Oral film for rapid active delivery

Abstract

The present invention discloses a method for treating neurological diseases or disorders by administering an oral film containing a therapeutic compound with an average particle size D90 of less than about 160 microns. The oral film comprises a water-soluble polymer matrix, a water swellable polymer matrix, or a combination thereof, along with an additive selected from a group including sweeteners, flavors, flavor enhancers, fillers, plasticizers, dyes, pigments, permeation enhancers, buffers, preservatives, silicon dioxide, anti-tacking agents, or any combination thereof. This innovative approach provides a convenient and effective means of delivering a desired amount of the therapeutic compound for the treatment of neurological conditions.

Description

Attorney Docket No.148570-006302 ORAL FILM FOR RAPID ACTIVE DELIVERY CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 562,057 filed March 6, 2024, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION

[0002] The invention relates generally to oral film strips effective to treat symptoms associated with disorders including neurological diseases or disorders. BACKGROUND INFORMATION

[0003] In the field of oral film technology, the particle size of the active ingredient has been recognized as a critical parameter affecting the dissolution and subsequent bioavailability of the active. Previous formulations have aimed to reduce the particle size of the active to enhance its dissolution rate and improve the overall performance of the oral film. Efforts have been made to control the particle size distribution of the active to ensure uniform dissolution kinetics and consistent dosing in individual unit doses.

[0004] Furthermore, the selection and incorporation of various additives in oral film formulations have been explored to enhance the stability, palatability, and therapeutic efficacy of the final product. Additives such as fillers, dyes, preservatives, and anti-tacking agents have been utilized to improve the physical properties and shelf-life of oral films. Despite these advancements in oral film technology, challenges remain in achieving rapid and efficient dissolution of the active ingredient in the oral cavity while maintaining the desired taste and texture of the film. However, none of these approaches have provided a comprehensive solution that combines the features described in this disclosure. SUMMARY OF THE INVENTION

[0005] The present invention relates to an oral film for delivering an active agent to treat a neurological disease or disorder.

[0006] In some aspects, the techniques described herein relate to a method of treating a neurological disease or disorder including administering an oral film for delivery of a desired amount of a therapeutic compound, said film including: (a) a water-soluble polymer matrix, a water swellable polymer matrix, or a combination thereof; (b) a therapeutic compound having an average particle size D90 of less than about 160 microns; and (c) anAttorney Docket No.148570-006300 additive selected from the group consisting of a sweetener, a flavor, a flavor enhancer, a filler, a plasticizer, a dye, a pigment, a permeation enhancer, a buffer, a preservative, silicon dioxide, an anti-tacking agent, and any combination thereof.

[0007] In some aspects, the techniques described herein relate to a method, wherein the therapeutic compound has an average particle size D90 of less than about 120 microns.

[0008] In some aspects, the techniques described herein relate to a method, wherein the therapeutic compound has an average particle size D90 of less than about.100 microns.

[0009] In some aspects, the techniques described herein relate to a method, wherein the therapeutic compound has an average particle size D50 of less than about 30 microns.

[0010] In some aspects, the techniques described herein relate to a method, wherein the therapeutic compound has an average particle size D50 of less than about 20 microns.

[0011] In some aspects, the techniques described herein relate to a method, wherein the therapeutic compound has an average particle size D10 of less than about 10 microns,

[0012] In some aspects, the techniques described herein relate to a method, wherein the therapeutic compound has an average particle size D10 of less than about 5 microns.

[0013] In some aspects, the techniques described herein relate to a method, wherein the oral film includes about 0.5 mg to-about 100 mg of the therapeutic compound.

[0014] In some aspects, the techniques described herein relate to a method, wherein the therapeutic compound is olanzapine.

[0015] In some aspects, the techniques described herein relate to a method, wherein, upon placing the film in a medium, more than about 1.0% of the therapeutic compound is dissolved after about 3 minutes.

[0016] In some aspects, the techniques described herein relate to a method, wherein, upon placing the film in a medium, more than about 40% of the therapeutic compound is dissolved after about 5 minutes.Attorney Docket No.148570-006300

[0017] In some aspects, the techniques described herein relate to a method, wherein, upon placing the film in a medium, more than about 50% of the therapeutic compound is dissolved after about 5 minutes. (d) (e) (f) 19.20.21.23.24.25.26.27.29.30.31.32.33.

[0018] In some aspects, the techniques described herein relate to a method, wherein the film includes a sweetener selected front the group consisting of: sucralose, stevia, acesulfame potassium, saccharin, fructose, aspartame, and any combination thereof.

[0019] In some aspects, the techniques described herein relate to a method, wherein the sweetener is present at about 0.5% to about 5% by weight of the oral film.

[0020] In some aspects, the techniques described herein relate to a method, wherein the film includes a fruit flavoring.

[0021] In some aspects, the techniques described herein relate to a method wherein the fruit flavoring is berry flavoring.

[0022] In some aspects, the techniques described herein relate to a method, wherein the berry flavoring is present in about 0.1% to about 15% by weight of the oral film.

[0023] In some aspects, the techniques described herein relate to a method, wherein less than about 10% by weight of the therapeutic compound is dissolved in an oral cavity.40. 41.

[0024] In some aspects, the techniques described herein relate to a method, wherein the neurological disease or disorder is acute agitation associated with schizophrenia, schizoaffective disorder, and bipolar disorder, maintenance treatment of schizophrenia, treatment-resistant depression, bipolar I disorder, Alzheimer's Disease, autism spectrum disorder, post-traumatic stress disorder, attention deficit disorder, hyperactivity disorder, delirium, or chemotherapy-induced nausea and vomiting. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present disclosure is based on the finding that a pharmaceutical composition including olanzapine in an oral film delivery formulation allows for rapid absorption and delivery of the active agent.Attorney Docket No.148570-006300

[0026] The present disclosure refers to the following International Patent Applications: WO2017192923 , WO2019067667 , WO2020051317 , WO2021097247, WO2022192476 , WO2023076281 , WO03030881, WO03030882, WO03030883, WO04066986, WO06031209, WO06039264, WO07030754, WO07067494, WO07075422, WO08039737, WO08100375, WO11017484, WO11143424, WO11100423, WO11106342, WO11106341, WO12040262, WO12054810, WO12141972, WO14043346, WO16094567, WO17192921, WO19067670, WO23069733, WO23245069, WO19246384, WO21087359, WO12058545, each of which are hereby incorporated by reference in their entirety.

[0027] Olanzapine buccal film is a formulation that incorporates olanzapine in a dissolving polymer matrix in a manner that is compact, portable and designed to be easily administered, with a pharmacokinetic profile comparable to injectable administered olanzapine, but with multimodal delivery. Multimodal delivery refers to the fact that the active ingredient is delivered in more than one route, e.g., transmucosal and gastrointestinal routes. Olanzapine buccal film can be applied to the buccal mucosa inside the cheek where the film adheres, hydrates and releases olanzapine such that it is absorbed transbucally and is also swallowed allowing some enteral absorption as well. Olanzapine buccal film is successfully placed and generally used without difficulty, even without patient cooperation immediately after an episode. Olanzapine buccal film is a convenient alternative for out-of- hospital treatment of neurological diseases or disorders. Olanzapine buccal film is also useful to treat acute neurological emergencies.

[0028] In the present disclosure, methods are presented to treat a neurological disease or disorder. In some aspects, the neurological disease or disorder is acute agitation associated with schizophrenia, schizoaffective disorder, and bipolar disorder, maintenance treatment of schizophrenia, treatment-resistant depression, bipolar I disorder, Alzheimer’s Disease, autism spectrum disorder, post-traumatic stress disorder, attention deficit disorder, hyperactivity disorder, delirium, or chemotherapy-induced nausea and vomiting.

[0029] Olanzapine will be administered with a monomodal delivery profile. In other embodiments, olanzapine can also be administered with a multimodal delivery profile. Olanzapine can be administered with a bimodal delivery profile.

[0030] The absorption of olanzapine through the mucosa is governed by several factors including i) the release rate from the film, ii) the surface area of the film, iii) the residenceAttorney Docket No.148570-006300 time of the film and iv) the ability of the molecule to permeate and traverse the oral mucosa to reach the vascular system. Despite significant improvements to the permeation rate, through the incorporation of a penetration enhancer into the formulation, a portion of the olanzapine is delivered transmucosally. Some the olanzapine is washed away through salivary flow or swallowed and drains into the gastrointestinal tract where it is absorbed into the body. The combination of these two absorption routes allows olanzapine buccal film to deliver faster olanzapine blood levels than can be achieved orally alone but due to the high oral bioavailability, also ensures a complete dose is delivered upon every application. The swallowed portion of the olanzapine however is also exposed to variations in the absorption rate due to a well-known food effect.

[0031] When delivered orally, olanzapine is typically absorbed rapidly and completely by the gastrointestinal tract. Onset of absorption can be as rapid as about 15 min or less and Tmax can also be observed in the range of about 1 hr to 1.5 hours for example. However, after a moderate fat meal, onset of absorption can be delayed to approximately 4.5 min and Tmax is pushed to about 2-3hours. Along with the delay in absorption comes a reduction in Cmax as absorption is spread out over a longer duration of time. The Cmax may decrease by approximately 20 to 40% after a moderate fat meal.

[0032] An olanzapine buccal film dose for each weight class will be selected (1) to provide a dose sufficiently high to ensure that the predicted median of the resulting olanzapine Cmax following a moderate fat meal will be similar to the median Cmax following the labeled dose of Zyprexa, and (2) to provide a dose for which the predicted median of the resulting olanzapine Cmax under fasting conditions will not exceed the median Cmax values observed and demonstrated as safe in Phase 1 studies with olanzapine buccal film. The predicted median olanzapine Cmax values with the proposed regimen administered under fasting conditions will not meaningfully exceed the median Cmax values observed in the healthy volunteers (adult men and women) who receive olanzapine buccal film 15 mg under fasting conditions in Phase 1 studies.

[0033] Mucosal surfaces, such as the oral mucosa, are a convenient route for delivering drugs to the body due to the fact that they are highly vascularized and permeable, providing increased bioavailability and rapid onset of action because it does not pass through the digestive system and thereby avoids first pass metabolism. In particular, the buccal andAttorney Docket No.148570-006300 sublingual tissues offer advantageous sites for drug delivery because they are highly permeable regions of the oral mucosa, allowing drugs diffusing from the oral mucosa to have direct access to systemic circulation. This also offers increased convenience and therefore increased compliance in patients. For certain drugs, or pharmaceutically active components, a permeation enhancer can help to overcome the mucosal barrier and improve permeability. Permeation enhancers reversibly modulate the penetrability of the barrier layer in favor of drug absorption. Permeation enhancers facilitate transport of molecules through the epithelium. Absorption profiles and their rates can be controlled and modulated by a variety of parameters, such as but not limited to film size, drug loading, enhancer type / loading, polymer matrix release rate and mucosa (residence time).

[0034] A pharmaceutical composition can be designed to deliver a pharmaceutically active component in a deliberate and tailored way. However, solubility and permeability of the pharmaceutically active component in vivo, in particular, in the mouth of a subject, can vary tremendously. A particular class of permeation enhancer can improve the uptake and bioavailability of the pharmaceutically active component in vivo. In particular, when delivered to the mouth via a film, the permeation enhancer can improve the permeability of the pharmaceutically active component through the mucosa and into the blood stream of the subject. The permeation enhancer can improve absorption rate and amount of the pharmaceutically active component by more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 150%, about 200% or more. or less than 200%, less than 150%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or a combination of these ranges, depending on the other components in the composition.

[0035] In certain embodiments, a pharmaceutical composition has a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a mucosal delivery-enhancing agent selected from: (a) an aggregation inhibitory agent; (b) a charge-modifying agent; (c) a pH control agent; (d) a degradative enzyme inhibitory agent; (e) a mucolytic or mucus clearing agent; (f) a ciliostatic agent; (g) a membrane penetration-enhancing agent selected from: (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome, or carrier; (iii) an alcohol; (iv) an enarnine; (v) an NO donor compound; (vi) a long chain amphipathic molecule; (vii) a smallAttorney Docket No.148570-006300 hydrophobic penetration enhancer; (viii) sodium or a salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or beta-cyclodextrin derivative; (xi) a medium- chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or salt thereof; (xiv) an N- acetylamino acid or salt thereof; (xv) an enzyme degradative to a selected membrane component; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) any combination of the membrane penetration enhancing agents recited in (i)-(x); (h) a modulatory agent of epithelial junction physiology; (1) a vasodilator agent; (j) a selective transport-enhancing agent; and (k) a stabilizing delivery vehicle, carrier, mucoadhesive, support or complex-forming species with which the compound is effectively combined, associated, contained, encapsulated or bound resulting in stabilization of the compound for enhanced transmucosal delivery, wherein the formulation of the compound with the transmucosal delivery-enhancing agents provides for increased bioavailability of the compound in blood plasma of a subject.

[0036] There are many reasons why the oral mucosa might be an attractive site for the delivery of therapeutic agents into the systemic circulation. Due to the direct drainage of blood from the buccal epithelium into the internal jugular vein first-pass metabolism in the liver and intestine may be avoided. First-pass effect can be a major reason for the poor bioavailability of some compounds when administered orally. Additionally, the mucosa lining the oral cavity is easily accessible, which ensures that a dosage form can be applied to the required site and can be removed easily in the case of an emergency. However, like the skin, the buccal mucosa acts as a barrier to the absorption of xenobiotics, which can hinder the permeation of compounds across this tissue. Consequently, the identification of safe and effective penetration enhancers has become a major goal in the quest to improve oral mucosal drug delivery. Chemical penetration enhancers are substances that control the permeation rate of a co-administered drug through a biological membrane. While extensive research has focused on obtaining an improved understanding of how penetration enhancers might alter intestinal and transdermal permeability, far less is known about the mechanisms involved in buccal and sublingual penetration enhancement. The buccal mucosa delineates the inside lining of the cheek as well as the area between the gums and upper and lower lips and it has an average surface area of 100 cm2. The surface of the buccal mucosa consists of a stratified squamous epithelium which is separated from the underlying connective tissue (lamina propria and submucosa) by an undulating basement membrane (a continuous layer ofAttorney Docket No.148570-006300 extracellular material approximately 1-2 μm in thickness). This stratified squamous epithelium consists of differentiating layers of cells which change in size, shape, and content as they travel from the basal region to the superficial region, where the cells are shed. There are approximately 40-50 cell layers, resulting in a buccal mucosa which is 500600 μm thick. Structurally the sublingual mucosa is comparable to the buccal mucosa but the thickness of this epithelium is 100-200 μm. This membrane is also non-keratinised and being relatively thinner has been demonstrated to be more permeable than buccal mucosa. Blood flow to the sublingual mucosal is slower compared with the buccal mucosa and is of the order of 1.0 mU min-1 / cm.-1.

[0037] The permeability of the buccal mucosa is greater than that of the skin, but less than that of the intestine. The differences in permeability are the result of structural differences between each of the tissues. The absence of organized lipid lamellae in the intercellular spaces of the buccal mucosa results in greater permeability of exogenous compounds, compared to keratinized epithelia of the skin; while the increased thickness and lack of tight junctions results in the buccal mucosa being less permeable than intestinal tissue. The primary barrier properties of the buccal mucosa have been attributed to the upper one-third to one-quarter of the buccal epithelium. Researchers have learned that beyond the surface epithelium, the permeability barrier of nonkeratinized oral mucosa could also be attributed to contents extruded from the membrane-coating granules into the epithelial intercellular spaces.

[0038] The intercellular lipids of the nonkeratinized regions of the oral cavity are of a more polar nature than the lipids of the epidermis, palate, and gingiva, and this difference in the chemical nature of the lipids may contribute to the differences in permeability observed between these tissues. Consequently, it appears that it is not only the greater degree of intercellular lipid packing in the stratum corneum of keratinized epithelia that creates a more effective barrier, but also the chemical nature of the lipids present within that barrier. The existence of hydrophilic and lipophilic regions in the oral mucosa has led researchers to postulate the existence of two routes of drug transport through the buccal mucosa paracellular (between the cells) and transcellular (across the cells).

[0039] Since drug delivery through the buccal mucosa is limited by the barrier nature of the epithelium and the area available for absorption, various enhancement strategies areAttorney Docket No.148570-006300 required in order to deliver therapeutically relevant amounts of drug to the systemic circulation. Various methods, including the use of chemical penetration enhancers, prodrugs, and physical methods may be employed to overcome the barrier properties of the buccal mucosa.

[0040] A chemical penetration enhancer, or absorption promoter, is a substance added to a pharmaceutical formulation in order to increase the membrane permeation or absorption rate of the co-administered drug, without damaging the membrane and / or causing toxicity. There have been many studies investigating the effect of chemical penetration enhancers on the delivery of compounds across the skin, nasal mucosa, and intestine. In recent years, more attention has been given to the effect of these agents on the permeability of the buccal mucosa. Since permeability across the buccal mucosa is considered to be a passive diffusion process the steady state flux (Jss) should increase with increasing donor chamber concentration (CD) according to Fick's first law of diffusion.

[0041] Surfactants and bile salts have been shown to enhance the permeability of various compounds across the buccal mucosa, both in vitro and in vivo. The data obtained from these studies strongly suggest that the enhancement in permeability is due to an effect of the surfactants on the mucosal intercellular lipids.

[0042] Fatty acids have been shown to enhance the permeation of a number of drugs through the skin, and this has been shown by differential scanning calorimetry and Fourier transform infrared spectroscopy to be related to an increase in the fluidity of intercellular lipids. Additionally, pretreatment with ethanol has been shown to enhance the permeability of tritiated water and albumin across ventral tongue mucosa, and to enhance caffeine permeability across porcine buccal mucosa. There are also several reports of the enhancing effect of Azone on the permeability of compounds through oral mucosa. Further, chitosan, a biocompatible and biodegradable polymer, has been shown to enhance drug delivery through various tissues, including the intestine and nasal mucosa.

[0043] Oral transmucosal drug delivery (OTDD) is the administration of pharmaceutically active agents through the oral mucosa to achieve systemic effects. OTDD continues to attract the attention of academic and industrial scientists. Despite limited characterization of the permeation pathways in the oral cavity compared with skin and nasal routes of delivery, recent advances in our understanding of the extent to which ionized molecules permeate theAttorney Docket No.148570-006300 buccal epithelium, as well as the emergence of new analytical techniques to study the oral cavity, and the progressing development of in silico models predictive of buccal and sublingual permeation, prospects are encouraging.

[0044] In order to deliver broader classes of drugs across the buccal mucosa, reversible methods of reducing the barrier potential of this tissue should be employed. This requisite has fostered the study of penetration enhancers that will safely alter the permeability restrictions of the buccal mucosa. It has been shown that buccal penetration 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 the drug permeation enhancement, bile salts are the most common.

[0045] In vitro studies on enhancing effect of bile salts on the buccal permeation of compounds show the effects of buccal epithelial permeability of dihydroxy bile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC) and tri-hydroxy bile salts, sodium glycocholate (GC) and sodium taurocholate (TC) at 100 mM concentration including permeability changes correlated with the histological effects. Fluorescein isothiocyanate (FITC), morphine sulfate will each be used as the model compound.

[0046] Chitosan has also been shown to promote absorption of small polar molecules and peptide / protein drugs through nasal mucosa in animal models and human volunteers. Other studies have shown an enhancing effect on penetration of compounds across the intestinal mucosa and cultured Caco-2 cells.

[0047] The permeation enhancer can be a phytoextract. A phytoextract can be an essential oil or composition including essential oils extracted by distillation of the plant material. In certain circumstances, the phytoextract can include synthetic analogues of the compounds extracted from the plant material (i.e., compounds made by organic synthesis).

[0048] Suitable permeation enhancers include natural or synthetic bile salts such as sodium fusidate; glycocholate or deoxycholate and their salts; fatty acids and derivatives such as sodium laurate, oleic acid, oleyl alcohol, monoolein, or palmitoylcamitine; chelators such as disodium EDTA, sodium citrate and sodium laurylsulfate, axone, sodium cholate, sodium 5- methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth-9, polysorbates, sterols, or glycerides, such as caprylocaproyl polyoxylglycerides, e.g.,Attorney Docket No.148570-006300 Labrasol. The permeation enhancer can include phytoextract derivatives and / or monolignols. The permeation enhancer can also be a fungal extract.

[0049] Fatty acids can be used as inactive ingredients in drug preparations or drug vehicles. Fatty acids can also be used as formulation ingredients due to their certain functional effects and their biocompatible nature. Fatty acids, both free and as part of complex lipids, are major metabolic fuel (storage and transport energy), essential components of all membranes and gene regulators. There are two families of essential fatty acids that are metabolized in the human body: -3 and -6 polyunsaturated fatty acids (PUFAs). If the first double bond is found between the third and the fourth carbon atom from the co carbon, they are called -3 fatty acids. If the first double bond is between the sixth and seventh carbon atom, they are called - 6 fatty acids. PUFAs are further metabolized in the body by the addition of carbon atoms and by desaturation (extraction of hydrogen). Linoleic acid, which is a -6 fatty acid, is metabolized to y-linolenic acid, dihomo-y-linolinic acid, arachidonic acid, adrenic acid, tetracosatetraenoic acid, tetracosapentaenoic acid and docosapentaenoic acid. a-linolenic acid, which is a -3 fatty acid is metabolized to octadecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid and docosahexaenoic acid (DHA).

[0050] Fatty acids, such as palmitic acid, oleic acid, linoleic acid and eicosapentaenoic acid, induced relaxation and hyperpolarization of porcine coronary artery smooth muscle cells via a mechanism involving activation of the Na+K+-ATPase pump and the fatty acids with increasing degrees of cis-unsaturation had higher potencies. Interestingly, the pulmonary vascular response to arachidonic acid, a metabolite of linoleic acid, can be either vasoconstrictive or vasodilative, depending on the dose, animal species, the mode of arachidonic acid administration, and the tones of the pulmonary circulation. For example, arachidonic acid has been reported to cause cyclooxygenase-dependent and independent pulmonary vasodilation.

[0051] The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are a target of catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline). Epinephrine (adrenaline) interacts with both - and - adrenoceptors, causing vasoconstriction and vasodilation, respectively. Although receptors are less sensitive to epinephrine, when activated, they override the vasodilation mediated byAttorney Docket No.148570-006300 -adrenoceptors because there are more peripheral 1 receptors than -adrenoceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. At lower levels of circulating epinephrine, -adrenoceptor stimulation dominates, producing vasodilation followed by decrease of peripheral vascular resistance. The 1-adrenoreceptor is known for smooth muscle contraction, mydriasis, vasoconstriction in the skin, mucosa and abdominal vicera and sphincter contraction of the gastrointestinal (GI) tract and urinary bladder. The 1- adrenergic receptors are member of the Gqprotein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, Gq, activates phospholipase C (PLC). The mechanism of action involves interaction with calcium channels and changing the calcium content in a cell. Many cells possess these receptors.

[0052] 1-adrenergic receptors can be a main receptor for fatty acids. For example, saw palmetto extract (SPE), widely used for the treatment of benign prostatic hyperplasia (BPH), has been reported to bind al-adrenergic, muscarinic and 1,4-dihydropyridine (1,4-DHP) calcium channel antagonist receptors. SPE includes a variety of fatty acids including lauric acid, oleic acid, myristic acid, palmitic acid and linoleic acid. Laurie acid and oleic acid can bind noncompetitively to al -adrenergic, muscarinic and 1,4-DHP calcium channel antagonist receptors.

[0053] In certain embodiments, a permeation enhancer can be an adrenergic receptor interacter. An adrenergic receptor interacter refers to a compound or substance that modifies and / or otherwise alters the action of an adrenergic receptor. For example, an adrenergic receptor interacter can prevent stimulation of the receptor by increasing or decreasing their ability to bind. Such interacters can be provided in either short-acting or long-acting forms. Certain short-acting interacters can work quickly, but their effects last only a few hours. Certain long-acting interacters can take longer to work, but their effects can last longer. The interacter can be selected and / or designed based on, e.g., one or more of the desired delivery and dose, active pharmaceutical ingredient, permeation modifier, permeation enhancer, matrix, and the condition being treated. An adrenergic receptor interacter can be an adrenergic receptor blocker. The adrenergic receptor interacter can be a terpene (e.g. volatile unsaturated hydrocarbons found in the essential oils of plants, derived from units of isoprenes) or a C3- C22 alcohol or acid, preferably a C7-C18 alcohol or acid. In certain embodiments, the adrenergic receptor interacter can include farnesol, linoleic acid, arachidonic acid, docosahexanoic acid, eicosapentanoic acid, and / or docosapentanoic acid. The acid can be aAttorney Docket No.148570-006300 carboxylic acid, phosphoric acid, sulfuric acid, hydroxamic acid, or derivatives thereof. The derivative can be an ester or amide. For example, the adrenergic receptor interacter can be a fatty acid or fatty alcohol.

[0054] The C3-C22 alcohol or acid can be an alcohol or acid having a straight 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; said hydrocarbon chain being optionally substituted with C.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C1-4 alkoxy, hydroxyl, halo, amino, nitro, cyano, C3-5 cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C3-5 alkylcarbonyloxy, C1-4 alkyloxycarbonyl, C1-4 alkylcarbonyl, or formyl; and further being optionally interrupted by -O-, -N(Ra)-, -N(Ra)-C(O)-O, -O-C(O)-N(Ra), N(Ra)-C(O)-N(Rb)-, or -O-C(O)-O-. Each of Raand Rb, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.

[0055] Fatty acids with a higher degree of unsaturation are effective candidates to enhance the permeation of drugs. Unsaturated fatty acids showed higher enhancement than saturated fatty acids, and the enhancement increased with the number of double bonds. Position of double bond also affects the enhancing activity of fatty acids. Differences in the physicochemical properties of fatty acid which originate from differences in the double bond position most likely determine the efficacy of these compounds as skin penetration enhancers. Skin distribution increases as the position of the double bond is shifted towards the hydrophilic end. It has also been reported that fatty acid which has a double bond at an even number position more rapidly effects the perturbation of the structure of both the stratum corneum and the dermis than a fatty acid which has double bond at an odd number position. Cis-unsaturation in the chain can tend to increase activity.

[0056] An adrenergic receptor interacter can be a terpene. Hypotensive activity of terpenes in essential oils has been reported. In certain embodiments, the permeation enhancer can be a sesquiterpene. Sesquiterpenes are a class of terpenes that consist of three isoprene units and have the empirical formula CI5H24. Like monoterpenes, sesquiterpenes may be acyclic or contain rings, including many unique combinations. Biochemical modifications such as oxidation or rearrangement produce the related sesquiterpenoids.Attorney Docket No.148570-006300

[0057] An adrenergic receptor interacter can be an unsaturated fatty acid such as linoleic acid. In certain embodiments, the permeation enhancer can be farnesol. Farnesol is a 15- carbon organic compound which is an acyclic sesquiterpene alcohol, which is a natural dephosphorylated form of farnesyl pyrophosphate. Under standard conditions, it is a colorless liquid. It is hydrophobic, and thus insoluble in water, but miscible with oils. Farnesol can be extracted from oils of plants such as citronella, neroli, cyclamen, and tuberose. It is an intermediate step in the biological synthesis of cholesterol from mevalonic acid in vertebrates. It has a delicate floral or weak citrus-lime odor and is used in perfumes and flavors. Farnesol selectively kills acute myeloid leukemia blasts and leukemic cell lines in preference to primary hemopoietic cells. Vasoactive properties of farnesyl analogues have been reported. Both Farnesol and N-acetyl-S-trans, trans-farnesyl-L-cysteine (AFC), a synthetic mimic of the carboxyl terminus of farnesylated proteins inhibited vasoconstriction in rat aortic rings.

[0058] The pharmaceutical composition can be a chewable or gelatin-based dosage form, spray, gum, gel, cream, tablet, liquid or film. The composition can include textures, for example, at the surface, such as microneedles or micro-protrusions. Recently, the use of micron-scale needles in increasing skin permeability has been shown to significantly increase transdermal delivery, including and especially for macromolecules. Most drug delivery studies have emphasized solid microneedles, which have been shown to increase skin permeability to a broad range of molecules and nanoparticles in vitro. In vivo studies have demonstrated delivery of oligonucleotides, reduction of blood glucose level by insulin, and induction of immune responses from protein and DNA vaccines. For such studies, needle arrays have been used to pierce holes into skin to increase transport by diffusion or iontophoresis or as drug carriers that release drug into the skin from a microneedle surface coating. Hollow microneedles have also been developed and shown to microinject insulin to diabetic rats. To address practical applications of microneedles, the ratio of microneedle fracture force to skin insertion force (i.e. margin of safety) is found to be optimal for needles with small tip radius and large wall thickness. Microneedles inserted into the skin of human subjects can be reported as painless. Together, these results suggest that microneedles represent a promising technology to deliver therapeutic compounds into the skin for a range of possible applications. Using the tools of the microelectronics industry, microneedles have been fabricated with a range of sizes, shapes and materials. Microneedles can be, for example,Attorney Docket No.148570-006300 polymeric, microscopic needles that deliver encapsulated drugs in a minimally invasive manner, but other suitable materials can be used.

[0059] The term "film" can include films and sheets, in any shape, including rectangular, square, or other desired shape. A film can be any desired thickness and size. In preferred embodiments, a film can have a thickness and size such that it can be administered to a user, for example, placed into the oral cavity of the user. A film can have a relatively thin thickness of from about 0.0025 mm to about 0.250 mm, or a film can have a somewhat thicker thickness of from about 0.250 mm to about 1.0 mm. For some films, the thickness may be even larger, i.e., greater than about 1.0 mm or thinner, i.e., less than about 0.0025 mm. A film can be a single layer or a film can be multi-layered, including laminated or multiple cast films. A permeation enhancer and pharmaceutically active component can be combined in a single layer, each contained in separate layers, or can each be otherwise contained in discrete regions of the same dosage form. In certain embodiments, the pharmaceutically active component contained in the polymeric matrix can be dispersed in the matrix. In certain embodiments, the permeation enhancer being contained in the polymeric matrix can be dispersed in the matrix.

[0060] Oral dissolving films can fall into three main classes: fast dissolving, moderate dissolving and slow dissolving. Oral dissolving films can also include a combination of any of the above categories. Fast dissolving films can dissolve in about 1 second to about 30 seconds in the mouth, including more than I second, more than 5 seconds, more than 10 seconds, more than 20 seconds, and less than 30 seconds. Moderate dissolving films can dissolve in about I to about 30 minutes in the mouth including more than l minute, more than 5 minutes, more than 10 minutes, more than 20 minutes or less than 30 minutes, and slow dissolving films can dissolve in more than 30 minutes in the mouth. As a general trend, fast dissolving films can include (or consist of) low molecular weight hydrophilic polymers (e.g., polymers having a molecular weight between about 1,000 to 9,000 daltons, or polymers having a molecular weight up to 200,000 daltons). In contrast, slow dissolving films generally include high molecular weight polymers (e.g., having a molecular weight in millions). Moderate dissolving films can tend to fall in between the fast and slow dissolving films.

[0061] It can be preferable to use films that are moderate dissolving films. Moderate dissolving films can dissolve rather quickly, but also have a good level of mucoadhesion.Attorney Docket No.148570-006300 Moderate dissolving films can also be flexible, quickly wettable, and are typically non- irritating to the user. Such moderate dissolving films can provide a quick enough dissolution rate, most desirably between about 1 minute and about 20 minutes, while providing an acceptable mucoadhesion level such that the film is not easily removable once it is placed in the oral cavity of the user. This can ensure delivery of a pharmaceutically active component to a user.

[0062] A pharmaceutical composition can include one or more pharmaceutically active components. The pharmaceutically active component can be a single pharmaceutical component or a combination of pharmaceutical components. The pharmaceutically active component can be an anti-inflammatory analgesic agent, a steroidal anti-inflammatory agent, an antihistamine, a local anesthetic, a bactericide, a disinfectant, a vasoconstrictor, a hemostatic, a chemotherapeutic drug, an antibiotic, a keratolytic, a cauterizing agent, an antiviral drug, an antirheumatic, an antihypertensive, a bronchodilator, an anticholinergic, an anti-anxiety drug, an antiemetic compound, a hormone, a peptide, a protein or a vaccine. The pharmaceutically active component can be the compound, pharmaceutically acceptable salt of a drug, a prodrug, a derivative, a drug complex or analog of a drug. The term "prodrug" refers to a biologically inactive compound that can be metabolized in the body to produce a biologically active drug or the "prodrug" can be a biologically active compound where in addition to its inherent biological activity can be metabolized to another or even preferred biologically active drug. In certain embodiments, the prodrug can have its own biological activity that can be similar to or different from the active drug. For example, the prodrug can be an ester of epinephrine, for example, dipivefrin which is hydrolysed into epinephrine. The prodrug can be a prodrug of benzodiazepines such as avizafone, which is a prodrug of olanzapine. Another prodrug from the benzodiazepine chemical series, and within the scope of this invention, is ethyl loflazepate. Chemical derivatives, analogs or prodrugs of all benzodiazepines are all considered within the scope of this invention.

[0063] In some embodiments, more than one pharmaceutically active component may be included in the film. The pharmaceutically active components can be ace-inhibitors, anti- anginal drugs, anti-arrhyttunias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations,Attorney Docket No.148570-006300 amphetamines, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplastics, anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants, blood modifiers, bone metabolism regulators, cardiovascular agents, central nervous system stimulates, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis management agents, enzymes, erectile dysfunction therapies, fertility agents, gastrointestinal agents, homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments, muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives, smoking cessation aids, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anti- coagulants, anti- thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, antispasmodics, uterine relaxants, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs, diagnostic agents, imaging agents, dyes, or tracers, and combinations thereof.

[0064] For example, the pharmaceutically active component can be buprenorphine, naloxone, acetaminophen, riluzole, clobazam, Rizatriptan, propofol, methyl salicylate, monoglycol salicylate, aspirin, mefenarnic acid, flufenamic acid, indomethacin, diclofenac, aiclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac, fenclofenac, clidanac, flurbiprofen, fentiazac, bufexamac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, tiaramide hydrochloride, hydrocortisone, predonisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, predonisolone acetate, methylpredonisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumetasone, fluorometholone, beclomethasone diproprionate, fluocinonide,Attorney Docket No.148570-006300 diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chiorpheniramine hydrochloride, chlorpheniramine maleate isothipendyi hydrochloride, 10 tripelennamine hydrochloride, promethazine hydrochloride, methdilazine hydrochloride dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p- buthylaminobenzoic acid 2-(die-ethylamino) ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dyclonine, dyclonine hydrochloride, thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone iodide, cetylpyridinium chloride, eugenol, trimethylarnmonium bromide, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbaxochrome sodium sultanate, 20 rutin, hesperidin, sulfamine, sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole, sulfisomidine, sulfamethizole, nitrofurazone, penicillin, meticillin, oxacillin, cefalotin, cefalordin, erythromcycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, salicylic acid, podophyllum resin, podolifox, cantharidin, chloroacetic acids, silver nitrate, protease inhibitors, thymadine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, attachment and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir, heparin, insulin, LHRH, TRH, interferons, oligonuclides, calcitonin, octreotide, omeprazone, fluoxetine, ethinylestradiol, amiodipine, paroxetine, enalapril, lisinopril, leuprolide, prevastatin, lovastatin, norethindrone, risperidone, olanzapine, albuterol, hydrochlorothiazide, pseudoephridrine, warfarin, terazosin, cisapride, ipratropium, busprione, methylphenidate, levothyroxine, zolpidem, levonorgestrel, glyburide, benazepril, medroxyprogesterone, clonazepam, ondansetron, losartan, quinapril, nitroglycerin, midazolam versed, cetirizine, doxazosin, glipizide, vaccine hepatitis B, salmeterol, sumatriptan, triamcinolone acetonide, goserelin, beclomethasone, granisteron, desogestrel, alprazolam, estradiol, nicotine, interferon beta IA, cromolyn, fosinopril, digoxin, fluticasone, bisoprolol, calcitril, captorpril, butorphanol, clonidine, premarin, testosterone, sumatriptan, clotrimazole, bisacodyl, dextromethorphan, nitroglycerine, nafarelin, dinoprostone, nicotine, bisacodyl, goserelin, or granisetron. In certain embodiments, the pharmaceutically activeAttorney Docket No.148570-006300 component can be epinephrine, a benzodiazepine such as olanzapine or lorazepam or alprazolarn.

[0065] Olanzapine

[0066] In one embodiment, a self-supporting individual film dosage form containing olanzapine has a substantially equivalent pharmacokinetic profile to that of an olanzapine tablet or gel. Olanzapine or its salts can be present in the individual film dosage form in an amount of from about 0.5 mg to about 100 mg per dosage, for example, at a 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 7.5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg dosage including greater than 1 mg, more than 5 mg, more than 20 mg, more than 30 mg, more than 40 mg, more than 50 mg, more than 60 mg, more than 70 mg, more than 80 mg, more than 90 mg, or less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, or less than 5 mg, or any combination thereof. About 20% to about 60%, about 30% to about 50%, about 30%, about 40%, about 50%, about 60%, or about 70% less olanzapine may be required in the self- supporting film dosage unit than in the corresponding oral tablet to achieve substantially equivalent Cmax, AUC, and Tmax values, i.e., within the range of about 80% to about 125%, at a confidence level of at least about 80%.

[0067] The active agent in the present disclosure may be incorporated into the polymer matrix or film in a controlled release form. For example, particles of active may be coated with polymers such as ethyl cellulose or polymethacrylate, commercially available under brand names such as Aquacoat ECD and Eudragit E-100, respectively. Solutions of active may also be absorbed on such polymer materials and incorporated into the inventive films. Other components such as fats and waxes, as well as sweeteners and / or flavors may also be employed in such controlled release compositions. An anti-oxidant may also be added to the film to prevent the degradation of the active, especially where the active is oxidation sensitive, for example, photosensitive.

[0068] Cosmetic active agents may include breath freshening compounds like menthol, other flavors; such as mint, cherry, lemon lime, mixed berry, or grapefruit, or fragrances, especially those used for oral hygiene, as well as actives used in dental and oral cleansing such asAttorney Docket No.148570-006300 quaternary ammonium bases. The effect of flavors may be enhanced using flavor enhancers like tartaric acid, vanillin, or the like.

[0069] As disclosed in U.S. Patent Publication No. 2017 / 0035689, which is incorporated by reference herein in its entirety, when the dosage form includes at least one antagonist in addition to the agonist, it may be desired to control the release of the antagonist, so as to minimize or wholly prevent the absorption of the antagonist from the dosage form when taken orally. In this fashion, the antagonist may be released faster and a larger proportion of it may be present as the ionized form in solution, thereby lessening the likelihood of its absorption in the body. In a dosage form that is placed in the oral cavity, the agonist may be absorbed buccally, so as to provide rapid absorption of the agonist into the body of the patient. At the same time, it may be desired to inhibit or reduce absorption of any antagonist buccally, thereby allowing the antagonist to be swallowed and destroyed in the stomach, or in some cases absorbed in the colon. It may be desired to reduce the absorption of the antagonist by chemical means, such as by controlling the local pH of the dosage form.

[0070] By controlling the local pH of the dosage form, the release and / or absorption of the active(s) therein may be controlled. For example, in a dosage that includes an amount of an agonist, the local pH may be controlled to a level that optimizes its release and / or absorption into the oral cavity of the patient. In dosages incorporating an agonist and an antagonist, the local pH may be controlled to a level that maximizes the release and / or oral absorption of the agonist while simultaneously minimizing the release and / or oral absorption of the antagonist. For example, the film dosage may include distinct regions, one region including an agonist and the other region including an antagonist, where the local pH of each region is optimized for the desired effect.

[0071] The dosage form for mucosal delivery may include a combination of an agonist (or partial agonist) and an antagonist. The film dosage form may include a combination of an agonist and an antagonist, while the dosage has a controlled local pH. The present disclosure is not limited to the use of any one particular agonist and / or antagonist. Any agonist (or partial agonist) and any antagonist may be incorporated herein. The agonist and optional antagonist should be selected from those agonists and antagonists that are useful in treating the particular symptom being treated. The dosage forms for mucosal delivery, including the inventive films discussed, may incorporate agonists and / or antagonists that are basic in nature. SuitableAttorney Docket No.148570-006300 agonists (and / or partial agonists) may include buprenorphine (pKa=8.42), sufentanil (pKa=8.0), morphine (pKa=8.0), fentanil (pKa=8.4), alfentanil (pKa=6.5), pethidine (pKa=8.7), apomorphine (pKa=8.9), alphaprodine (pKa=8.7), remifentanil (pKa=7.O), methadone (pKa=9.2), codeine (pKa=8.2), dihydrocodeine (pKa=9.4), morphine (pKa=8.0), oxycodone (pKa=8.53), oxymorphone (pKa=8.17), tramadol (pKa=9.41), or pharmaceutically acceptable salts thereof. Suitable antagonists (and / or partial antagonists) may include naloxone, maltrexone, nalorphine and levallorphan, or therapeutically acceptable salts thereof.

[0072] As discussed above, the local pH of the film is preferably controlled to provide the desired release and / or absorption of the agonist and antagonist. Suitable agonists may have a pKa of about 5 to about 9.5, and most preferably from about 8.0 to about 9.0. Suitable antagonists may have a pKa of about 6.0 to about 9.0, and most preferably about 7.0 to about 9.0. For example, naloxone has a pKa of about 7.94.

[0073] In one embodiment, the self-supporting film includes a polymer matrix, a therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof, and a buffer. The agonist may be a partial agonist, or an opioid agonist, such as buprenorphine. The buffer is preferably capable of providing a local pH of the composition within a range that provides a controllable level and desirably an optimal treatment level of absorption of the agonist. For example, it may be desired to provide an absorption of buprenorphine that is bioequivalent to a Suboxone® tablet.

[0074] Certain agonists, such as buprenorphine, are capable of being suitably absorbed when the local pH of the film composition is either between about 3 to about 4 or between about 5 to about 9. Thus, the local pH for the film including the agonist may be either from about 3 to about 4 or from about 5 to about 9. To provide a maximum absorption of buprenorphine, for example, the local pH of the film may be about 5.5. To provide an absorption of buprenorphine that is bioequivalent to the Suboxone® tablet, the local pH of the film may be about 6 to about 7. The resulting dosage is a film that allows for a rapid and effective release of the agonist (such as buprenorphine) into the oral cavity of the user. At the same time, the film desirably has a sufficient adhesion profile, such that the film cannot easily be removed, or cannot be removed at all, from the oral cavity of the user once it has been placed into the cavity. Full release of the agonist may take place within less than about thirty minutes, e.g.,Attorney Docket No.148570-006300 within about 10 minutes to about 30 minutes and preferably remains in the oral cavity for at least 1 minute and desirably about 1 to about 30 minutes.

[0075] It may be desirable to combine the opioid agonist (or partial agonist) in the film composition with an opioid antagonist or a pharmaceutically acceptable salt thereof. The agonist and antagonist may be dispersed throughout the dosage separately or the agonist and antagonist may be separately dispersed in individual film regions. Most desirably the antagonist includes naloxone, but any suitable antagonist may be selected as desired. The antagonist may optionally be water-soluble, so as to render separation of the antagonist and agonist difficult, thereby lessening the potential for diversion abuse of the agonist.

[0076] As with a film including an agonist, a film including an agonist and an antagonist is desirably pH-controlled through the inclusion of a buffer. At the desired local pH level of the agonist and the antagonist, optimal absorption of the agonist may be achieved while the absorption of the antagonist may be greatly inhibited.

[0077] The film may contain any desired level of self-supporting film forming polymer, such that a self-supporting film composition is provided. In one embodiment, the film contains a polymer matrix in an amount of at least about 25% by weight of the film composition. The polymer matrix may be present in an amount of at least about 50% by weight of the film composition, or in a range of about 25% to about 75%, or about 30% to about 50% by weight of the film composition.

[0078] Any desired level of agonist and optional antagonist may be included in the dosage, so as to provide the desired therapeutic effect. In certain embodiments, the film composition. includes about 2 mg to about 16 mg, or about 4 mg to about 12 mg, of agonist per dosage. The film composition may include about 0.5 mg to about 5 mg, or about 1 mg to about 3 mg of antagonist per dosage. If an antagonist is incorporated into the film, the film composition may include the antagonist in a ratio of about 6:1-2:1 agonist to antagonist. Most desirably, the film composition contains about 4:1 agonist to antagonist per dosage. For example, in one embodiment, the dosage includes an agonist in an amount of about 12 mg, and includes an antagonist in an amount of about 3 mg.

[0079] The film may include at least one buffer so as to control the local pH of the film. Any desired level of buffer may be incorporated into the film so as to provide the desired local pHAttorney Docket No.148570-006300 level. The buffer is preferably provided in an amount sufficient to control the release from the film and / or the absorption into the body of the agonist and the optional antagonist. In a desired embodiment, the film includes buffer in a ratio of buffer to agonist in an amount of from about 2:1 to about 1:5 (buffer:agonist). The buffer may alternatively be provided in a 1:1 ratio of buffer to agonist. A film including an antagonist preferably has a local pH of about 2 to about 4. Any buffer may be used as desired. In some embodiments, the buffer may include Sodium citrate, citric acid. Succinic acid, malic acid, phosphoric acid, boric acid, and combinations thereof. The buffer may include a buffering system including a combination of components, such as Citric Acid / Sodium Citrate, Succinic Acid / Monosodium Succinate, Glycine / Sodium Glycine, Malic Acid / Sodium Malate, Phosphoric Acid / Sodium Phosphate, Fumaric Acid / Sodium Fumarate, Monosodium Phosphate / Disodium Phosphate, and Boric Acid / Sodium Borate.

[0080] In this embodiment, the film includes a polymer matrix, an agonist, and an optional antagonist, while the film has a controlled local pH to the level desired. The buffer is desirably present in an amount to provide a therapeutically adequate absorption of the agonist, while simultaneously limiting or preventing substantial absorption of the antagonist. Controlling of the local pH allows for the desired release and / or absorption of the components, and thus provides a more useful and effective dosage.

[0081] The film dosage composition may include a polymer matrix, a therapeutically effective amount of agonist, a therapeutically effective amount of antagonist, and a buffering system. A "therapeutically effective amount" of an antagonist is intended to refer to an amount of the antagonist that is useful in diverting abuse of the agonist by a patient. The buffering system may include a buffer in addition to a solvent. The buffering system desirably includes a sufficient level of buffer so as to provide a desired local pH level of the film.

[0082] Biological macromolecule actives fall into four major classes: proteins (including amino acids and enzymes), carbohydrates, nucleic acids (e.g., DNA and RNA, including nucleosides and nucleotides), and lipids. The biological macromolecule active used herein may be a protein, macromolecular carbohydrate, glycoprotein, proteoglycan, lignin, biological poly-acid, or a nucleic acid. The protein may be an enzyme such as an apoenzyme or an isoenzyme.Attorney Docket No.148570-006300

[0083] The biological macromolecule active may be synthetic or semi-synthetic. The biological macromolecule active may be or a natural product. Isolated biological macromolecules may be used, for example, in identifying genetic defects, diagnosing diseases, development of new drugs or treatments, and studying gene expression. Purified nucleic acids are derived from biological material samples, such as whole blood, plasma, blood serum, urine, feces, saliva, sperm, tissue, cells, and other body fluids, materials, or plant tissue.

[0084] The biological macromolecule active used in the films disclosed herein may be any FDA-approved biologic drug, such as, but not limited to: abciximab (ReoPro), alteplase (Cathflo Activase, Activase), reteplase (Retavase), tenecteplase (TNKase), abobotulinumtoxinA (Dysport), onabotulinumtoxinA (Botox), incobotulinumtoxinA (Xeomin), anakinra (Kineret), rimabotulinumtoxinB (Myobloc), follitropin alpha (Gonal f), abobotulinumtoxinA (Dysport), onabotulinumtoxinA (Botox), collagenase (Santyl), ecallantide (Kalbitor), incobotulinumtoxinA (Xeomin), collagenase clostridium histolyticum (Xiaflex), aflibercept (Eylea), ranibizumab (Lucentis), incobotulinumtoxinA (Xeomin), ocriplasmin (Jetrea), bevacizumab (Avastin), pegaptanib (Macugen), abatacept (Orencia), adalimumab (Humira), adalimumab-atto (Amjevita), certolizumab pegol (Cimzia), etanercept (Enbrel), etanercept-szzs (Erelzi), golimumab (Simponi), golimumab injection (Simponi Aria), infliximab (Remicade), infliximab-dyyb (Inflectra), secukinumab (Cosentyx), tocilizumab (Actemra), ustekinumab (Stelara), anakinra (Kineret), canakinumab (Ilaris), golimumab injection (Simponi Aria), infliximab (Remicade), infliximab-dyyb (Inflectra), rituximab (rituxan), tocilizumab (Actemra), ustekinumab (Stelara), interferon beta-lb (Betaseron), interferon beta-lb (Extavia), daclizumab (Zenapax), daclizumab (Zinbryta), interferon beta-la (Avonex), natalizumab (Tysabri), interferon beta-la (Rebif), peginterferon beta-la (Plegridy), ixekizumab (Taltz), brodalumab (Siliq), Rilonacept (Arcalyst), belimumab (Benlysta), interferon gamma-lb (Actimmune), asparaginase (Elspar), asparaginase erwinia chrysanthemi (Erwinaze), blinatumomab (Blincyto), interferon alfa-2b (Intron A), obinutuzumab (Gazyva), ofatumumab (Arzerra), pegaspargase (Oncaspar), sargramostim (Leukine), nivolumab (Opdivo), brentuximab vedotin (Adcetris), ibritumomab tiuxetan (Zevalin), rituximab (Rituxan), ado-trastuzumab emtansine (Kadcyla), pertuzumab (Perjeta), trastuzumab (Herceptin), aldesleukin (Proleukin), daratumumab (Darzalex), elotuzumab (Empliciti), pembrolizumab (Keytruda), ipilimumab (Yervoy), atezolizumab (Tecentriq),Attorney Docket No.148570-006300 cetuximab (Erbitux), necitumumab (Portrazza), nivolumab (Opdivo), ramucirumab (Cyramza), cetuximab (Erbitux), panitumumab (Vectibix), ziv-aflibercept (Zaltrap), capromab pendetide (ProstaScint), trastuzumab (Herceptin), bevacizumab (Avastin), olaratumab (Lartruvo), elosulfase alfa (Vimizim), idursulfase (Elaprase), iaronidase (Aldurazyme), asfotase alfa (Strensiq), pegloticase (Krystexxa), hypercholesterolemia, alirocumab (Praluent), evolocumab (Repatha), albiglutide (Tanzeum), dulaglutide (Trulicity), becaplermin (Regranex), agalsidase beta (Fabrazyme), alglucosidase alfa (Myozyme, Lumizyme), canakinumab (Ilaris), galsulfase (Naglazyme), metreleptin (Myalept), rasburicase (Elitek), sebelipase alfa (Kanuma), parathyroid hormone (Natpara), bezlotoxumab (Zinplava), interferon alfa-n3 (Alferon N Injection), peginterferon alfa-2a (Pegasys), peginterferon alfa-2b (Peglntron, Sylatron), palivizumab (Synagis), siltuximab (Sylvant), pegfilgrastim (Neulasta), epoetin alfa (Epogen / Procrit), methoxy polyethylene glycol-epoetin beta (Mircera), basiliximab (Simulect), belatacept (Nulojix), palifermin (Kepivance), eculizumab (Soliris), oprelvekin (Neumega), romiplostim (Nplate), glucarpidase (Voraxaze), idarucizumab (Praxbind), obiltoxaximab (Anthim), Raxibacumab, dornase alfa (Pulmozyme), mepolizumab (Nucala), reslizumab (Cinqair), and omalizumab (Xolair).

[0085] Other suitable actives for use herein are disclosed in U.S. Patent Publication No. 2015 / 0190476, which is incorporated by reference herein in its entirety.

[0086] Pharmacokinetic Profile

[0087] A pharmacokinetic profile is the measure of the movement of a pharmaceutical active into, through, and out of the body, including the time course of its absorption, bioavailability, distribution, metabolism, and excretion. Means of measuring the pharmacokinetic profile include Cmax, AUC and Tmax. Cmax or "Cmax" as used herein means the maximum observed plasma concentration. Tmax or "Tmax" as used herein means the time point of maximum observed plasma concentration. Tmax is the time at which Cmax is attained.

[0088] The term "AUC" as used herein means "area under the curve" in a plot of concentration of drug in plasma versus time. AUC is usually given for the time interval zero to infinity (AUCinf), however, clearly plasma drug concentrations cannot be measured ‘to infinity’ for a patient so mathematical approaches are used to estimate the AUC from a limited number of concentration measurements (AUCt). In a practical sense, the AUC (from zero toAttorney Docket No.148570-006300 infinity) represents the total amount of drug absorbed by the body, irrespective of the rate of absorption. This is useful when trying to determine whether two formulations of the same dose release the same dose of drug to the body. The AUC of a transmucosal dosage form compared to that of the same dosage administered intravenously serves as the basis for a measurement of bioavailability.

[0089] A pharmacokinetic profile of two dosage forms containing the same active that is "substantially equivalent" as used herein means that the relative mean Cmax and AUC between the two is within about 75% to about 130% at a confidence level of at least about 80% or greater.

[0090] In an embodiment, the pharmacokinetic profile of the film dosage form (pKPfilm) is about 80% to about 125%, or about 90% to about 115% of the pharmacokinetic profile of the corresponding enterally delivered dosage form (pKPingestible) at a confidence level of at least about 80%, at least about 70%, or at least about 60%. In another embodiment, the pharmacokinetic profile of the film dosage form (pKPfilm) is about 95% to about 110% of the pharmacokinetic profile of the corresponding enterally delivered dosage form (pKPIngestible) at a confidence level of at least about 80%, at least about 70%, or at least about 60%.

[0091] When the active is a small molecule, one or both of the AUC and Cmax of the self- supporting film dosage form is about 75% to about 130%, about 80% to about 130%, about 80% to about 125%, about 85% to about 120%, about 90% to about 115%, about 90% to about 110%, or about 95% to about 110%, at a confidence level of at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98%, of the AUC and / or Cmax of the corresponding enterally delivered dosage form. When the active is a small molecule, the Tmax of the self-supporting film dosage form is about 75% to about 130%, about 80% to about 130%, about 80% to about 125%, about 85% to about 120%, about 90% to about 115%, about 90% to about 110%, or about 95% to about 110%, at a confidence level of at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98%, of the Tmax of the corresponding enterally delivered dosage form. For example, the AUC of the self-supporting film dosage form is about 80% to about 125%, at a confidence level of at least about 80%, of the AUC of the corresponding enterally delivered dosage form, and / or theAttorney Docket No.148570-006300 Cmax of the self-supporting film dosage form is about 80% to about 125%, at a confidence level of at least about 80%, of the Cmax of the corresponding enterally delivered dosage form, and / or the Tmax of the self-supporting film dosage form is about 80% to about 125%, at a confidence level of at least about 80%, of the Tmax of the corresponding enterally delivered dosage form.

[0092] When the active is a biological macromolecule, one or both of the AUC and Cmax of the self-supporting film dosage form is about 80% to about 125%, about 85% to about 120%, about 90% to about 115%, about 90% to about 110%, or about 95% to about 110%, at a confidence level of at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98%, of the AUC and Cmax of the corresponding intravenously delivered dosage form. When the active is a biological macromolecule, the Tmax of the self-supporting film dosage form is about 75% to about 130%, about 80% to about 130%, about 80% to about 125%, about 85% to about 120%, about 90% to about 115%, about 90% to about 110%, or about 95% to about 110%, at a confidence level of at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98%, of the Tmax of the corresponding intravenously delivered dosage form. For example, the AUC of the self-supporting film dosage form is about 80% to about 125%, at a confidence level of at least about 80%, of the AUC of the corresponding intravenously delivered dosage form, and / or the Cmax of the self- supporting film dosage form is about 80% to about 125%, at a confidence level of at least about 80%, of the Cmax of the corresponding intravenously delivered dosage form, and / or the Tmax of the self-supporting film dosage form is about 80% to about 125%, at a confidence level of at least about 80%, of the Tmax of the corresponding intravenously delivered dosage form.

[0093] In another embodiment, the pharmacokinetic profile of the film dosage form (pKPfilm) is about 80% to about 125%, or about 90% to about 115% of the pharmacokinetic profile of the corresponding intravenously delivered dosage form (pKPingestible) at a confidence level of at least about 80%, at least about 70%, or at least about 60%. In another embodiment, the pharmacokinetic profile of the film dosage form (pKPfilm) is about 95% to about 110% of the pharmacokinetic profile of the corresponding intravenously delivered dosage form (pKPIngestible) at a confidence level of at least about 80%, at least about 70%, or at least about 60%.Attorney Docket No.148570-006300

[0094] In an embodiment, the pharmacokinetic profile of the film dosage form (pKPfilm) is about 80% to about 125%, or about 90% to about 115% of the pharmacokinetic profile of the corresponding enterally or parenterally delivered non-film dosage form (pKPIngestible) at a confidence level of at least about 80%, at least about 70%, or at least about 60%. In another embodiment, the pharmacokinetic profile of the film dosage form (pKPfilm) is about 95% to about 110% of the pharmacokinetic profile of the corresponding enterally or parenterally delivered non-film dosage form (pKPingestible) at a confidence level of at least about 80%, at least about 70%, or at least about 60%.

[0095] When the active is a small molecule, one or both of the AUC and Cmax of the self- supporting film dosage form is about 75% to about 130%, about 80% to about 130%, about 80% to about 125%, about 85% to about 120%, about 90% to about 115%, about 90% to about 110%, or about 95% to about 110%, at a confidence level of at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98%, of the AUC and / or Cmax of the corresponding enterally or parenterally delivered non-film dosage form. When the active is a small molecule, the Tmax of the self- supporting film dosage form is about 75% to about 130%, about 80% to about 130%, about 80% to about 125%, about 85% to about 120%, about 90% to about 115%, about 90% to about 110%, or about 95% to about 110%, at a confidence level of at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98%, of the Tmax of the corresponding enterally or parenterally delivered non- film dosage form. For example, the AUC of the self-supporting film dosage form is about 80% to about 125%, at a confidence level of at least about 80%, of the AUC of the corresponding enterally or parenterally delivered non-film dosage form, and / or the Cmax of the self-supporting film dosage form is about 80% to about 125%, at a confidence level of at least about 80%, of the Cmax of the corresponding enterally or parenterally delivered non- film dosage form, and / or the Tmax of the self-supporting film dosage form is about 80% to about 125%, at a confidence level of at least about 80%, of the Tmax of the corresponding enterally or parenterally delivered non-film dosage form.

[0096] Penetration Enhancer

[0097] Any penetration enhancer known for use in the art may be incorporated into the dosage forms of the present disclosure. The term "penetration enhancer" is interchangeable with absorption enhancer. When delivered to the mouth via a film, a penetration enhancer isAttorney Docket No.148570-006300 a component that can improve the permeability of the pharmaceutical active through the mucosa and into the blood stream of the subject.

[0098] The penetration enhancer may a nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide. The penetration enhancer may be selected from the group consisting of a maltoside or maltoside derivative, a sucroside or sucroside derivative, and an essential oil or a component of an essential oil. The penetration enhancer may be selected from the group consisting of alkyl thiomaltoside, maltoside, maltotrioside, maltopyranoside, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, tetradecyl-P-D-maltoside, dodecyl-P-D-maltoside, tridecyl-P-D-maltoside, sucroside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate and combinations thereof.

[0099] The permeation enhancer can improve absorption rate and amount of the pharmaceutical active by more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%. more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 150%, about 200% or more, or less than 200%, less than 150%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or a combination of these ranges, depending on the other components in the composition.

[0100] In certain embodiments, the self-supporting film comprises a pharmaceutically acceptable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a mucosal delivery-enhancing agent selected from: (a) an aggregation inhibitory agent; (b) a charge-modifying agent; (c) a pH control agent; (d) a degradative enzyme inhibitory agent; (e) a mucolytic or mucus clearing agent; (f) a ciliostatic agent; (g) a membrane penetration-enhancing agent selected from: (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome, or carrier; (iii) an alcohol; (iv) an enamine; (v) an NO donor compound; (vi) a long chain amphipathic molecule; (vii) a small hydrophobic penetration enhancer; (viii) sodium or a salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or beta-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or salt thereof; (xiv) an N-acetylamino acid or salt thereof; (xv) an enzyme degradative to a selected membrane component; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterolAttorney Docket No.148570-006300 synthesis; and (xi) any combination of the membrane penetration enhancing agents recited in (i)-(x); (h) a modulatory agent of epithelial junction physiology; (i) a vasodilator agent; (j) a selective transport-enhancing agent; and (k) a stabilizing delivery vehicle, carrier, mucoadhesive, support or complex-forming species with which the compound is effectively combined, associated, contained, encapsulated or bound resulting in stabilization of the compound for enhanced transmucosal delivery, wherein the formulation of the compound with the transmucosal delivery-enhancing agents provides for increased bioavailability of the compound in blood plasma of a subject. Penetration enhancers have been described in J. Nicolazzo, et al., J. of Controlled Disease, 105 (2005) 1-15, which is incorporated by reference herein.

[0101] Surfactants and bile salts have been shown to enhance the permeability of various compounds across the buccal mucosa, both in vitro and in vivo. The data obtained from these studies strongly suggest that the enhancement in permeability is due to an effect of the surfactants on the mucosal intercellular lipids.

[0102] Fatty acids have been shown to enhance the permeation of a number of drugs through the skin, and this has been shown by differential scanning calorimetry and Fourier transform infrared spectroscopy to be related to an increase in the fluidity of intercellular lipids.

[0103] Additionally, pretreatment with ethanol has been shown to enhance the permeability of tritiated water and albumin across ventral tongue mucosa, and to enhance caffeine permeability across porcine buccal mucosa. There are also several reports of the enhancing effect of Azone RTM on the permeability of compounds through oral mucosa. Further, chitosan, a biocompatible and biodegradable polymer, has been shown to enhance drug delivery through various tissues, as including the intestine and nasal mucosa.

[0104] It has been shown that buccal penetration 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 the drug permeation enhancement, bile salts are the most common.

[0105] In vitro studies on enhancing effect of bile salts on the buccal permeation of compounds is discussed. Recent studies exist on the effects of buccal epithelial permeabilityAttorney Docket No.148570-006300 of dihydroxy bile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC) and tri-hydroxy bile salts, sodium glycocholate (GC) and sodium taurocholate (TC) at 100 mM concentration including permeability changes correlated with the histological effects. Fluorescein isothiocyanate (FITC), morphine sulfate can each be used as the model compound. Chitosan has also been shown to promote absorption of small polar molecules and peptide / protein drugs through nasal mucosa in animal models and human volunteers. Other studies have shown an enhancing effect on penetration of compounds across the intestinal mucosa and cultured Caco-2 cells.

[0106] The permeation enhancer can be a phytoextract. A phytoextract can be an essential oil or composition including essential oils extracted by distillation of the plant material. In certain circumstances, the phytoextract can include synthetic analogues of the compounds extracted from the plant material (i.e., compounds made by organic synthesis). The phytoextract can include a phenylpropanoid, for example, phenyl alanine, eugenol, eugenol acetate, a cinnamic acid, a cinnamic acid ester, a cinnamic aldehyde, a hydrocinnamic acid, chavicol, or safrole, or a combination thereof. The phytoextract can be an essential oil extract of a clove plant, for example, from the leaf, stem or flower bud of a clove plant. The clove plant can be Syzygium aromaticum. The phytoextract can include about 20 to about 95% eugenol, including about 40 to about 95% eugenol, including about 60 to about 95% eugenol, and for example, about 80-95% eugenol. The extract can also include about 5% to about 15% eugenol acetate. The extract can also include caryophyllene. The extract can also include up to about 2.1% -humulene. Other volatile compounds included in lower concentrations in clove essential oil can be P-pinene, limonene, farnesol, benzaldehyde, 2-heptanone or ethyl hexanoate. Other permeation enhancers may be added to the composition to improve absorption of the drug. Suitable permeation enhancers include natural or synthetic bile salts such as sodium fusidate; glycocholate or deoxycholate and their salts; fatty acids and derivatives such as sodium laurate, oleic acid, oleyl alcohol, monoolein, or palmitoylcarnitine; chelators such as disodium EDTA, sodium citrate and sodium lauryl sulfate, atone, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth-9, polysorbates, sterols, or glycerides, such as caprylocaproyl polyoxylglycerides, e.g., Labrasol. The permeation enhancer can include phytoextract derivatives and / or monolignols. The permeation enhancer can also be a fungal extract.Attorney Docket No.148570-006300

[0107] Some natural products of plant origin have been known to have a vasodilatory effect. Specifically, vasorelaxant effects of eugenol have been reported in a number of animal studies. Calcium channel blockade is suggested to be responsible for vascular relaxation induced by a plant essential oil, or its main constituent, eugenol.

[0108] Many studies have reported effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on vascular reactivity after being administered as ingestible forms. Some studies found that EPA-DHA or EPA alone suppressed the vasoconstrictive effect of norepinephrine or increased vasodilatory responses to acetylcholine in the forearm microcirculation. Another study found that both EPA and DHA increased systemic arterial compliance and tended to reduce pulse pressure and total vascular resistance. Meanwhile, a study found that DHA, but not EPA, enhanced vasodilator mechanisms and attenuates constrictor responses in forearm microcirculation in hyperlipidemic overweight men. Another study found vasodilator effects of DHA on the rhythmic contractions of isolated human coronary arteries in vitro.

[0109] In an embodiment, the film comprises a permeation enhancer that includes one or more of a phenylpropanoid, farnesol, Labrasol, and linoleic acid. In an embodiment, the permeation enhancer is a phenylpropanoid that is selected from the group consisting of: eugenol; eugenol acetate; a cinnamic acid; a cinnamic acid ester; a cinnamic aldehyde; a hydrocinnamic acid; chavicol; safrole; or a combination thereof.

[0110] In an embodiment, the film comprises a permeation enhancer that is a phytoextract. The phytoextract may be an essential oil extract of a clove plant, an essential oil extract of a leaf of a clove plant, an essential oil extract of a flower bud of a clove plant, an essential oil extract of a stem of a clove plant, or a combination thereof. In an embodiment, the phytoextract can be synthetic. The phytoextract may include about 20% to about 95% eugenol, about 40% to about 95% eugenol, about 60% to about 95% eugenol, or about 80% to about 95% eugenol.

[0111] Pharmaceutically Acceptable Film

[0112] Another embodiment is a pharmaceutically acceptable film for oral mucosal delivery of a pharmaceutical active comprising the pharmaceutical active and a water-soluble or water swellable film-forming polymer matrix. The terms used in this embodiment have the same meanings as defined above.Attorney Docket No.148570-006300

[0113] The pharmaceutical active may be a small molecule or biological macromolecule. In an embodiment, the pharmaceutical active is rizatriptan, or a salt, prodrug, derivative, analogue, or ester thereof, optionally in combination with an NSAID. In an embodiment, the pharmaceutical active is testosterone. In another embodiment, the pharmaceutical active is olanzapine, or a salt, prodrug, derivative, analogue, or ester thereof. In another embodiment, the pharmaceutical active is pregabalin (Lyrica), or a salt, prodrug, derivative, analogue, or ester thereof. In yet another embodiment, the pharmaceutical active is epinephrine, or a salt, prodrug, derivative, analogue, or ester thereof. In a further embodiment, the pharmaceutical active is sildenafil, or a salt, prodrug, derivative, analogue, or ester thereof. In a further embodiment, the pharmaceutical active is clobazam, or a salt, prodrug, derivative, analogue, or ester thereof. In a still further embodiment, the pharmaceutical active is riluzole, or a salt, prodrug, derivative, analogue, or ester thereof. In a further embodiment, the pharmaceutical active is apomorphine, or a salt, prodrug, derivative, analogue, or ester thereof. In yet another embodiment, the pharmaceutical active is buprenorphine, or a salt, prodrug, derivative, analogue, or ester thereof, optionally in combination with naloxone.

[0114] The polymer matrix may include a polyethylene oxide composition, water or a water-containing solvent, and silicon dioxide. The silicon dioxide may be present in about 0.02% to about 3%, about 0.02% to about 1%, about 0.1% to about 3%, about 0.1% to about 1%, about 0.05% to about 2%, about 1% to about 3%, about 0.5% to about 2%, or about 0.5% to about 1.5% by weight of the polymer matrix.

[0115] A "polyethylene oxide composition" as used herein refers to one or more than one polyethylene oxide, and optionally silicon dioxide. The polyethylene oxide composition may comprise one polyethylene oxide or a mixture of two, three, or four polyethylene oxides of different molecular weights. In an embodiment, the polymer matrix includes a polyethylene oxide composition of two polyethylene oxides. For example, a polyethylene oxide composition may contain a first polyethylene oxide having a molecular weight below 500,000, and a second polyethylene oxide having a molecular weight above 500,000. In an embodiment thereof, the first polyethylene oxide has a molecular weight of about 100,000, 200,000 or 300,000, and the second polyethylene oxide has a molecular weight of about 700,000, 800,000 or 900,000.Attorney Docket No.148570-006300

[0116] In an embodiment, the polymer matrix includes a polyethylene oxide composition of three polyethylene oxides. For example, a polyethylene oxide composition may contain a first polyethylene oxide having a molecular weight below 500,000, a second polyethylene oxide having a molecular weight above 500,000, and a third polyethylene oxide having a molecular weight below 500,000 but greater than the first polyethylene oxide. In an embodiment thereof, the first polyethylene oxide has a molecular weight of about 100,000, 200,000 or 300,000, the second polyethylene oxide has a molecular weight of about 700,000, 800,000 or 900,000, and the third polyethylene oxide has a molecular weight of about 200,000, 300,000 or 400,000.

[0117] In an embodiment thereof, the pharmaceutically acceptable film is an individual unit dosage form, each individual unit dosage form contains about 0.5% to about 50% less active than the corresponding enterally delivered dosage form, and, when it is administered to a patient, one or more of the AUC, Cmax or Tmax of the pharmaceutical active is about 80% to about 125% of the AUC, Cmax or Tmax, respectively, of the corresponding enterally delivered dosage form.

[0118] In another embodiment thereof, the pharmaceutically acceptable film is an individual unit dosage form, the active is a biological macromolecule, each individual unit dosage form contains about 10% to about 10,000% more active than the corresponding intravenously delivered dosage form, and, when it is administered to a patient, one or more of the AUC, Cmax or Tmax of the pharmaceutical active is about 80% to about 125% of the AUC, Cmax or Tmax, respectively, of the corresponding enterally delivered dosage form.

[0119] In another embodiment thereof, the pharmaceutically acceptable film is an individual unit dosage form, each individual unit dosage form contains about 0.5% to about 50% less active than the corresponding enterally or parenterally delivered non-film dosage form, and, when it is administered to a patient, one or more of the AUC, Cmax or Tmax of the pharmaceutical active is about 80% to about 125% of the AUC, Cmax or Tmax, respectively, of the corresponding enterally or parenterally delivered non-film dosage form.

[0120] One or more of the AUC, Cmax or Tmax of the pharmaceutical active may be about 80% to about 125%, about 90% to about 115%, or about 95% to about 110% of the AUC, Cmax or Tmax of the corresponding dosage form of a different administration and / or form at a confidence level of at least about 80%, at least about 70%, or at least about 60%.Attorney Docket No.148570-006300

[0121] Uses of Films

[0122] Another embodiment is a method of treating a patient comprising administering a self-supporting film or pharmaceutically acceptable film disclosed herein to the patient in need thereof. The terms used in this embodiment have the same meanings as defined above.

[0123] The films of the present invention are well suited for many uses. The high degree of desired active uniformity in the film makes them particularly well suited for incorporating pharmaceuticals. Furthermore, the polymers used in construction of the films may be chosen to allow for a range of disintegration times for the films. A variation or extension in the time over which a film will disintegrate may achieve control over the rate that the active is released, which may allow for a sustained release delivery system. In addition, the films may be used for the administration of a desired amount of a pharmaceutical active to any of several body surfaces, especially those including mucosal membranes, such as those found in the oral (i.e., sublingual, lingual, buccal, and gingival), anal, vaginal, ocular, nasal, aural, ophthalmological, and peritoneal environments; the surface of a wound, either on a skin surface or within the body such as during surgery or left in place after surgery to deliver the desired amount of active after the surgical procedure is completed; the surface of an organ (i.e., kidney, lung, liver, heart, etc.), and other similar surfaces.

[0124] The films may be used to orally administer a pharmaceutical active. This is accomplished by preparing the films as described above and introducing them to the oral cavity of an animal, such as a mammal. This film may be prepared and adhered to a second or support layer from which it is removed prior to use, i.e. introduction to the oral cavity. An adhesive may be used to attach the film to the support or backing material which may be any of those known in the art, and is preferably not water-soluble. If an adhesive is used, it will desirably be a food grade adhesive that is ingestible and does not alter the properties of the active. Mucoadhesive compositions are particularly useful. The film compositions in many cases serve as mucoadhesives themselves.

[0125] The films may be applied under or to the tongue of the patient, such as a mammal or human, including both an adult human and a child. When this is desired, a specific film shape, corresponding to the shape of the tongue may be preferred. Therefore, the film may be cut to a shape where the side of the film corresponding to the back of the tongue will be longer than the side corresponding to the front of the tongue. Specifically, the desired shape may beAttorney Docket No.148570-006300 that of a triangle or trapezoid. Desirably, the film will adhere to the oral cavity preventing it from being ejected from the oral cavity and permitting more of the active to be introduced to the oral cavity as the film dissolves.

[0126] Another use for the films of the present invention takes advantage of the films' tendency to dissolve quickly when introduce to a liquid. A pharmaceutical active may be introduced to a liquid by preparing a film in accordance with the present invention, introducing it to a liquid, and allowing it to dissolve. This may be used either to prepare a liquid dosage form of a pharmaceutical active, or to flavor a beverage.

[0127] The films of the present invention are desirably packaged in sealed, air and moisture resistant packages to protect the active from exposure oxidation, hydrolysis, volatilization and interaction with the environment. Moreover, the films of the present invention dissolve instantly upon contact with saliva or mucosal membrane areas, eliminating the need to wash the dose down with water.

[0128] Desirably, a series of such unit doses are packaged together in accordance with the prescribed regimen or treatment, e.g., a 10 to 90-day supply, depending on the particular therapy. The individual films can be packaged on a backing and peeled off for use.

[0129] In one embodiment, a composition including epinephrine or its salts or esters can have a biodelivery profile similar to that of epinephrine administered by injection, for example, using an EpiPen. Epinephrine can be present in an amount of from about .01 mg to about 100 mg per dosage, for example, at a 0.1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg dosage, including greater than 0.1 mg, more than 5 mg, more than 20 mg, more than 30 mg, more than 40 mg, more than 50 mg, more than 60 mg, more than 70 mg, more than 80 mg, more than 90 mg, or less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, or less than 5 mg, or any combination thereof. In another example, a composition including olanzapine can have a biodelivery profile similar to that of a olanzapine tablet or gel, or better. Olanzapine or its salts can be present in an amount of from about 0.5 mg to about 100 mg per dosage, for example, at a 0.5 mg, I mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg dosage including greater than 1 mg, more than 5 mg, more than 20 mg, more than 30 mg, more than 40 mg, more than 50 mg, more than 60 mg, more than 70 mg, more than 80 mg, more thanAttorney Docket No.148570-006300 90 mg, or less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, or less than 5 mg, or any combination thereof.

[0130] In another embodiment, a composition (e.g., including alprazolam, olanzapine or epinephrine) can have a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a mucosal delivery-enhancing agent selected from: (a) an aggregation inhibitory agent; (b) a charge- modifying agent; (c) a pH control agent; (d) a degradative enzyme inhibitory agent; (e) a mucolytic or mucus clearing agent; (f) a ciliostatic agent; (g) a membrane penetration- enhancing agent selected from: (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome, or carrier; (iii) an alcohol; (iv) an enamine; (v) an NO donor compound; (vi) a long chain amphipathic molecule; (vii) a hydrophobic penetration enhancer; (viii) sodium or a salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or beta-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or salt thereof; (xiv) an N-acetylamino acid or salt thereof; (xv) an enzyme degradative to a selected membrane component; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) any combination of the membrane penetration enhancing agents recited in (1)-(x); (h) a modulatory agent of epithelial junction physiology; (i) a vasodilator agent; (j) a selective transport-enhancing agent; or (k) a stabilizing delivery vehicle, carrier, mucoadhesive, support or complex-forming species with which the compound is effectively combined, associated, contained, encapsulated or bound resulting in stabilization of the compound for enhanced mucosal delivery, wherein the formulation of the compound with the transmucosal delivery-enhancing agents provides for increased bioavailability of the compound in a blood plasma of a subject. The formulation can include approximately the same active pharmaceutical ingredient (API): enhancer ratio as in the other examples for olanzapine and alprazolam.

[0131] A film and / or its components can be water-soluble, water swellable or water- insoluble. The term "water-soluble" can refer to substances that are at least partially dissolvable in an aqueous solvent, including but not limited to water. The term "water- soluble" may not necessarily mean that the substance is 100% dissolvable in the aqueous solvent. The term "water-insoluble" refers to substances that are not dissolvable in an aqueous solvent, including but not limited to water. A solvent can include water, or alternatively canAttorney Docket No.148570-006300 include other solvents (preferably, polar solvents) by themselves or in combination with water.

[0132] The composition can include a polymeric matrix. Any desired polymeric matrix may be used, provided that it is orally dissolvable or erodible. The dosage should have enough bioadhesion to not be easily removed and it should form a gel like structure when administered. They can be moderate-dissolving in the oral cavity and particularly suitable for delivery of pharmaceutically active components, although both fast release, delayed release, controlled release and sustained release compositions are also among the various embodiments contemplated.

[0133] Branched Polymers

[0134] The pharmaceutical composition film can include dendritic polymers which can include highly branched macromolecules with various structural architectures. The dendritic polymers can include dendrimers, dendronised polymers (dendrigrafted polymers), linear dendritic hybrids, multi-arm star polymers, or hyperbranched polymers.

[0135] Hyperbranched polymers are highly branched polymers with imperfections in their structure. However, they can be synthesized in a single step reaction which can be an advantage over other dendritic structures and are therefore suitable for bulk volume applications. The properties of these polymers apart from their globular structure are the abundant functional groups, intramolecular cavities, low viscosity and high solubility. Dendritic polymers have been used in several drug delivery applications. The dendritic polymers can have internal cavities which can encapsulate drugs. The steric hindrance caused by the highly dense polymer chains might prevent the crystallization of the drugs. Thus, branched polymers can provide additional advantages in formulating crystallizable drugs in a polymer matrix.

[0136] Examples of suitable dendritic polymers include 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, poly(amidoamine) based dendrons, dendrimers or hyperbranched polymers.Attorney Docket No.148570-006300

[0137] Other examples of hyperbranched polymers include poly(amines)s, polycarbonates, poly(etherketone)s, polyurethanes, polycarbosilanes, polysiloxanes, polyester amines, poly(sulfoneamine)s, poly(urea urethane)s or polyether polyols such as polyglycerols.

[0138] A film can be produced by a combination of at least one polymer and a solvent, optionally including other components. The solvent may be water, a polar organic solvent including, but not limited to, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride. The film may be prepared by utilizing a selected casting or deposition method and a controlled drying process. For example, the film may be prepared through a controlled drying processes, which include application of heat and / or radiation energy to the wet film matrix to form a visco-elastic structure, thereby controlling the uniformity of content of the film. The controlled drying processes can include air alone, heat alone or heat and air together contacting the top of the film or bottom of the film or the substrate supporting the cast or deposited or extruded film or contacting more than one surface at the same time or at different times during the drying process.

[0139] A polymer included in the films may be water-soluble, water-swellable, water- insoluble, or a combination of one or more either water-soluble, water-swellable or water- insoluble polymers. The polymer may include cellulose, cellulose derivatives or gums. Specific examples of useful water-soluble polymers include, but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof. Specific examples of useful water-insoluble polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and combinations thereof. For higher dosages, it may be desirable to incorporate a polymer that provides a high level of viscosity as compared to lower dosages.

[0140] As used herein the phrase "water-soluble polymer" and variants thereof refer to a polymer that is at least partially soluble in water, and desirably fully or predominantly solubleAttorney Docket No.148570-006300 in water, or absorbs water. Polymers that absorb water are often referred to as being water- swellable polymers. The materials useful with the present invention may be water-soluble or water-swellable at room temperature and other temperatures, such as temperatures exceeding room temperature. Moreover, the materials may be water-soluble or water-swellable at pressures less than atmospheric pressure. In some embodiments, films formed from such water-soluble polymers may be sufficiently water-soluble to be dissolvable upon contact with bodily fluids. Other polymers useful for incorporation into the films include biodegradable polymers, copolymers, block polymers or combinations thereof. It is understood that the term "biodegradable" is intended to include materials that chemically degrade, as opposed to materials that physically break apart (i.e., bioerodible materials). The polymers incorporated in the films can also include a combination of biodegradable or bioerodible materials. Among the known useful polymers or polymer classes which meet the above criteria are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanes, polyoxalates, poly(alpha- esters), polyanhydrides, 30 polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymers thereof. Additional useful polymers include, stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propane acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid) / poly(glycolic acid) / polyethyleneglycol copolymers, copolymers of polyurethane and (polylactic acid), copolymers of alpha-amino acids, and caproic acid, copolymers of alpha- benzyl glutamate and polyethylene glycol, copolymers of succinate and poly(glycols), polyphosphazene, polyhydroxy-alkanoates or mixtures thereof. The polymer matrix can include one, two, three, four or more components. Although a variety of different polymers may be used, it is desired to select polymers that provide mucoadhesive properties to the film, as well as a desired dissolution and / or disintegration rate. In particular, the time period for which it is desired to maintain the film in contact with the mucosal tissue depends on the type of pharmaceutically active component contained in the composition. Some pharmaceutically active components may only require a few minutes for delivery through the mucosal tissue, whereas other pharmaceutically active components may require up to several hours or even longer. Accordingly, in some embodiments, one or more water-soluble polymers, as described above, may be used to form the film. In other embodiments, however, it may be desirable to use combinations of water-soluble polymers and polymers that are water-swellable, water-insoluble and / or biodegradable, as provided above. The inclusion ofAttorney Docket No.148570-006300 one or more polymers that are water-swellable, water-insoluble and / or biodegradable may provide films with slower dissolution or disintegration rates than films formed from water- soluble polymers alone. As such, the film may adhere to the mucosal tissue for longer periods of time, such as up to several hours, which may be desirable for delivery of certain pharmaceutically active components.

[0141] Desirably, an individual film dosage of the pharmaceutical film can have a suitable thickness, and small size, which is between about 0.0625-3 inch by about 0.0625-3 inch. The film size can also be greater than 0.0625 inch, greater than 0.5 inch, greater than I inch, greater than 2 inches, about 3 inches, or greater than 3 inches, less than 3 inches, less than 2 inches, less than I inch, less than 0.5 inch, less than 0.0625 inch in at least one aspect, or greater than 0.0625 inch, greater than 0.5 inch, greater than I inch, greater than 2 inches, or greater than 3 inches, about 3 inches, less than 3 inches, less than 2 inches, less than l inch, less than 0.5 inch, or less than 0.0625 inch in another aspect. The aspect ratio, including thickness, length, and width can be optimized by a person of ordinary skill in the art based on the chemical and physical properties of the polymeric matrix, the active pharmaceutical ingredient, dosage, enhancer, and other additives involved as well as the dimensions of the desired dispensing unit. The film dosage should have good adhesion when placed in the buccal cavity or in the sublingual region of the user. Further, the film dosage should disperse and dissolve at a moderate rate, most desirably dispersing within about 1 minute and dissolving within about 3 minutes. In some embodiments, the film dosage may be capable of dispersing and dissolving at a rate of between about I to about 30 minutes, for example, about I to about 20 minutes, or more than 1 minute, more than 5 minutes, more than 7 minutes, more than 10 minutes, more than 12 minutes, more than 15 minutes, more than 20 minutes, more than 30 minutes, about 30 minutes, or less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, or less than 1 minute. Sublingual dispersion rates may be shorter than buccal dispersion rates.

[0142] For instance, in some embodiments, the films may include polyethylene oxide alone or in combination with a second polymer component. The second polymer may be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer or any combination thereof. Suitable water-soluble polymers include, without limitation, any of those provided above. In some embodiments, the water- soluble polymer may include hydrophilic cellulosic polymers, such as hydroxypropylAttorney Docket No.148570-006300 cellulose and / or hydroxypropylmethyl cellulose. In some embodiments, one or more water- swellable, water-insoluble and / or biodegradable polymers also may be included in the polyethylene oxide-based film. Any of the water-swellable, water-insoluble or biodegradable polymers provided above may be employed. The second polymer component may be employed in amounts of about 0% to about 80% by weight in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight, including greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, and greater than 70%, about 70%, 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 weight.

[0143] Additives may be included in the films. Examples of classes of additives include preservatives, antimicrobials, excipients, lubricants, buffering agents, stabilizers, blowing agents, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, anti-adherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, anti-tacking agents, anti-static agents and mixtures thereof. These additives may be added with the pharmaceutically active component(s).

[0144] As used herein, the term "stabilizer" means an excipient capable of preventing aggregation or other physical degradation, as well as chemical degradation, of the active pharmaceutical ingredient, another excipient, or the combination thereof.

[0145] Stabilizers may also be classified as antioxidants, sequestrants, pH modifiers, emulsifiers and / or surfactants, and UV stabilizers as discussed above and in more detail below.

[0146] Antioxidants (i.e., pharmaceutically compatible compound(s) or composition(s) that decelerates, inhibits, interrupts and / or stops oxidation processes) include, in particular, the following substances: tocopherois and the esters thereof, sesamol of sesame oil, coniferyl benzoate of benzoin resin, nordihydroguaietic resin and nordihydroguaiaretic acid (NDGA), t5 gallates (among others, methyl, ethyl, propyl, amyl, butyl, lauryl gallates), butylated hydroxyanisole (BHA / BHT, also butyl-p-cresol); ascorbic acid and salts and esters thereof (for example, acorbyl palmitate), erythorbinic acid (isoascorbinic acid) and salts and estersAttorney Docket No.148570-006300 thereof, monothioglycerol, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT), propionic acid. Typical antioxidants are tocopherol such as, for example, a-tocopherol and the esters thereof, butylated hydroxytoluene and butylated hydroxyanisole. The terms "tocopherol" also includes esters of tocopherol. A known tocopherol is a-tocopherol. The term "a-tocopherol" includes esters of a-tocopherol (for example, a-tocopherol acetate).

[0147] Sequestrants (i.e., any compounds which can engage in host-guest complex formation with another compound, such as the active ingredient or another excipient; also referred to as a sequestering agent) include calcium chloride, calcium disodium ethylene diamine tetra-acetate, glucono delta-lactone, sodium gluconate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate, and combinations thereof. Sequestrants also include cyclic oligosaccharides, such as cyclodextrins, cyclomannins (5 or more a-D- mannopyranose units linked at the 1,4 positions by a linkages), cyclogalactins (5 or more fl- D-galactopyranose units linked at the 1,4 positions by p linkages), cycloaltrins (5 or more a- D-altropyranose units linked at the 1,4 positions by a linkages), and combinations thereof.

[0148] pH modifiers include acids (e.g., tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, ascorbic acid, acetic acid, succininc acid, adipic acid and maleic acid), acidic amino acids (e.g., glutamic acid, aspartic acid, etc.), inorganic salts (alkali metal salt, alkaline earth metal salt, ammonium salt, etc.) of such acidic substances, a salt of such acidic substance with an organic base (e.g., basic amino acid such as lysine, arginine and the like, meglumine and the like), and a solvate (e.g., hydrate) thereof. Other examples of pH modifiers include silicified microcrystalline cellulose, magnesium aluminometasilicate, calcium salts of phosphoric acid (e.g., calcium hydrogen phosphate anhydrous or hydrate, calcium, sodium or potassium carbonate or hydrogencarbonate and calcium lactate or mixtures thereof), sodium and / or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g., croscarmellose sodium and / or calcium), polacrilin potassium, sodium and or / calcium alginate, docusate sodium, magnesium calcium, aluminium or zinc stearate, magnesium palmitate and magnesium oleate, sodium stearyl fumarate, and combinations thereof.

[0149] Examples of emulsifiers and / or surfactants include poloxamers or pluronics, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium laurylAttorney Docket No.148570-006300 sulfate, polyethoxylated and hydrogenated castor oil, alkyl polyoside, a grafted water soluble protein on a hydrophobic backbone, lecithin, glyceryl monostearate, glyceryl monostearate / polyoxyethylene stearate, cetostearyl alcohol, sodium lauryl sulfate, carbomer, phospholipids, (Cto-C20)-alkyl and alkylene carboxylates, alkyl ether carboxylates, fatty alcohol sulfates, fatty alcohol ether sulfates, alkylamide sulfates and sulfonates, fatty acid alkylamide polyglycol ether sulfates, alkanesulfonates and hydroxyalkanesulfonates, olefinsulfonates, acyl esters of isethionates, a-sulfo fatty acid esters, alkylbenzenesulfonates, alkylphenol glycol ether sulfonates, 25 sulfosuccinates, sulfosuccinic monoesters and diesters, fatty alcohol ether phosphates, protein / fatty acid condensation products, alkyl monoglyceride sulfates and sulfonates, alkylglyceride ether sulfonates, fatty acid methyltaurides, fatty acid sarcosinates, sulforicinoleates, and acylglutamates, quaternary ammonium salts (e.g., di-(C10-C24)-alkyl-dimethylammonium chloride or bromide), (C10-C24)-alkyl-dimethylethylammonium chloride or bromide, (C10- C24)-alkyl -trimethyl ammonium chloride or bromide (e. g., cetyltrimethylammonium chloride or bromide), (C10-C24)-alkyl-dimethylbenzyl ammonium chloride or bromide (e.g., (C12—C18)-alkyl-dimethylbenzylammonium chloride), N—(C10-C18)-alkyl- pyridinium chloride or bromide (e.g., N—(C12-C16)-alkyl-pyridinium chloride or bromide), N—(C10-C18)-alkyl-isoquinolinium chloride, bromide or monoalkyl sulfate, N—(C12-C18)-alkyl-polyoylaminoformylmethylpyridinium chloride, N—(C12-C18)-alkyl- N-methylmorpholinium chloride, bromide or monoalkyl sulfate, N—(C12-C18)-alkyl-N- ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C16-C18)-alkyl-pentaox ethylammonium chloride,, di isobutylphenoxyethoxyethyldimethyl-benzylammonium chloride, salts of N,N-di- ethylaminoethylstearylamide and -oleylamide with hydrochloric acid, acetic acid, lactic acid, citric acid, phosphoric acid, N-acylaminoeihyl-N,N-diethyl-N- methylammonium chloride, bromide or monoalkyl sulfate, and N-acylaminoethyl-N,N- diethyl-N-benzylammoniurn chloride, bromide or monoalkyl sulfate (in the foregoing, "acyl" standing for, e.g., stearyl or oleyl), and combinations thereof.

[0150] Examples of UV stabilizers include UV absorbers (e.g., benzophenones), UV quenchers (i.e., any compound that dissipates UV energy as heat, rather than allowing the energy to have a degradation effect), scavengers (i.e., any compound that eliminates free radicals resulting from exposure to UV radiation), and combinations thereof.Attorney Docket No.148570-006300

[0151] In other embodiments, stabilizers include ascorbyl palmitate, ascorbic acid, alpha tocopherol, butylated hydroxytoluene, buthylated hydroxyanisole, cysteine HCl, citric acid, ethylenediamine tetra acetic acid (EDTA), methionine, sodium citrate, sodium ascorbate, sodium thiosulfate, sodium metabi sulfite, sodium bisulfite, propyl gallate, glutathione, thioglycerol, singlet oxygen quenchers, hydroxyl radical scavengers, hydroperoxide removing agents, reducing agents, metal chelators, detergents, chaotropes, and combinations thereof. "Singlet oxygen quenchers" include, but are not limited to, alkyl imidazoles (e.g., histidine, L-camosine, histamine, imidazole 4-acetic acid), indoles (e.g., tryptophan and derivatives thereof, such as N- acetyl-S-methoxy tryptamine, N-acetylserotonin, 6-methoxy- I,2,3,4-tetrahydro-beta-carboline), sulfur-containing amino acids (e.g., methionine, ethionine, djenkolic acid, lanthionine, N-formyl methionine, felinine, S-allyl cysteine, S-aminoethyl-L- cysteine), phenolic compounds (e.g., tyrosine and derivatives thereof), aromatic acids (e.g., ascorbate, salicylic acid, and derivatives thereof), azide (e.g., sodium azide), tocopherol and related vitamin E derivatives, and carotene and related vitamin A derivatives. "Hydroxyl radical scavengers" include, but are not limited to azide, dimethyl sulfoxide, histidine, mannitol, sucrose, glucose, salicylate, and L-cysteine.

[0152] "Hydroperoxide removing agents" include, but are not limited to catalase, pyruvate, glutathione, and glutathione peroxidases. "Reducing agents" include, but are not limited to, cysteine and mercaptoethylene. "Metal chelators" include, but are not limited to, EDTA, EGTA, o-phenanthroline, and citrate. "Detergents" include, but are not limited to, SDS and sodium lauroyl sarcosyl. "Chaotropes" include, but are not limited to guandinium hydrochloride, isothiocyanate, urea, and formamide. As discussed herein, stabilizers can be present in 0.0001%-50% by weight, including greater than 0.0001%, greater than 0.001%, greater than 0.01%, greater than 0.1%, greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% by weight.

[0153] Useful additives can include, for example, gelatin, vegetable proteins such as sunflower protein, soybean proteins, cotton seed proteins, peanut proteins, grape seed proteins, whey proteins, whey protein isolates, blood proteins, egg proteins, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar-agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gumAttorney Docket No.148570-006300 tragancanth), pectin, water-soluble derivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such as carboxymethylcellulose and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acids and polyacrylic acid esters, polymethacrylic acids and polymethacrylic acid esters, polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP), polyvinylpyrrolidone (PVP), PVA / vinyl acetate copolymer, or polycrotonic acids; also suitable are phthalated gelatin, gelatin succinate, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and rnethacrylates possessing, for example, a tertiary or quaternary amino group, such as the diethylaminoethyl group, which may be quaternized if desired; or other similar polymers.

[0154] The additional components can range up to about 80%, desirably about 0.005% to 50% and more desirably within the range of 1% to 20% based on the weight of all composition components, including greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, about 80%, greater than 80%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, about 3%, or less than 1%.

[0155] Other additives can include anti-tacking, flow agents and opacifiers, such as the oxides of magnesium aluminum, silicon, titanium, etc., desirably in a concentration range of about 0.005% to about 5% by weight and desirably about 0.02% to about 2% based on the weight of all film components, including greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, greater than 1.5%, greater than 2%, greater than 4%, about 5%, greater than 5%, less than 4%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.02%.

[0156] In certain embodiments, the composition can include plasticizers, which can include polyalkylene oxides, such as polyethylene glycols, polypropylene glycols,Attorney Docket No.148570-006300 polyethylene-propylene glycols, organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sugar alcohols sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, phytoex tracts, fatty acid esters, fatty acids, oils and the like, added in concentrations ranging from about 0.1% to about 40%, and desirably ranging from about 0.5% to about 20% based on the weight of the composition including greater than 0.5%, greater than 1%, greater than 1.5%, greater than 2%, greater than 4%, greater than 5%, greater than 10%, greater than 15%, about 20%, greater than 20%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 2%, less than 1%, or less than 0.5%. There may further be added compounds to improve the texture properties of the film material such as animal or vegetable fats, desirably in their hydrogenated form. The composition can also include compounds to improve the textural properties of the product. Other ingredients can include binders which contribute to the ease of formation and general quality of the films. Non-limiting examples of binders include starches, natural gums, pregelatinized starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, or polyvinylalcohols.

[0157] Further potential additives include solubility enhancing agents, such as substances that form inclusion compounds with active components. Such agents may be useful in improving the properties of very insoluble and / or unstable actives. In general, these substances are doughnut- shaped molecules with hydrophobic internal cavities and hydrophilic exteriors. Insoluble and / or instable pharmaceutically active components may fit within the hydrophobic cavity, thereby producing an inclusion complex, which is soluble in water. Accordingly, the formation of the inclusion complex permits very insoluble and / or unstable pharmaceutically active components to be dissolved in water. A particularly desirable example of such agents are cyclodextrins, which are cyclic carbohydrates derived from starch. Other similar substances, however, are considered well within the scope of the present invention.

[0158] Suitable coloring agents include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors are dyes, their corresponding lakes, and certain natural and derived colorants. Lakes are dyes absorbed on aluminum hydroxide. Other examples of coloring agents include known azo dyes, organic or inorganic pigments, or coloring agents of natural origin. Inorganic pigmentsAttorney Docket No.148570-006300 are preferred, such as the oxides or iron or titanium, these oxides, being added in concentrations ranging from about 0.001 to about 10%, and preferably about 0.5 to about 3%, including greater than 0.001%, greater than 0.01%, greater than 0.1%, greater than 0.5%, greater than 1%, greater than 2%, greater than 5%, about 10%, greater than 10%, less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001%, based on the weight of all the components.

[0159] Flavors may be chosen from natural and synthetic flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavors. Other useful flavorings include aldehydes and esters such as benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), or 2- dodecenal (citrus, mandarin), combinations thereof and the like.

[0160] The sweeteners may be chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof, saccharin and its various salts such as the sodium salt; dipeptide-based sweeteners such as aspartame, neotame, advantame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methy1-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof, and natural intensive sweeteners, such as Lo Han Kuo. Other sweeteners may also be used.

[0161] Anti-foaming and / or de-foaming components may also be used with the films. These components aid in the removal of air, such as entrapped air, from the film-forming compositions.

[0162] Such entrapped air may lead to non-uniform films. Simethicone is one particularly useful anti-foaming and / or de-foaming agent. The present invention, however, is not soAttorney Docket No.148570-006300 limited and other suitable anti-foam and / or de-foaming agents may be used. Simethicone and related agents may be employed for densification purposes. More specifically, such agents may facilitate the removal of voids, air, moisture, and similar undesired components, thereby providing denser and thus more uniform films. Agents or components which perform this function can be referred to as densification or densifying agents. As described above, entrapped air or undesired components may lead to non-uniform films.

[0163] Any other optional components described in commonly assigned U.S. Patent No. 7,425,292 and U.S. Patent No.8,765,167, referred to above, also may be included in the films described herein.

[0164] The film compositions further desirably contains a buffer so as to control the pH of the film composition. Any desired level of buffer may be incorporated into the film composition so as to provide the desired pH level encountered as the pharmaceutically active component is released from the composition. The buffer is preferably provided in an amount sufficient to control the release from the film and / or the absorption into the body of the pharmaceutically active component. In some embodiments, the buffer may include sodium citrate, citric acid, bitartrate salt and combinations thereof.

[0165] The pharmaceutical films described herein may be formed via any desired process. In one embodiment, the film dosage composition is formed by first preparing a wet composition, the wet composition including a polymeric carrier matrix and a therapeutically effective amount of a pharmaceutically active component. The wet composition is cast into a film and then sufficiently dried to form a self-supporting film composition. The wet composition may be cast into individual dosages, or it may be cast into a sheet, where the sheet is then cut into individual dosages.

[0166] The pharmaceutical composition can adhere to a mucosal surface. The present invention finds particular use in the localized treatment of body tissues, diseases, or wounds which may have moist surfaces and which are susceptible to bodily fluids, such as the mouth, the vagina, organs, or other types of mucosal surfaces. The composition carries a pharmaceutical, and upon application and adherence to the mucosal surface, offers a layer of protection and delivers the pharmaceutical to the treatment site, the surrounding tissues, and other bodily fluids. The composition provides an appropriate residence time for effective drug delivery at the treatment site, given the control of erosion in aqueous solution or bodily fluidsAttorney Docket No.148570-006300 such as saliva, and the slow, natural erosion of the film concomitant or subsequent to the delivery.

[0167] The residence time of the composition depends on the erosion rate of the water erodible polymers used in the formulation and their respective concentrations. The erosion rate may be adjusted, for example, by mixing together components with different solubility characteristics or chemically different polymers, such as hydroxyethyl cellulose and hydroxypropyl cellulose; by using different molecular weight grades of the same polymer, such as mixing low and medium molecular weight hydroxyethyl cellulose; by using excipients or plasticizers of various lipophilic values or water solubility characteristics (including essentially insoluble components); by using water soluble organic and inorganic salts; by using crosslinking agents such as glyoxal with polymers such as hydroxyethyl cellulose for partial crosslinking; or by post-treatment irradiation or curing, which may alter the physical state of the film, including its crystallinity or phase transition, once obtained. These strategies might be employed alone or in combination in order to modify the erosion kinetics of the film. Upon application, the pharmaceutical composition film adheres to the mucosal surface and is held in place. Water absorption softens the composition, thereby diminishing the foreign body sensation. As the composition rests on the mucosal surface, delivery of the drug occurs. Residence times may be adjusted over a wide range depending upon the desired timing of the delivery of the chosen pharmaceutical and the desired lifespan of the carrier. Generally, however, the residence time is modulated between about a few seconds to about a few days. Preferably, the residence time for most pharmaceuticals is adjusted from about 5 seconds to about 24 hours. More preferably, the residence time is adjusted from about 5 seconds to about 30 minutes. In addition to providing drug delivery, once the composition adheres to the mucosal surface, it also provides protection to the treatment site, acting as an erodible bandage. Lipophilic agents can be designed to slow down erodability to decrease disintegration and dissolution.

[0168] It is also possible to adjust the kinetics of erodability of the composition by adding excipients which are sensitive to enzymes such as amylase, very soluble in water such as water soluble organic and inorganic salts. Suitable excipients may include the sodium and potassium salts of chloride, carbonate, bicarbonate, citrate, trifluoroacetate, benzoate, phosphate, fluoride, sulfate, or tartrate. The amount added can vary depending upon how much the erosion kinetics is to be altered as well as the amount and nature of the other componentsAttorney Docket No.148570-006300 in the composition. Emulsifiers typically used in the water-based emulsions described above are, preferably, either obtained in situ if selected from the linoleic, palmitic, myristoleic, Jamie, stearic, cetoleic or oleic acids and sodium or potassium hydroxide, or selected from the laurate, palmitate, stearate, or oleate esters of sorbitol and sorbitol anhydrides, polyoxyethylene derivatives including monooleate, monostearate, monopalmitate, monolaurate, fatty alcohols, alkyl phenols, allyl ethers, alkyl aryl ethers, sorbitan monostearate, sorbitan monooleate and / or sorbitan monopalmitate.

[0169] The amount of pharmaceutically active component to be used depends on the desired treatment strength and the composition of the layers, although preferably, the pharmaceutical component comprises from about 0.001% to about 99%, more preferably from about 0.003 to about 75%, and most preferably from about 0.005% to about 50% by weight of the composition, including, more than 0.005%, more than 0.05%, more than 0.5%, more than 1%, more than 5%, more than 10%, more than 15%, more than 20%, more than 30%, about 50%, more than 50%, less than 50%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.05%, or less than 0.005%. The amounts of other components may vary depending on the drug or other components but typically these components comprise no more than 50%, preferably no more than 30%, and most preferably no more than 15% by total weight of the composition.

[0170] The thickness of the film may vary, depending on the thickness of each of the layers and the number of layers. As stated above, both the thickness and amount of layers may be adjusted in order to vary the erosion kinetics. Preferably, if the composition has only two layers, the thickness ranges from 0.005 mm to 2 mm, preferably from 0.01 to 1 mm, and more preferably from 0.1 to 0.5 mm, including greater than 0.1 mm, greater than 0.2 mm, about 0.5 mm, greater than 0.5 mm, less than 0.5 mm, less than 0.2 mm, or less than 0.1 mm. The thickness of each layer may vary from 10 to 90% of the overall thickness of the layered composition, and preferably varies from 30 to 60%, including 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%. Thus, the preferred thickness of each layer may vary from 0.01 mm to 0.9 mm, or from 0.03 mm to 0.5 mm.Attorney Docket No.148570-006300

[0171] As one skilled in the art will appreciate, when systemic delivery, e.g., transmucosal or transdermal delivery is desired, the treatment site may include any area in which the film is capable of delivery and / or maintaining a desired level of pharmaceutical in the blood, lymph, or other bodily fluid. Typically, such treatment sites include the oral, aural, ocular, anal, nasal, and vaginal mucosal tissue, as well as the skin. If the skin is to be employed as the treatment site, then usually larger areas of the skin wherein movement will not disrupt the adhesion of the film, such as the upper arm or thigh, are preferred.

[0172] The pharmaceutical composition can also be used as a wound dressing. By offering a physical, compatible, oxygen and moisture permeable, flexible barrier which can be washed away, the film can not only protect a wound but also deliver a pharmaceutical in order to promote healing, aseptic, scarification, to ease the pain or to improve globally the condition of the sufferer. Some of the examples given below are well suited for an application to the skin or a wound. As one skilled in the art will appreciate, the formulation might require incorporating a specific hydrophilic / hygroscopic excipient which would help in maintaining good adhesion on dry skin over an extended period of time. Another advantage of the present invention when utilized in this manner is that if one does not wish that the film be noticeable on the skin, then no dyes or colored substances need be used. If, on the other hand, one desires that the film be noticeable, a dye or colored substance may be employed.

[0173] While the pharmaceutical composition can adhere to mucosal tissues, which are wet tissues by nature, it can also be used on other surfaces such as skin or wounds. The pharmaceutical film can adhere to the skin if prior to application the skin is wet with an aqueous- based fluid such as water, saliva, wound drainage or perspiration. The film can adhere to the skin until it erodes due to contact with water by, for example, rinsing, showering, bathing or washing. The film may also be readily removed by peeling without significant damage to tissue.

[0174] Dissolution. rate is the rate at which the oral film or active dissolves, which is a calculated amount of % released. at a point in time. The dissolution rate is obtained by performing dissolution testing in a selected apparatus, and is measured according to certain dissolution parameters. The dissolution parameters include storage conditions, such as time„ temperature, and relative humidity, and testing parameters, such things as the apparatus, rotation speed, media, media temperature, sampling time points, sample volume, sampleAttorney Docket No.148570-006300 filter, HPLC -column, mobile phase, flow rate, column temperature, injection volume., detection wavelength, and run time.

[0175] “Active dissolution rate" is the rate at which the active dissolves, which is a calculated amount of % released at a point in time. In the case of an oral film dosage form, as disclosed herein, the oral film dissolves and releases the active, which then undergoes dissolution at a precise rate (i.e., the active dissolution rate). Dissolution of the active may also be expressed as % active. dissolved (average) at a point in time.

[0176] Unless otherwise noted, dissolution of the active is measured under storage conditions of the oral film of about 0 months to about 36 months, more than 0 to about. 36 months, about 6 to about 36 months, about 6 to about 24 months, about .9 months to about 18 months, or about 12 months, at about 20°C to about 60°C, about 25°C to about 40°C, or about 25°C, and up to about 75% relative humidity (RH), e.g., at about 60% RR.

[0177] The dissolution tests may be conducted under “sink” conditions, defined as the volume of medium at least three times that required in order to form a saturated solution of drug substance. When sink conditions are present, it is more likely that dissolution results will reflect the properties of the dosage form. Different media may be required for different drug products, based upon the characteristics of the active, such as solubility, and route of administration. As readily understood by one of ordinary skill in the art, in developing a dissolution method, the above factors may be considered. With that, USP <1092> defines a range of media to evaluate: “Typical media for dissolution may Maude the. following (not listed in order of preference) dilute hydrochloric acid, buffers (phosphate or acetate) in the physiologic pH range of 1:2 to 73, simulated gastric or intestinal fluid (with or without enzymes), water, and surfactants (with or without acids or buffers).” The surfactant may be, but is not limited to, polysorbate 80, sodium lauryl sulfate, and bile salts. For some drugs, incompatibility of the drug with certain buffers or salts may influence the choice of buffer. The molarity of the buffers and acids used can influence the solubilizing effect, and this factor may be evaluated. Aqueous solutions (acidic. or buffer solutions) may contain a percentage of a surfactant, e.g., sodium dodecyl sulfate (SDS), polysorbate, or lauryldimethylamine oxide, to enhance the solubility of the drug.

[0178] In an embodiment, dissolution of the active is measured in dilute hydrochloric. acid, a buffer (e.g., phosphate or acetate) in the physiologic pH range of 1.2 to 7.5, (includingAttorney Docket No.148570-006300 but not limited to, 0.0$ molar monobasic potassium phosphate buffer of pH 6.8) simulated gastric or intestinal fluid (with or without enzymes) (e.g., 0.1N HU), water, and surfactants (e.g., polysorbate 80, sodium lauryl sulfate, and bile salts). In another embodiment, dissolution of the active is measured in dilute hydrochloric acid, 0.05 molar monobasic potassium phosphate buffer of pH 6.8, 0.1N HU, water, or 05% sodium lauryl sulfate.

[0179] Uses of Thin Films

[0180] The thin films disclosed herein are well suited for many. uses. The high degree of uniformity of the components and film makes them particularly well suited for incorporating pharmaceuticals. Furthermore, the polymers used in construction of the films may be chosen to allow for a range of disintegration times for the films. A variation or extension in the time over which a film will disintegrate may achieve control over the rate that the active is released, which may allow for 4 sustained release delivery system. In addition, the films may be used for the administration of an active to any of several body surfaces, especially those including mucous membranes, such as oral, anal, vaginal, ophthalmological, the surface of a wound, either on a. skin surface or within a body such as during surgery, and similar surfaces.

[0181] The films may be used to orally administer an active. This is accomplished by preparing the films as described above and introducing them to the oral cavity of a mammal. This film may be prepared and adhered to a second or support layer from which it is removed prior to use, i.e. introduction to the oral cavity. An adhesive may be used to attach the film to the support or backing material which may be any of those known in the art, and is preferably not water soluble. If an adhesive is used, it will desirably be a food grade adhesive that is ingestible and does not alter the properties of the active. Mucoadhesive compositions are particularly useful. The film compositions in many cases serve as mucoadhesives themselves.

[0182] The films may be applied under or to the tongue of the mammal. When this is desired, a specific film shape, corresponding to the shape of the tongue may be preferred. Therefore, the film may be cut to a shape where the side of the film corresponding to the back of the tongue will be longer than the side corresponding to the front of the tongue. Specifically, the desired shape may be that of a triangle or trapezoid. Desirably, the film will adhere to the oral cavity preventing it from being ejected from the oral cavity and permitting more. of the active to be introduced to the oral cavity as the film dissolves.Attorney Docket No.148570-006300

[0183] Another use for the films disclosed. herein takes advantage of the films' tendency to dissolve quickly when introduce to a liquid. An active may be introduced to a liquid. by preparing a film in accordance with the present. invention, introducing it to a liquid, and allowing it to dissolve. This may be used either to prepare a liquid dosage form of an active, or to flavor a beverage.

[0184] The films of the present invention are desirably packaged in sealed, air and moisture resistant packages to protect the active from exposure oxidation, hydrolysis, volatilization and interaction with the environment. Moreover, the films of the present invention dissolve instantly upon. contact with saliva or mucosal membrane areas, eliminating the need to wash the dose down with water.

[0185] Desirably, a series of such unit doses are packaged together in accordance with the prescribed regimen or treatment, e.g., a l0-90 day supply, depending on the particular therapy. The individual self-supporting films can be packaged individually without a backing, or on a backing and peeled off for use.

[0186] Methods of Use

[0187] Also disclosed herein are methods of treating a neurological disease or disorder in a human comprising administering to the human an oral film for delivery of a desired amount of an active in an individual unit dose. The film comprises: a) a water-soluble.polymer, water swellable polymer matrix, or a water-soluble and water meltable polymer matrix; b) the active having an average particle size D90 of less than. about 160 microns; and c) an additive selected from the group consisting of a. sweetener, a flavor, a flavor enhancer, a filler, a plasticizer, a dye, a pigment, a permeation enhancer, a "buffer, a preservative, silicon dioxide, an anti-tacking agent, and any combination thereof. The active in. the oral film may have any of the dissolution profiles and rates discussed above.

[0188] The active may be any of the actives described herein. In certain embodiments, the active may be clobazam, olanzapine, riluzole, or any combination thereof.

[0189] Another embodiment is directed to a method of treating Lentiox-Gastaut syndrome in a human comprising administering to the human the oral film. -disclosed herein.

[0190] The terms used in connection with these embodiments (methods of use) have the same meanings and definitions as discussed above.Attorney Docket No.148570-006300

[0191] The features and advantages of the present invention are more fully shown by the following examples which are provided for purposes of illustration, and are not to be construed as limiting the invention in any way.

[0192] For an oral film containing olanzapine, upon placing the film in a medium, more than about 2% of the olanzapine may be dissolved after about 3 minutes, more than about 10% of the olanzapine may be dissolved after about 5 minutes, more than about 15% of the olanzapine may be dissolved after about 5 minutes, or about 20% to about 25% of the olanzapine may be. dissolved after about 5 minutes, optionally measured by PION technology. More than about 25%, more than about 30%, or about 35% to about 40% of the olanzapine may be dissolved- after about 10 minutes, optionally measured by PION technology. More than about 42%, more than about 48%, or about 50% to about 55% of the olanzapine may be dissolved after about 15 minutes, optionally measured by PION technology. More than about .55%, more than about 60%, or about 60% to about 70% of the olanzapine may be dissolved after about 20 minutes, optionally measured by PION technology. More than about more than about 90%, or about 92% to about. 9&% of the olanzapine may be dissolved after about 30 minutes, optionally measured by PION technology Any combination of the above-noted dissolutions at different timepoints within the scope of the invention.

[0193] For an oral film containing about 5 mg olanzapine, more than about 2% of the olanzapine may be dissolved after about 3 minutes, more than about 15% of the olanzapine may be dissolved after about S minutes, or about 21% of the olanzapine may be dissolved after about 5 minutes, optionally measured by PION technology. For the oral film containing about 5 mg olanzapine, more than about 30%, less than about 38%, or Omit 36% of the olanzapine may be dissolved after about 10 minutes, optionally measured by PION technology. For the film containing about 5 mg olanzapine, less than about 55%, more than about 45%, or about 50% of the olanzapine may be dissolved after about 15 minutes, optionally measured by PION technology. For the film containing about S mg olanzapine, less than about 70%, more than about 60%, or about.64% of the olanzapine may be dissolved after about 20 minutes, optionally measured by PION technology. Any combination of the above-noted dissolutions at different rime points is within the scope of the invention.Attorney Docket No.148570-006300

[0194] For an oral film containing about 15 mg olanzapine, mom than about 2% of the olanzapine may be dissolved after about 3 minutes, more than about 20% of the olanzapine may be dissolved after about S minutes, more than about 25% of the olanzapine may be dissolved after about 5 minutes, and / or about 27% of the olanzapine may be dissolved after about 5 minutes, optionally measured by PION technology. For the film containing about 15 mg olanzapine. More than about 35%, less than about 45%, or about 41% of the olanzapine may be dissolved after about.10 minutes, optionally measured by PION technology. For the film containing about 15 mg olanzapine, lest-than about 60%, more than about 45%, more than about. 50%, or about 55% of the olanzapine may be dissolved after about 15 minutes, optionally measured by PION technology. For the film containing about 15 mg olanzapine, less. than about 70%, more than about 60%, more than about 65%, or about 68% of the olanzapine is dissolved after about 20 minutes, optionally measured by PION technology. Any combination of the above-noted dissolutions at. different. time points is within the scope of the invention.

[0195] The following examples are provided to further illustrate the embodiments of the present invention but are not intended to limit the scope of the invention. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used. EXAMPLES

[0196] Example 1

[0197] Olanzapine Solubility and Permeability

[0198] Olanzapine will be applied in the buccal area (cheek) to diffuse through the oral mucosa and enter directly into the bloodstream. Solubility of olanzapine will also be studied using various excipients.

[0199] The following excipients will be studied to improve solubility.Attorney Docket No.148570-006300

[0200] The following excipients can also be applied for similar enhancement properties: cinnamon leaf, basil, bay leaf, nutmeg, Kolliphor® TPGS, PEG Succinate, Kolliphor® EL, Polyoxyl 35 Castor Oil USP / NF, Menthol, N-Methyl-2-pyrrolidone, SLS (SDS), SDBS, Dimethyl Phthalate, Sucrose Pahnitate (Sisterna PS750-C), Sucrose Stearate (Sisterna SP70- C), CHAPS, Octyl glucoside, Triton X 100 (Octoxynol-9), Ethyl Maltol (flavorant powder), Brij 58 (Ceteth-20), Vitamin E tocopherol, tocopherol acetate or tocopherol succinate, sterols, phytoextracts, essential oils or Cod Liver Oil. Results will be obtained in a solution of olanzapine having a concentration of 8.00 mg / mi.

[0201] Example 2

[0202] In one investigation, the usability of olanzapine buccal soluble film will be studied as an oral treatment in adult patients with a neurological disorder such as acuteAttorney Docket No.148570-006300 agitation associated with bipolar disorder. Olanzapine buccal soluble film is an exemplary embodiment of the claimed subject matter. Olanzapine buccal soluble film is a novel dosage form of olanzapine for the management of selected patients with neurological disorders who require intermittent use of olanzapine to control episodes of increased agitation associated with bipolar disorder. Olanzapine buccal soluble film is administered by placing the film against the inner aspect of the cheek, where it adheres, dissolves and releases drug onto the buccal mucosa. The olanzapine buccal soluble film dosage form is expected to be accepted by a broad range of patients with a neurological disorder. A Phase 2 pharmacokinetic study in the neurological monitoring center will assess safety, pharmacokinetics and usability of olanzapine buccal soluble film.

[0203] A Phase 2, multi-center, open-label, crossover study in adult subjects will be completed during two treatment visits separated by at least three weeks. The study will enroll male and female subjects 17-65 years of age with a clinical diagnosis of agitation associated with bipolar disease who require EMU evaluation. Subjects will receive olanzapine buccal soluble film administered in 12.5 mg during a first state (Treatment A) and a second state (during or within 5 min of acute agitation; Treatment B). Usability endpoints for investigator placement of olanzapine buccal soluble film include: (1) whether successful placement is achieved, (2) number of attempts needed to successfully insert the film, (3) whether the subject spits or blows out the film, and (4) whether or not olanzapine buccal soluble film is swallowed.

[0204] Example 3

[0205] Another investigation will evaluate the pharmacokinetics of olanzapine buccal soluble film in adult patients with agitation associated with bipolar disease. A comparison of bioavailability with various administrations will be assessed.

[0206] As indicated above, olanzapine soluble film is an exemplary embodiment of the claimed subject matter. It is a novel dosage form of olanzapine under development for the management of selected patients with agitation associated with bipolar disease who require intermittent use of olanzapine to control episodes of increased agitation activity. In this study, the investigators will assess pharmacokinetic (PK) performance during or immediately after the agitation activity. Subjects will be investigated while undergoing a clinical neurological monitoring unit evaluation and on another PK-only visit, with the visits separated byAttorney Docket No.148570-006300 approximately 3 weeks. The study will investigate the olanzapine maximal plasma concentration (Cmax), time to maximal concentration (Tmax), and partial area under the curve (partial AUC) at 2 or 4 hours in adult subjects with agitation following single doses of olanzapine soluble film under varying conditions.

[0207] These results demonstrate surprisingly that a single dose of olanzapine soluble film 12.5 mg administered to adults with neurological disorders provides exposure to olanzapine under both ictal / peri-ictal conditions that is comparable to that obtained under inter-ictal conditions.

[0208] Example 5. Dissolution Study of Oral Films Containing Olanzapine

[0209] Oral thin films containing olanzapine will be prepared containing 0.5 mg and 15 mg of the active. Dissolution of 5 mg and 15 mg DBSF under storage conditions of 12 months at 25°C will be tested using traditional dissolution and PION technology. Traditional dissolution as used herein is a common approach to testing dissolution characteristics of solid oral dosage forms, such as tablets and capsules. The traditional dissolution method utilizes a modified USP Apparatus 5 setup, with a modified sample holder necessary for holding the film stationary. All other aspects of the traditional dissolution method are similar to those of other solid oral dosage forms, including manual sampling and collection of samples at specified time points, then offline analysis of the samples using HPLC. The traditional dissolution method is limited in practical terms to the frequency and consistency of manual sampling and removal of sample aliquots. The PION technology utilizes a traditional dissolution bath, with a non-traditional setup. The bath is set up with Apparatus 2 (paddle) with a modified sample holder mounted. above the paddle. In-line fiber optic probes are positioned inside the vessel. The samples are tested in-situ at. predefined intervals. The sampling is automated and analyzed in-line with no sample removal, manual sampling, or offline HPLC testing necessary. A comparison of system parameters between the traditional dissolution and PION technology for testing the olanzapine buccal film are presented in Table 1.

[0210] Table 1: System Parameters for Traditional Dissolution and PION TechnologyAttorney Docket No.148570-006300

[0211] The proposed dosing regimen for olanzapine buccal film is designed to provide olanzapine exposure in patients equivalent to the exposure that will be achieved when the reference drug, Zyprexa, which is administered according to its approved product label. Invention of an appropriate dosing regimen for olanzapine buccal film will be equivalent to creating a mapping such that an appropriate olanzapine buccal film dose in mg is specified for any patient based on age group and weight category in the olanzapine. The appropriate dose of olanzapine buccal film will be that dose expected to provide equivalent exposure to olanzapine as the exposure provided by labeled dose of olanzapine. The initial emphasis of this effort is to create this mapping for adult age group (patients age 12 and older). Differences between olanzapine film and Zyprexa may include (1) The pharmacokinetics of olanzapine buccal film may be linear. For olanzapine buccal film, both Cmax and AUC may be proportional to the dose, whereas for Zyprexa the Cmax may be less than proportional to the dose. (2) olanzapine buccal film may exhibit a food effect. Cmax for olanzapine buccal film may be following a moderate fat meal, and also following a high-fat meal with no effect on AUC. It may be assumed that Zyprexa, because of its injectable administration, is not subject to a significant food effect.

[0212] Table 2 Formulation Development PlanAttorney Docket No.148570-006300

[0213] Description of DBSF Doses

[0214] The dose proportionality of olanzapine buccal film will be formally investigated in a crossover study in healthy volunteers at doses of 5mg, 10mg and 15mg. A 15mg dose will be included as the top dose in the proportionality study to establish linearity and provide flexibility as a potential titration dose.

[0215] The next study will be a crossover study to provide a direct comparison of the pharmacokinetics of olanzapine buccal film and the Zyprexa. This four-treatment, four- period crossover will compare one olanzapine buccal film dose (15mg) against three doses (5mg, 12.5mg, and 20mg) of Zyprexa. Because olanzapine buccal film may be shown to be dose-proportional, one dose level for olanzapine buccal film may be sufficient. The purpose of this pivotal comparison will be to investigate the relationship between olanzapine buccal film and the Zyprexa exposures (both Cmax and AUC) over the Zyprexa dosing range (5-20 mg). The study design will also allow for formal investigation of dose-proportionality for Zyprexa.

[0216] Food Effect Studies

[0217] Two food effect studies will be conducted with olanzapine buccal film: a two arm crossover to investigate the effect of a standard high fat meal, and a four-arm crossover to investigate the effect of position (upright or reclining) under fasting conditions and the effect of a standard moderate fat meal and a standard high fat meal under reclining conditions. The two-arm food effect study may show that a high fat meal taken within 30 minutes of administration may reduce Cmax on average with no effect on AUC. The four- arm study may show that position (whether upright or reclining) will have no little to no effect on olanzapine PK. The effect of a high fat meal (reclining condition) in the four-arm study may be in close agreement with the effect observed in the two-arm study. The moderate fat meal taken within 30 minutes of administration may reduced Cmax on averageAttorney Docket No.148570-006300 with no effect on AUC. Food may also be associated with a delay in Tmax. For example, median Tmax fasted may be approximately 1 hour whereas median Tmax under fed conditions may be 2-3 h. When conducting the food effect study for olanzapine buccal film, it is anticipated that the portion of the drug swallowed, will then be subject to a food effect as well. The study may show that the unique attributes of the formulation could result in a different food effect when compared to oral Valium. Following the administration of a high fat meal, olanzapine buccal film may demonstrate a food effect that has a reduction in Cmax, but no reduction in AUC.

[0218] Another objective of this study will be to determine if the administration procedure could be altered to drive more transmucosal absorption. An increase in the early (transmucosal) portion of the profile might then be sufficient to reduce the Tmax. To achieve this a second fasting arm will be added.

[0219] Olanzapine buccal film will be administered with the subjects sitting upright with the film applied to the buccal mucosa for a period of 5 min. At this time, they can swallow any remaining drug product. To drive further absorption, olanzapine buccal film is administered with the subject reclining on his or her side with the film placed the film on the lower buccal mucosa (such that all saliva will pool to the sight of administration). With subjects in this reclining position, olanzapine buccal film will be administered in crossover fashion under conditions of fasting, a moderate fat meal, and high fat meal. The time that subjects are requested to swallow will be increased from 5 min to 15 min to increase residence time. (A fourth treatment administration fasting in an upright position will be added as a control.) Residence time is routinely reported as one of three key drivers for transmucosal absorption (the others being surface area and permeation kinetics).

[0220] Population PK modeling will be used to select a dosing regimen to compensate for the differences in PK between olanzapine buccal film and Zyprexa (Table 3). In brief, the recommended olanzapine buccal film dose corresponding to each adult weight class as defined in Zyprexa label will be selected (1) to provide a dose sufficiently high to ensure that the predicted median of the resulting olanzapine Cmax following a moderate fat meal will be similar to the median Cmax following the labeled dose of Zyprexa, and (2) to provide a dose for which the predicted median of the resulting olanzapine Cmax under fasting conditions will not exceed the median Cmax values observed and demonstrated as safe in Phase 1 healthyAttorney Docket No.148570-006300 volunteer studies with olanzapine buccal film. Simulations based on population PK modeling may demonstrate that under conditions of a moderate fat meal, the proposed olanzapine buccal film dosing regimen will produce for each weight class a Cmax similar to the Cmax expected following the labeled dose of Zyprexa.

[0221] Table 3 Olanzapine Buccal Film Dosing Algorithm

[0222] *The performance of this dosing regimen will be evaluated in a clinical study (olanzapine buccal film Crossover with Zyprexa) in Patients with Agitation) reported below.

[0223] EMU Study

[0224] A study will be conducted in patients with agitation to determine whether the pharmacokinetics of olanzapine administered as olanzapine buccal film will be changed when olanzapine buccal film is given to patients in the interical state (not having agitation) vs. the ictal / periictal state (during or within 5 minutes of cessation of an agitation event). This study will be conducted with a fixed dose of olanzapine buccal film (12.5 mg to all patients) independent of weight.

[0225] Pharmacokinetic parameters will be derived from a single- dose, crossover study in which plasma samples for determination of olanzapine concentrations will be drawn at various times up to 4 h after administration of 12.5 mg olanzapine buccal film either when no agitation activity is observed in the preceding 3 h (interictal) or within 5 min of an agitation event (periictal). The study subjects will be adult men and women ages 17-65 with poorly controlled agitation events with impaired awareness. Patients will be excluded from analysis if both treatments are not completed, critical time points are missing, pre-dose olanzapine concentrations are >5% of the subsequent concentrations, or olanzapine buccal film is administered in a manner contrary to instructions. Cmax andAttorney Docket No.148570-006300 AUC0-4h values are geometric means; Tmax values are median values. 90% geometric confidence interval (CI) values will be determined using ln-transformed data.

[0226] Olanzapine Buccal Film Crossover with Zyprexa in Patients with a History of Agitation Associated with Bipolar Disorder

[0227] The performance of the proposed olanzapine buccal film dosing regimen will be tested in a head to head two-period crossover comparison with the Zyprexa (an olanzapine injectable formulation) in patients. The primary objective will be to compare the PK performance of olanzapine buccal film administered after a moderate fat meal with the Zyprexa administered after a moderate fat meal. Olanzapine buccal film will be administered according to the proposed weight-adjusted dosing regimen in Table 3 and Zyprexa will be administered according to the dosing regimen in the FDA-approved label. In addition, patients will be able to enroll in an optional third period to receive olanzapine buccal film after a high-fat meal. A secondary objective of the study will be to compare the PK performance of olanzapine buccal film administered after a high fat meal with the Zyprexa administered after a moderate fat meal.

[0228] The onset of the absorption profile may not significantly change with food but a clear bimodal absorption profile may be seen. Tmax may be shifted out more significantly than would be predicted if the entire dose is oral and a higher concentration is present to drive absorption. To verify this hypothesis and to attempt to quantify the amount of transmucosal delivery achieved during the administration of olanzapine buccal film, mathematical peak deconvolution will be utilized to describe each of the modes of absorption in the observed profiles. The profiles can then be analyzed individually and because of the high bioavailability resulting from either route of absorption, an estimate of the contribution from each route can be achieved.

[0229] Peak Deconvolution

[0230] Several profiles will be chosen for peak deconvolution using the procedure described below. The resulting profiles will then be analyzed for AUCO-t using Prism software. The ratio of the AUCO-t from each profile against the combined profile will then be used to assign a percentage to the transmucosal and oral routes of absorption. The profiles chosen will be the average profiles obtained from the four-arm crossover study using 15mg olanzapine buccal film fasted upright, 15mg olanzapine buccal film after a moderate fat meal,Attorney Docket No.148570-006300 15mg olanzapine buccal film after a high fat meal, and lastly, 5mg olanzapine buccal film from the dose proportionality study.

[0231] Rationale: Olanzapine buccal film is a novel dosage form of olanzapine under development for the management of patients with refractory agitation disorders requiring intermittent use of olanzapine to control increased agitation activity. We will assess the pharmacokinetic (PK) performance of olanzapine buccal film administered to adults with neurological agitation according to a weight-based regimen (dose range 12.5-17.5 mg) compared to Zyprexa administered according to the weight-based regimen recommended in the FDA-approved label (dose range 12.5-20 mg).

[0232] Methods: Adult men and women ages 18-65 years with a history of agitation associated with bipolar disorder on a stable regimen of >1 anti-neurological distress drug (no change in the 30 days prior to receiving study drug and no change anticipated over the course of the study) will be enrolled in a 2-period crossover study to receive a single dose of either olanzapine buccal film or Zyprexa in a randomized sequence and separated by a 28-day washout. Doses will be administered within 30 min of a standardized moderate-fat meal. Subjects will be confined to the clinic until 24 h after dosing. Olanzapine plasma samples will be obtained pre-dose and at intervals until 10 d after dosing to enable analysis of maximal plasma concentration (Cmax), time to C. (T.), area under the curve to the last measurable concentration (AUC0_T), and AUC extrapolated to infinity (AUC0_INF). Subjects will be monitored for adverse events (AE) throughout the study.

[0233] Although the invention has been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

Attorney Docket No.148570-006300 What is claimed is:

1. A method of treating a neurological disease or disorder comprising administering an oral film for delivery of a desired amount of a therapeutic compound, said film comprising: a) a water-soluble polymer matrix, a water swellable polymer matrix, or a combination thereof; b) a therapeutic compound having an average particle size D90 of less than about 160 microns; and an additive selected from the group consisting of a sweetener, a flavor, a flavor enhancer, a filler, a plasticizer, a dye, a pigment, a permeation enhancer, a buffer, a preservative, silicon dioxide, an anti-tacking agent, and any combination thereof.

2. The method of claim 1, wherein the therapeutic compound has an average particle size D90 of less than about 120 microns.

3. The method of claim 2, wherein the therapeutic compound has an average particle size D90 of less than about.100 microns.

4. The method of claim 2, wherein the therapeutic compound has an average particle size D50 of less than about 30 microns.

5. The method of claim 4, wherein the therapeutic compound has an average particle size D50 of less than about 20 microns.

6. The method of claim 5, wherein the therapeutic compound has an average particle size D10 of less than about 10 microns, 7. The method of claim 6, wherein the therapeutic compound has an average particle size D10 of less than about 5 microns.

8. The method of claim 1, wherein the oral film comprises about 0.5 mg to-about 100 mg of the therapeutic compound.

9. The method of claim 8, wherein the therapeutic compound is olanzapine.

10. The method of claim 1, wherein, upon placing the film in a medium, more than about 1.0% of the therapeutic compound is dissolved after about 3 minutes.

11. The method of claim 1, wherein, upon placing the film in a medium, more than aboutAttorney Docket No.148570-006300 12. The method of claim 1, wherein, upon placing the film in a medium, more than about 50% of the therapeutic compound is dissolved after about 5 minutes.

13. The method of claim 1, wherein the film comprises a sweetener selected front the group consisting of: sucralose, stevia, acesulfame potassium, saccharin, fructose, aspartame, and any combination thereof.

14. The method of claim 13, wherein the sweetener is present at about 0.5% to about 5% by weight of the oral film.

15. The method of claim 1, wherein the film comprises a fruit flavoring.

16. The method of claim 15 wherein the fruit flavoring is berry flavoring.

17. The method of claim 16, wherein the berry flavoring is present in about 0.1% to about 15% by weight of the oral film.

18. The method of claim 1, wherein less than about 10% by weight of the therapeutic compound is dissolved in an oral cavity.

19. The method of claim 1, wherein the neurological disease or disorder is acute agitation associated with schizophrenia, schizoaffective disorder, and bipolar disorder, maintenance treatment of schizophrenia, treatment-resistant depression, bipolar I disorder, Alzheimer’s Disease, autism spectrum disorder, post-traumatic stress disorder, attention deficit disorder, hyperactivity disorder, delirium, or chemotherapy-induced nausea and vomiting.