and / or bottom surfaces of the film. Desirably, the particles are applied to be fixable to the film, such as by embedding in the film. Further, such particles desirably do not become completely encapsulated or completely embedded in the film and remain exposed on the film surface, such as when the particles are partially embedded or partially encapsulated. The particles may be any useful functional agent, cosmetic agent, pharmaceutical agent, or combination thereof. Desirably, the pharmaceutical agent is a flavoring agent or a sustained-release pharmaceutical agent. Useful functional agents include flavoring agents and sweetening agents. Useful cosmetic agents include bad breath freshening agents or blood stasis removing agents such as menthol containing menthol crystals.

[0133] Monitoring and control of the film thickness also contribute to the production of a uniform film by providing a film of uniform thickness. The film thickness can be monitored with an instrument such as a beta-ray thickness gauge. The instrument is connected to another instrument at the end of a drying device, i.e., a drying oven or tunnel, and communicates via a feedback loop to control and adjust the opening in the coating device to obtain control of a uniform film thickness. Film products are generally formed by combining a polymer and a polar solvent, each appropriately selected, and optionally any active ingredient or filler, as desired. 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 desirably formed into a film by roll coating and then dried by a rapid and controlled drying process, desirably to maintain the film's uniformity, more specifically, a uniform heterogeneity that does not self-aggregate. The resulting film desirably contains less than about 10% by weight of solvent, more desirably less than about 8% by weight of solvent, even more desirably less than about 6% by weight of solvent, and most desirably less than about 2%. The solvent can be water, a polar organic solvent such as, but not limited to, ethanol, isopropanol, acetone, methylene chloride, or any combination thereof.

[0134] Also, considerations of the above parameters such as, but not limited to, rheological properties, viscosity, mixing method, casting method, and drying method also affect the material selection of the various components of the present invention. Further, such considerations, together with appropriate material selection, provide a composition of the present invention comprising a pharmaceutical and / or cosmetic dosage form or film product in which the distribution of the active agent in the cast wet film is substantially uniform such that dosage units of equal size can be cut from the continuously cast and dried film and this substantially uniform distribution is maintained during the drying process, and these dosage units have a substantially uniform amount of the active agent present, i.e., the amount of the active agent present varies by no more than 10% of the desired amount of the active agent per dosage unit. Desirably, the uniformity of the continuously cast self-supporting film is measured by individual unit dosages of substantially equal size cut from the self-supporting continuous cast film, which vary by no more than 10% of the desired amount of the at least one active agent. For the sake of clarity, assume that the desired amount of the film unit dosage is, for example, 10 mg of a given drug. The film of the present invention requires a uniformity such that the substantially equal unit dosages of the film cut from the continuously cast and dried film vary by no more than 10% of the desired amount, i.e., the variation in unit dosage is 1 mg or less, + / - 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 prior to drying. The term "continuously cast" refers to a relatively high-speed manufacturing process in which a wet film substrate is cast and formed thereon, then followed by a drying device such as an oven, and then further continuously conveyed to a roll-up mandrel for storage or directly to a cutting and packaging station using a conveyor substrate. The term continuous is intended to distinguish processes such as those carried out in a laboratory where a wet film substrate is cast onto a tray. After combining the desired components to form a multi-component substantially homogeneous substrate comprising a polymer, water, and optionally an activator or other components, this combination is formed into a wet sheet or film by any of the methods known in the art such as extrusion, coating, spraying, casting, or drawing of the multi-component substrate. If a multilayer film is desired, this may be achieved by coextrusion of two or more combinations of the same or different components. A multilayer film may also be achieved by continuously coating, continuously spraying, or continuously casting a wet film substrate onto an already formed, preferably already dried, film layer. Although a variety of different continuous film-forming techniques are available, it is desirable to select a method that provides a soft film such as reverse roll coating. The flexibility of the film allows for winding and transportation of the film sheet for storage or prior to cutting into individual dosage forms. Desirably, the films are also self-supporting, or in other words, able to maintain their integrity and structure in the absence of an independent support. Further, the films of the present invention may be selected from edible or ingestible materials.

[0136] The continuous coating method or the continuous casting method is particularly useful for the purpose of forming the film of the present invention. Particularly when a multilayer film is desired, specific examples include reverse roll coating, gravure coating, dip or immersion coating, metering rod or Mayer 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 when forming a film according to the present invention. This technique provides excellent control and uniformity of the resulting film, which is desirable in the present invention. In this technique, the coating material is measured on the applicator roller by precisely setting the gap between the upper metering roller and the lower application roller thereunder. The coating moves from the application roller to the substrate as it passes over a support roller adjacent to the application roller. Both the three-roll method and the four-roll method are common.

[0137] The gravure coating method is by an engraved roller filled with the coating material in the engraved dots or lines of the roller advancing in the coating bath. Excess coating on the roller is wiped off by a doctor blade, and then the coating is adhered to the substrate as it passes between the engraved roller and the pressure roller. Offset gravure is common, and the coating adheres to an intermediate roller before moving to the substrate. In a simple method of dip or immersion coating, the substrate is immersed in the coating bath, which is usually of low viscosity so that the coating can return into the layer when the substrate emerges.

[0138] In the meter ring rod coating method, an excessive amount of coating adheres to the substrate when passing over the bus roller. A wound wire type meter ring rod, also known as a Mayer bar, enables a 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 method, the coating is extruded by gravity or under pressure from the slot onto the substrate. If the coating is 100% solid, this process is called "extrusion", and in this case, the line speed is often much faster than the extrusion speed. This allows the coating to be made much thinner than the width of the slot. The gap or knife over roll method involves applying a coating to the substrate and then passing it through the "gap" between the "knife" and the support roller. When the coating and the substrate pass through, the excess is shaved off. Air knife coating is where a coating is applied to the substrate and the excess is "blown off" by a strong jet from the air knife. This technique is useful for aqueous coatings. In the curtain coating method, a tank with a slot at the bottom allows a continuous curtain of coating to fall into the gap between two conveyors. The object to be coated passes along the conveyor at a controlled speed and thus receives the coating on its upper surface. The substrate can be any material known to be used in the art. For example, the material can be a polyester film such as polyethylene terephthalate, which may optionally be coated, a plastic sheet, glass or cellulose-based paper. The substrate can be polyethylene terephthalate (e.g., Mylar) or tracing paper. If the substrate is polyethylene terephthalate, it can be biaxially oriented polyethylene terephthalate optionally corona treated on its bottom or top surface.

[0139] Film drying The drying stage is also a contributing factor regarding the maintenance of the uniformity of the film composition. A controlled drying method is particularly important when the components within the film may tend to strongly agglomerate or clump 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 an accurate dosage film that does not require a controlled drying method is to cast the film onto a predetermined well or to apply the desired amount of the active agent to individual dosage units after cutting the dosage units from a continuously cast film (containing no active agent) on the manufacturing line. These two alternative methods do not have the problems associated with maintaining the uniformity of the active agent content from the mixing step to the drying step, which are the same as those of a continuously cast film in which the active agent is incorporated into the film substrate prior to casting. In these alternative methods, there is no opportunity for the movement of the active agent to adjacent dosage forms. If an ordered or rapid drying process is desired, this can be achieved by various methods. Various methods can be used, 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, a uniform heterogeneity that does not self-agglomerate, is maintained.

[0140] As described above, the wet continuous cast film is dried using a hot air stream that does not cause the lip ringing, mass transfer of the wet fluidity cast film substrate, or early surface skinning as described above. The parameters selected to achieve this include the distance, angle, and speed from above such that the force generated when hitting the film does not exceed the yield value of the film substrate, i.e., the level of force at which the film-forming composition forming the substrate can move or otherwise cause its lip ringing and non-uniformity is below. Desirably, although not necessarily, the film is exposed to a high temperature difference such that when the film enters the oven, the moisture content is rapidly removed and the fluid substrate rapidly solidifies, locking the activator into a more solid structure. As long as attention is paid to ensuring the preservation of the uniformity of the film during the drying process, the continuous cast film substrate can be dried using only the air emitted from the upper surface or the top of the carrier substrate, only the air emitted from the lower part of the carrier substrate, or only the air emitted from both the upper and lower parts (the upper and lower surfaces of the film) of the carrier substrate. Thus, in one aspect of the drying process, the film can be dried from the bottom of the film towards the top of the film. Desirably, the upper air stream present should not cause the non-uniform state described above. After the initial setting period has elapsed and sufficient solidification has occurred, a viscoelastic structure is formed, and the possibility of rippling and early skinning, if not eliminated, is significantly reduced. This can occur within the first few minutes of the drying process, for example, within approximately the first 0.5 to about 4.0 minutes. The control of drying in this way prevents the destruction and reformation of the upper surface of the film resulting from conventional drying methods. Drying a continuously cast wet film in a manufacturing situation involves casting a wet fluidity film substrate onto a carrier substrate.

[0141] In some cases, it may be preferable to initiate the drying process by supplying an air stream to the bottom surface of the film and thus to the underside of the carrier substrate. The heat from the air stream in this case is first applied to the underside of the film in order to provide the energy necessary to evaporate or otherwise remove the liquid carrier. The film dried in this manner dries more rapidly and uniformly compared to an air-dried film (drying in ambient air) or one dried by conventional drying means. In contrast to an air-dried film which dries first at the top surface and edges, the film dried by applying heat to the bottom surface dries at the center as well as at the edges simultaneously. This also prevents the sedimentation of components which occurs in films dried by conventional means. The external air temperature at which the film is dried can be about 130° C. or less as long as the film substrate does not reach its boiling point (e.g. 100° C.) or a temperature so high as to compromise its uniformity. Desirably, the external air temperature can be about 100° C. or less, or about 80° C. or less. As an alternative way of controlling the drying process which can be used alone or in combination with the other controlled methods disclosed above, it 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 can be avoided. In addition, it has been found that the length of the drying time can be appropriately controlled, i.e. balanced with the heat sensitivity and volatility of the components, in particular the aroma oils and drugs. The amount of energy, the temperature and the length and speed of the conveyor can be balanced in order to adapt to such active agents and to minimize losses, decomposition or ineffectiveness in the final film.

[0142] A specific example of a suitable drying method is disclosed by U.S. Patent No. 4,631,837 to Magoon (the "Magoon"), which is incorporated herein by reference in its entirety and which is particularly directed to a method for drying fruit pulp. In one embodiment of the present invention, the inventors have adapted this method for the production of the present film. The Magoon method and apparatus are based on the interesting properties of water. Water transfers energy by conduction and convection to and within itself, but only radiates energy to and within itself. Thus, the Magoon apparatus includes an infrared-transmissive surface on which the pulp is placed. The underside of the surface is in contact with a water bath whose temperature is controlled. The temperature of the water bath is preferably controlled to be slightly below the boiling point of water. When the fruit pulp containing water is placed on the surface of the apparatus, this creates a "reflectivity window". This means that infrared energy can only be radiated from the surface to the area of the surface occupied by the pulp only until the pulp dries. The Magoon apparatus provides a film of the present invention having an effective drying time that reduces examples of strong aggregation of the components of the film.

[0143] The thickness of the final dry self-supporting film and the dosage units made therefrom disclosed herein can vary depending on the thickness of each layer and the number of layers. Both the layer thickness and the number of layers (i.e., one or multiple layers, e.g., 2, 3, 4, or more) can be adjusted to vary the corrosion kinetics. The film can initially be about 500 μm to about 1,500 μm, or about 508 μm (20 mils) to about 1524 μm (60 mils) thick, and when dried, will be about 3 μm to about 250 μm, or about 2.54 μm (0.1 mil) to about 254 μm (10 mils) thick. Desirably, the dried 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. If the final self-standing film product (or dosage unit prepared therefrom) has two layers, the total film thickness can range from about 0.005 mm to about 2 mm, from about 0.01 mm to about 1 mm, or from about 0.1 mm to about 0.5 mm. The total film thickness can be greater than about 0.1 mm, greater than about 0.2 mm, 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 is variable from about 10% to about 90%, or from about 30% to about 60% of the total thickness of the laminated self-standing film. Any one layer can be greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 70%, greater than 90%, about 90%, less than 90%, less than 70%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the total thickness of the laminated self-standing film. The preferred thickness of each layer is variable 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 can dissolve (including disperse and dissolve) 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-standing film products and dosage units disclosed herein can dissolve in greater than about 1 minute, greater than about 5 minutes, greater than about 7 minutes, greater than about 10 minutes, greater than about 12 minutes, greater than about 15 minutes, greater than about 20 minutes, greater than about 30 minutes, about 30 minutes, or less than about 30 minutes, less than about 20 minutes, less than about 15 minutes, less than about 12 minutes, less than about 10 minutes, less than about 7 minutes, less than about 5 minutes, or less than about 1 minute. The sublingual dissolution rate can be shorter than the buccal dissolution rate. More specifically, oral dissolving film dosage units (also referred to as "unit doses") belong to three main types: fast-dissolving, medium-dissolving, and slow-dissolving. Oral dissolving film dosage units can include any combination of the above categories. Fast-dissolving film dosage units can dissolve in the oral cavity in about 1 second to about 30 seconds, for example, 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. Medium-dissolving film dosage units can dissolve in the oral cavity in about 1 to about 30 minutes, for example, 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. Slow-dissolving film dosage units can dissolve in the oral cavity in more than about 30 minutes, for example, about 30 minutes to about 24 hours, about 30 minutes to about 12 hours, about 30 minutes to about 10 hours, and about 1 hour to about 10 hours. Fast-dissolving film dosage units can include (or consist of) low molecular weight hydrophilic polymers (for example, polymers having a molecular weight of about 1,000 to about 9,000 daltons, or polymers having a molecular weight up to about 200,000 daltons). In contrast, slow-dissolving film dosage units can include high molecular weight polymers (for example, having a molecular weight of several million).

[0145] Medium-dissolving film dosage units can have certain advantages such as having a good degree of mucoadhesion while dissolving somewhat faster. Medium-dissolving film dosage units are also soft, have rapid water uptake, and generally cause no irritation to the patient. Such medium-dissolving film dosage units can provide an acceptable degree of mucoadhesion such that once the film is placed in the patient's oral cavity, it is not easily removed, while providing a sufficiently fast dissolution rate, for example, about 1 minute to about 20 minutes. This can ensure complete delivery of the pharmaceutical active 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 on the oral mucosa, i.e., for example, on the buccal or sublingual side. Although various different film-forming techniques can be used, it is desirable to select a method that provides a soft film such as reverse roll coating. The flexibility of the film allows for winding and transportation of the film sheet for storage or before cutting 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. Further, the polymers used in constructing the film can be selected to allow for a range of disintegration times of the film. By varying or extending the time at which the film disintegrates, control over the rate at which the active agent is released can be achieved, which enables a sustained release system. In addition, the film can also be used for administration of the active agent to any of several body surfaces, particularly to mucous membranes such as the oral cavity, anus, vagina, eye, skin surface or wound surfaces within the body during surgery, and similar surfaces. The film can be used for oral administration of the active agent. This is achieved by preparing the films as described above and introducing them into the oral cavity of a mammal. The film is prepared and adhered to a second layer or support layer that is removed before its use, i.e., before its introduction into the oral cavity. An adhesive can be used to attach the film to the support material or substrate material, and this adhesive can be any of those known in the art, preferably being water-insoluble. When an adhesive is used, it is preferably an ingestible food-grade adhesive that does not alter the properties of the active agent. A mucoadhesive composition is particularly useful. The film composition often acts as a mucoadhesive itself.

[0147] The film can be applied to the sublingual area or tongue of a mammal. If this is desired, a specific film shape corresponding to the shape of the tongue may be preferred. Thus, the film can be cut into a shape where the side of the film corresponding to the back of the tongue is longer than the side corresponding to the front of the tongue. Specifically, the desired shape can be a triangular or trapezoidal shape. Desirably, the film adheres to the oral cavity and is not expelled from the oral cavity, and more of the active agent can 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 immediately when placed in a liquid. The active agent can be introduced into the liquid by preparing the film according to the present invention, placing it in the liquid, and enabling its dissolution. 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 preferably packaged in a sealed, airtight, and moisture-proof package to protect the active agent from oxidation, hydrolysis, volatilization, and exposure to interaction with the environment. Further, the films of the present invention dissolve immediately upon contact with saliva or the mucosal area, eliminating the need to wash down the dosage with water. Preferably, a series of such unit dosages are packaged together according to a defined regimen or treatment, such as a supply for 10 - 90 days, for example, depending on the particular therapy. The individual self-standing films can be packaged without a substrate or on a substrate and peeled off for use.

[0148] Method of use Also disclosed herein is a method of treating epilepsy, epileptic seizures, and other forms of seizures in a human, the method comprising administering to the human an oral film for delivery of a desired amount of an active agent in each unit dosage. The film comprises: a) a water-soluble polymer substrate, a water-swellable polymer substrate, or a water-soluble and water-swellable polymer substrate; 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 a sweetening agent, a flavoring agent, a seasoning, a filler, a plasticizer, a coloring agent, a pigment, a penetration enhancer, a buffering agent, a preservative, silicon dioxide, an anti-sticking agent, 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 can be any of the active agents described herein. In certain embodiments, the active agent can be clobazam, diazepam, riluzole, or any combination thereof. Another embodiment is directed to a method of treating Lennox - Gastaut syndrome in a human, the method comprising administering to the human an oral film disclosed herein. The terms used with respect to these embodiments (usage methods) have the same meanings and definitions as described above.

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

Example

[0150] Example 1 - Clobazam To compare the pulverizing agent and the micronizing agent, an oral film having the following composition shown in Table 1 was prepared.

Table 1

[0151] Figure 3 shows the average agent dissolution plots of films (N = 3) containing 5 mg of pulverized clobazam (D90 = 106 microns) and micronized clobazam (D90 = 8.3 microns), as well as the RLD Onfi tablets. Table 2 represents some of the graph display data points shown in Figure 3.

Table 2

[0152] Example 2 - Dissolution test of an oral film containing diazepam Diazepam (DBSF)-containing oral thin films containing 5 mg and 15 mg of the active agent were prepared. The 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 technology. 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 is equipped with a modified sample holder necessary to hold the film stationary and uses a modified USP apparatus 5 setup. All other aspects of the conventional dissolution method are the same as those of other solid oral dosage forms, including manual sample collection and sample collection at specific time points, followed by offline analysis of the samples using HPLC. The conventional dissolution method is limited in terms of the practical aspects of the frequency and consistency of manual sample collection and sample aliquot removal. The PION technology uses a conventional dissolution tank that is not a conventional setup. This tank is set using apparatus 2 (paddle), and a modified sample holder is attached to the paddle. An in-line fiber optic probe is placed inside the container. Samples are tested in-situ at predetermined intervals. Sample collection is automatic and analyzed in-line, eliminating the need for sample removal, manual sample collection, or offline HPLC testing. A comparison of the system parameters of 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 measured by conventional dissolution. Figure 5 is a graph showing the active agent dissolution profile of DBSF measured by PION technology. A comparison of some data points and 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 activator dissolution profiles for the 5 mg oral films are similar, but those for the 15 mg oral films are not. However, using the PION technology, the activator dissolution profiles become much more precise and improved over a greater number of available time intervals. In conventional dissolution, the activator dissolution profile only includes seven data points, but the activator dissolution profile obtained using the PION technology is five times that amount. Additionally, when using the PION technology, the data is obtained immediately, whereas the first data point for conventional dissolution is 5 minutes. In these fast-dissolving dosage forms, the activity up to 5 minutes can be an important differentiating factor.

[0155] Example 3 - Dissolution Test of Oral Film Containing Riluzole An oral thin film containing 50 mg of riluzole (ROSF) was prepared. The dissolution of 50 mg of ROSF after storage at 25°C for approximately 6 months was tested in 0.1 N HCl (a medium simulating gastric conditions) using conventional dissolution and the PION technology. The parameters used for conventional dissolution and the PION technology for testing ROSF are shown in Table 3 above. Figure 6 is a graph of the activator dissolution profile of ROSF measured by conventional dissolution testing. Figure 7 is a graph of the activator dissolution profile of ROSF measured by the PION technology. Table 6 shows a comparison of several data points and the results obtained by conventional dissolution and the results obtained by the PION technology.

Table 6

[0156] Example 4 - Dissolution Test of Oral Film Containing Clobazam An oral thin film containing clobazam (COSF) having a composition as shown in Table 7 and containing 5 mg, 10 mg, and 20 mg of the activator was prepared.

Table 7

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

[0158] Figure 8 is a graph showing the activator dissolution profile of 5 mg of COSF measured by conventional dissolution after storage under storage conditions and accelerated conditions at about 24 months, 25 °C, 40 °C, and RH60, respectively. As shown therein, the film is released almost completely at very fast sampling points. There is no information on the activator dissolution profile at the very important time up to 10 minutes when most of the dissolution occurs. Also, it is clearly seen from this graph that conventional dissolution lacks accuracy, and there is no detectable difference between the activator dissolution profiles of two samples from 0 - 10 minutes.

[0159] In contrast, FIGS. 9 and 10 show the activator dissolution profiles of COSF samples measured by the PION technique. As shown in these figures, there are clearly detectable differences between different storage conditions and between samples of different dosages. FIG. 9 is a graph of the activator dissolution profiles of COSF measured by the PION technique at different dosages and temperatures, and FIG. 10 is an enlarged and smoothed curve of the same test as FIG. 9. FIG. 10 plots the activator dissolution profiles from 0 to 10 minutes after storage at about 12 months, about 25°C, and about 40°C under different storage conditions for these COSF dosages. Using some data points and the PION technique, the comparison of the results obtained at different temperatures is shown in Tables 8 and 9.

Table 8

Table 9

[0160] The calculations represented in FIGS. 9 and 10 and Tables 8 and 9 show the accuracy made possible by using the PION technique, including measurement data points of less than 1 minute. This allows for distinguishable and measurable differences between oral films containing different amounts of activator and dosage forms under different storage conditions. FIGS. 11 and 12 plot the second derivatives of the activator dissolution profiles measured by the PION technique in FIGS. 9 and 10. Using this, the calculation of the exact inflection points (identified on the figure) can be achieved.

[0161] Example 5: COSF Dosage Comparison CLOBAMAZEPAM (COSF)-containing oral thin films having the composition as shown in Table 7 and containing 5 mg, 10 mg and 20 mg of the active agent were prepared. These films were stored at about 25 °C and 60% RH for about 24 months, and then tested using PION technology to determine how the active agent dissolution profiles differed among COSFs containing different amounts of the active agent. The parameters used in the PION technology are shown in Table 3 above. Figure 13 is a graph of the actually obtained data points, and Figure 14 is a smoothed curve of the data points shown in Figure 13. As shown in these figures, there are detectable differences among the active agent dissolution profiles of each film. The 5 mg COSF has a rapid release property (the steepest curve, reaching 100% in 2.5 minutes), followed by the 10 mg COSF (reaching 100% in 3.0 minutes), and finally the 20 mg COSF has the slowest release profile, approaching 100% after 7.0 minutes.

[0162] Figure 15 is a first derivative graph of the active agent dissolution profile of Figure 13. This graph provides information on 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 curve in this figure, the 5 mg and 10 mg COSFs are released faster and more completely within the first minute, and the 20 mg COSF is released more slowly, that is, the curve is shorter and wider (lower intensity). For all curves, the first derivative approaches 0 when the release is complete and the drug concentration in the container reaches a plateau. The first derivative curves of the 5 mg and 10 mg COSFs are substantially equal and reach the plateau earlier than the 20 mg COSF curve. As described above with respect to Figure 8 in this case as well, these differences shown in Figures 13, 14 and 15 are not represented when using conventional dissolution. It is only when there is the enhanced discrimination ability of the PION technology where these differences can be detected and recorded.

[0163] Example 6: Comparison of COSF under Different Storage Conditions The 5 mg, 10 mg, and 20 mg COSF prepared as described above were tested using the PION technology either 1) after storage for approximately 24 months at RH 60 and approximately 25 °C; 2) after storage for approximately 24 months at RH 60 and approximately 40 °C; or 3) at the completion of the finished product (no storage time, T = approximately 0 months). The parameters used for the PION technology are shown in Table 3 above. To determine how different storage conditions affect the dissolution rate, the active agent dissolution profiles were compared.

[0164] Figure 16 shows the active agent dissolution profiles of 5 mg, 10 mg, and 20 mg COSF after storage for approximately 24 months at RH 60 and approximately 25 °C, and after storage for approximately 24 months at RH 60 and approximately 40 °C. 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, but the 20 mg COSF sample had the slowest dissolution profile. Here, the enhanced discrimination ability of the PION system could be observed. The active agent dissolution profiles obtained using the PION technology are precise 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 shows the similarity or lack thereof between different samples (strength / storage condition / storage period / etc.). Using the PION technology, the similarity or lack of similarity is clearer than with conventional dissolution due to improved accuracy and first derivative formation. As shown in Table 10, for example, statistical similarity is shown between 5 mg and 10 mg at 25 °C, and no statistical similarity is shown between 5 mg and 10 mg, 25 °C and 40 °C. Regarding similarity, the f2 (similarity coefficient) must not be less than 50, and the f1 (dissimilarity coefficient) must not exceed 15. [Table 10]

[0166] Figure 18 shows the dissolution profiles of the active ingredients of 5 mg, 10 mg, and 20 mg COSF after storage at about 25 °C for about 24 months, RH60, 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 product samples (T = 0) of the same strength. For statistical similarity, the active ingredient dissolution profiles of the finished product 5 mg and 10 mg COSF are not statistically similar to the equivalent stored samples. The active ingredient dissolution profile of the finished product 20 mg COSF sample is statistically similar to the stored 20 mg COSF sample.

Table 11

[0167] Example 7: Comparison of Media To determine how the choice of media affects the dissolution rate, 5 mg, 10 mg, and 20 mg COSF were prepared and tested using the PION technology (without storage period). The parameters used for the PION technology are shown in Table 3 above. Thus, the dissolution of the active ingredient in each film is tested in a bath of either 0.1 N HCl, a 0.05 molar solution of monopotassium phosphate adjusted to pH 6.8 with sodium hydroxide, or water. Figure 20 shows the activator 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 ability of the PION technology, the selected media do not affect dissolution, and samples of the same strength dissolved in various media are statistically equivalent. In conventional dissolution, without clear solubility problems, activator dissolution profiles generally do not provide this high level of information.

[0168] Example 8: Comparison of Release from Liquid Mixtures and Films Experiments were designed to evaluate the effect of additional excipients on the release of the activator. Specificity is an aspect of method development to ensure that the quantification of the activator is not interfered with by any excipients contained in the pharmaceutical product. Thus, the activator dissolution profiles of the following samples were measured by the PION technology and presented in Figure 22: · 5 mg COSF finished product (shown as "nominal 5 mg" in Figure 22); · Liquid mixture of the film composition before drying; · Placebo, i.e., a film containing all excipients other than the activator; and · 5 mg COSF finished product containing twice the amount of excipients (shown as "5 mg w / 2 placebo" in Figure 22). As shown in Figure 22, the placebo, i.e., the film without the activator, shows some interference - about 20% response. Thus, the excipients and the film dosage form alone affect the activator dissolution profile. Figure 23 is the first derivative curve of Figure 22. The activator in the liquid mixture was assumed to dissolve faster than the activator in the film, which requires hydration, swelling, and subsequent release of the activator. However, unexpectedly, it was found that the film had a faster dissolution profile than the liquid mixture. Based on these results, it is considered that a dry film that absorbs moisture into the substrate promotes the release and dissolution of the activator.

[0169] Example 9: Evaluation of Substrate Performance During manufacturing, specifically, an experiment was conducted to change the substrate used in the drying stage of an oral film containing 20 mg of clobazam. In particular, substrates with a 1016 μm (40 mil) gap and various substrates for comparative evaluation were used, and coated with a 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

[0170] Example 10: Evaluation of the solubility of clobazam in COSF intermediates and finished products Experiments were conducted to evaluate the solubility of clobazam in liquid mixtures (before drying) and oral films (COSF). Oral thin films containing 10 mg and 20 mg of clobazam were prepared and then dissolved in 1.5 ml of water. Two other samples were also evaluated, one being the active ingredient in water (without excipients added to the oral film composition), and the other being the liquid mixture for the film tested before film formation (i.e., drying). The results of the evaluation are shown in Table 13.

Table 13

[0171] While the presently preferred specific embodiments of the invention have been described, it will be understood by those skilled in the art that changes and modifications may 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. An 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 having an average 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 upon placement of said film in a medium, greater than about 2% of said active agent dissolves in said medium after about 3 minutes.

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

3. 3. The film of claim 2, wherein the active agent has an average particle size D90 of less than about 100 microns.

4. 3. The film of claim 2, wherein the active agent has an average particle size D50 of less than about 30 microns.

5. 5. The film of claim 4, wherein the active agent has an average particle size D50 of less than about 20 microns.

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

7. 7. The film of claim 6, wherein the active agent has an average particle size D10 of less than about 5 microns.

8. The film of claim 1, wherein each unit dose contains from about 0.5 mg to about 100 mg of the active agent.

9. 9. The film of claim 8, wherein the active agent is clobazam.

10. 10. The film of claim 1, wherein when the film is placed in a medium, greater than about 10% of the active agent dissolves after about 3 minutes.

11. 10. The film of claim 1, wherein when the film is placed in a medium, greater than about 40% of the active agent dissolves after about 5 minutes.

12. 10. The film of claim 1, wherein when the film is placed in a medium, greater than about 50% of the active agent dissolves after about 5 minutes.

13. 1. An oral film for delivering a desired amount of an active agent in each unit dose, comprising: d) a water-soluble, water-swellable, or water-soluble and water-swellable polymeric substrate; e) clobazam, the active agent having a mean particle size D90 of less than about 160 microns; and f) additives 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; Including, A film, wherein upon placement of the film in a medium, greater than about 20% of the active agent dissolves in the medium after about 3 minutes.

14. 14. The film of claim 13, wherein the active agent has an average particle size D90 of less than about 120 microns.

15. 15. The film of claim 14, wherein the active agent has an average particle size D90 of less than about 100 microns.

16. 14. The film of claim 13, wherein the active agent has an average particle size D50 of less than about 30 microns.

17. 17. The film of claim 16, wherein the active agent has an average particle size D50 of less than about 20 microns.

18. 15. The film of claim 14, wherein the active agent has an average particle size D10 of less than about 10 microns.

19. 20. The film of claim 18, wherein the active agent has an average particle size D10 of less than about 5 microns.

20. 14. The film of claim 13, wherein when the film is placed in a medium, greater than about 30% of the active agent dissolves after about 3 minutes.

21. 14. The film of claim 13, wherein when the film is placed in a medium, greater than about 55% of the active agent dissolves after about 5 minutes.

22. 14. The film of claim 13, wherein when the film is placed in a medium, greater than about 5% of the active agent dissolves after about 1.5 minutes.

23. 14. The film of claim 13, wherein each unit dose contains from about 2 mg to about 20 mg of clobazam.

24. 24. The film of claim 23, wherein each unit dose contains about 5 mg of clobazam.

25. 25. The film of claim 24, wherein when the film is placed in a medium, greater than about 30% of the active agent dissolves after about 1 minute.

26. 25. The film of claim 24, wherein when the film is placed in a medium, greater than about 80% of the active agent dissolves after about 2 minutes.

27. 25. The film of claim 24, wherein when the film is placed in a medium, greater than about 95% of the active agent dissolves after about 2.5 minutes.

28. 24. The film of claim 23, wherein each unit dose contains about 10 mg of clobazam.

29. 30. The film of claim 28, wherein when the film is placed in a medium, greater than about 50% of the active agent dissolves after about 1.5 minutes.

30. 30. The film of claim 28, wherein when the film is placed in a medium, greater than about 70% of the active agent dissolves after about 2.5 minutes.

31. 24. The film of claim 23, wherein each unit dose contains about 20 mg of clobazam.

32. 32. The film of claim 31, wherein when the film is placed in a medium, greater than about 2% of the active agent dissolves after about 1.5 minutes.

33. 32. The film of claim 31, wherein when the film is placed in a medium, greater than about 40% of the active agent dissolves after about 3.5 minutes.

34. 14. The film of claim 13, comprising a sweetener selected from the group consisting of sucralose, stevia, acesulfame potassium, saccharin, fructose, aspartame, and any combination thereof.

35. 35. The film of claim 34, wherein the sweetening agent is present at about 0.5 to about 5% by weight of the composition.

36. 14. The film of claim 13, comprising a flavoring agent that is a fruit flavor.

37. 37. The film of claim 36, wherein the fruit flavor is a berry flavor.

38. 38. The film of claim 37, wherein the berry flavoring is present in an amount of from about 0.1 to about 15% by weight.

39. 14. The film of claim 13, wherein less than about 10% by weight of the total amount of active agent is dissolved in the oral film.

40. 40. The film of any one of claims 1-39, wherein prior to test dissolution, the film is stored under one or more of the following conditions: from about 0 months to about 36 months, from about 20°C to about 60°C, a relative humidity (RH) up to about 75%, and any combination thereof.

41. The film of any one of claims 1 to 40, wherein the medium is any solvent that provides an immersion condition.

42. 42. The film of claim 41, wherein the medium is selected from the group consisting of dilute hydrochloric acid, a buffer in the physiological pH range of 1.2 to 7.5, simulated gastrointestinal fluids, water, a surfactant, and any combination thereof.

43. The film of claim 1, further comprising any one or more of claims 2-12, 39, and 40.

44. The film of claim 13, further comprising any one or more of claims 14 to 42.

45. 45. A method of treating epilepsy and / or seizures in a human comprising administering to said human a unit dose of the oral film of any one of claims 1-44.

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