WO2025147530A1 - Naloxone buccal film product and uses thereof - Google Patents

Abstract

The present disclosure provides a naloxone film product for treatment and prevention of opioid overdoses. Also provided is a method of making the film product. The film product comprises a naloxone composition and at least one polymer.

Description

Docket No.10403/012319-WO0 NALOXONE BUCCAL FILM PRODUCT AND USES THEREOF RELATED APPLICATIONS This application claims priority to U.S. Provisional application Serial No. 63/618,072 filed January 5, 2024 which is incorporated by reference in its entirety. 1. FIELD The present disclosure provides a naloxone film product. Also provided is a method of making the film product and a method of treating or preventing an opioid overdose with the film product. 2. BACKGROUND Drug overdose is the predominant cause of unintentional mortality in the United States, with opioids being responsible for more than 70% of drug-related fatalities. On a daily basis, an estimated 200 individuals succumb to opioid overdoses in the United States. This alarming and persistently escalating rate of overdose deaths has prompted the declaration of an opioid epidemic. Over the 15-year timeframe spanning from 1999 to 2014, deaths associated with drug overdoses experienced a threefold increase, and this trend has continued since then. The genesis of the opioid epidemic can be traced back to the excessive prescription of opioid medications during the late 1990s. Subsequently, there was a shift towards more cautious prescribing practices due to the realization of the addictive potential of these medications. The difficulty in obtaining long-term opioid prescriptions drove many individuals to transition from prescription opioids to heroin. Concurrently, there was a notable surge in the initiation of opioid use with heroin, as opposed to prescription medications, with the proportion rising from 8.7% to 31.6%. In more recent times, the opioid epidemic has been characterized by a substantial proportion of deaths linked to synthetic opioids (e.g., fentanyl), accounting for over 73% of opioid-related fatalities. {10403/012319-US0/03532073.1} The escalation in heroin use, especially among individuals with no prior opioid exposure, combined with the heightened risk posed by synthetic additives, has significantly exacerbated the gravity of the opioid crisis. Federal agencies, such as the Drug Enforcement Agency (DEA) and the Centers for Disease Control and Prevention (CDC), have responded to this crisis by issuing recommendations for the implementation of guidelines for opioid prescribing, allocating increased funding for substance use treatment, and enhancing harm reduction strategies, including syringe service programs and the distribution of naloxone. (Sisson et al. 2023). Naloxone was first approved in the United States in 1971 under new drug application (NDA) 016636 as an injection product that could be administered subcutaneously (SC), intramuscularly (IM), or intravenously (IV). It is a nonselective opioid receptor antagonist, exhibiting the highest affinity for the mu-opioid receptor. When promptly administered, naloxone has the capability to reverse the life-threatening consequences of an opioid overdose, mitigating the risk of hypoxia-related harm and fatality. Nonetheless, there exist limitations to the utility of naloxone in this context. The antagonistic effects of naloxone may encounter challenges when addressing certain opioids, such as buprenorphine, which could necessitate larger doses of the antagonist than what is readily available. Additionally, it is noteworthy that the duration of action of naloxone is comparatively shorter than that of most opioids. Consequently, even with an antagonist on hand, it cannot serve as a replacement for seeking immediate medical assistance in cases of opioid overdose. Therefore, there is a need for new formulations and methods for combating opioid overdoses. 3. SUMMARY The present disclosure provides a film product comprising naloxone composition. In certain embodiments, the naloxone composition comprises naloxone in free base form or a pharmaceutically-acceptable salt, derivative, or solvate thereof. The film product can also include one or more polymers, and in certain embodiments, two or more {10403/012319-US0/03532073.1} polymers, as well as additional excipients such as surfactants, solubilizers and penetration enhancers (e.g., lipophilic enhancers). In certain embodiments, the film is intended for buccal administration to an oral cavity (including oral mucosa, tongue or cheek) of a subject in need thereof. In certain embodiments, the present disclosure relates to a naloxone buccal film, comprising: about 20 – 65 wt% naloxone or a pharmaceutically-acceptable salt or solvate thereof, and two or more polymers, wherein at least one polymer has a molecular weight below 65,000, and at least one polymer has a molecular weight of at least 65,000, and wherein the total amount of polymers is up to about 70 wt% of the film. In certain embodiments, the total amount of polymer having a molecular weight below 65,000 is from about 10 wt% to about 45 wt % of the film. In certain embodiments, the total amount of polymer having a molecular weight of at least 65,000 is less than about 25 % of the film. In certain embodiments, the total amount of polymer having a molecular weight of at least 65,000 is less than about 20 % of the film. In certain embodiments, film has an onset time of release of the naloxone of less than about 10 minutes. In certain embodiments, the film releases more than about 85% of the naloxone in less than about 10 minutes. In certain embodiments, the film comprises a polymer selected from the group consisting of hydroxypropylmethyl cellulose (HPMC), hydroxpropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose (CMC), gelatin, pullulan, sodium alginate, pectin, chitosan, poly(acrylic acid)^^carrageenan, and starch. In certain embodiments, the total amount of polymers is between about 5 wt% and about 70 wt% of the film. In certain embodiments, the film product comprises at least one HPMC polymer. In certain embodiments, the film product comprises at least two HPMC polymers. In {10403/012319-US0/03532073.1} certain embodiments, the film product comprises at least one HPMC polymer having a molecular weight below 65,000. In certain embodiments, the film product comprises least one HPMC polymer having a molecular weight of at least 65,000. In certain embodiments, the film product comprises at least one HPMC polymer having a molecular weight below 65,000, and at least one HPMC polymer having a molecular weight of at least 65,000. In certain embodiments, the film product comprises at least one HPMC polymer, wherein the total amount of HPMC polymer is about 3 to about 40 wt% of the film. In certain embodiments, the film product comprises at least two HPMC polymers, wherein the total amount of HPMC polymer is about 3 to about 40 wt% of the film. In certain embodiments, the at least one polymer having a molecular weight below 65,000 is selected from the group consisting of HPMC E3, HPMC E6, HPMC E15, PEG 400, povidone K12, povidone K25, and povidone K29/32. In certain embodiments, the at least one polymer having a molecular weight of at least 65,000 is selected from the group consisting of HPMC E50, HPMC K100LV, HPMC K100M, HPMC K200M, HEC 250G, HEC 250HX, HEC 250 HHX, PEO N10, PEO N60K, PEO 303,PVA 18-88, HPC L, poly(acrylic acid), and PVP-K90. In certain embodiments, the total amount of polymers is about 3 wt% to about 70 wt% of the film, for example about 5 wt% to about 70 wt% of the film, or about 5 wt% to about 60 wt% of the film. In certain embodiments, the film product further comprises at least one of a surfactant, plasticizer, a penetration enhancer (e.g., a lipophilic enhancer), a solubilizer, an emulsifier, a thickening agent, a stabilizer, a preservative, a taste modifier, a sweetening or flavoring agent, a coloring agent, a saliva-stimulating agent, an antioxidant, a buffering agent, or any combination thereof. In certain embodiments, the film product comprises at least one surfactant. The surfactant can facilitate onset time of naloxone penetration or release. The surfactant can be a cationic surfactant, an anionic surfactant, a zwitterionic surfactant, or a nonionic surfactant. {10403/012319-US0/03532073.1} In certain embodiments, the surfactant is selected from the group consisting of a polyoxylglyceride fatty acid ester, an alkylene glycol fatty acid ester (e.g., ethylene glycol fatty acid ester or propylene glycol fatty acid ester), a polyglycerol fatty acid ester, a polyoxyl hydrogenated castor oil, a polysorbate, a sorbitan fatty acid ester, a polyoxyethylene alkyl ether polysorbate, sodium lauryl sulfate, and a poloxamer. In certain embodiments, the film product comprises a polyoxylglyceride fatty acid ester. In certain embodiments, the film product comprises a polysorbate. In certain embodiments, the film product comprises a polyoxylglyceride fatty acid ester and a polysorbate. In certain embodiments, the polyoxylglyceride fatty acid ester comprises caprylocaproyl polyoxyl glycerides. In certain embodiments, the polyoxylglyceride fatty acid ester comprises caprylocaproyl polyoxyl-8 glycerides. In certain embodiments, the caprylocaproyl polyoxyl-8 glycerides comprise about 10-25 wt% of the film. In certain embodiments, the film product comprises caprylocaproyl polyoxyl-8 glycerides and polysorbate in a total amount 15-25 wt% of the film. In certain embodiments, the film product further comprises at least one lipophilic enhancer. In certain embodiments, the at least one lipophilic enhancer facilitates penetration of the naloxone active ingredient. In certain embodiments, the at least one lipophilic enhancer is selected from the group consisting of an alkylene glycol fatty acid ester, a fatty acid monoglyceride, a fatty acid diglyceride, a fatty acid triglyceride, a fatty alcohol, a polyoxyalkylene fatty alcohol ether, and a fatty acid. In certain embodiments, the at least one lipophilic enhancer is selected from the group consisting of: propylene glycol monolaurate, glyceryl monocaprylate, caprylic/capric triglyceride, oleic acid, oleyl alcohol, and polyoxyethylene 10 oleoyl ether. In certain embodiments, the film comprises a pharmaceutically-acceptable salt of naloxone. In an embodiment, the pharmaceutically-acceptable salt is a hydrochloride (HCl) salt. In certain embodiments, film product comprises about 30-55 wt % of naloxone or the pharmaceutically-acceptable salt or solvate thereof. {10403/012319-US0/03532073.1} In certain embodiments, film product has a thickness of about 0.01 mm to about 0.15 mm. In further aspects, provided is a method of treating opioid overdose in a subject in need thereof, the method comprising administering a therapeutically-effective amount of a naloxone buccal film of the present disclosure to an oral mucosa or tongue of the subject. In further aspects, provided is a method of treating opioid dependence in a subject in need thereof, the method comprising administering a therapeutically-effective amount of a naloxone buccal film of the present disclosure to an oral mucosa or tongue of the subject. In further aspects, provided is a method of treating pain in a subject in need thereof, the method comprising administering a therapeutically-effective amount of a naloxone buccal film of the present disclosure to an oral mucosa or tongue of the subject. In further aspects, provided is a method for treating a subject exhibiting symptoms of respiratory depression associated with known or suspected opioid overdose, the method comprising administering a therapeutically-effective amount of a naloxone buccal film of the present disclosure to an oral mucosa or tongue of the subject. In certain embodiments, about 2 mg - 30 mg of the naloxone or pharmaceutically- acceptable salt thereof is delivered from the film to the subject. In certain embodiments, the subject is a human. In further aspects, provided is a method for preparing the naloxone film product of the present disclosure. The method comprises (a) mixing a naloxone composition with at two or more polymers in a solvent to form a mixture, wherein at least one polymer has a molecular weight below 65,000, and at least one polymer has a molecular weight of at least 65,000 wherein the total amount of polymers is less than about 70 wt% of the mixture, and the naloxone is about 20 – 65 wt% of the mixture; (b) performing a solvent vapor coating process on the mixture to form a film; and (c) drying the film. In certain embodiments, the film is dried to less than about 10% by weight water. In certain embodiments, the mixture formed in step (a) is a uniform mixture. {10403/012319-US0/03532073.1} In certain embodiments, step (a) comprises mixing naloxone in a solvent comprising water, alcohol or a mixture thereof to form a mixture; optionally adding a surfactant and/or a lipophilic enhancer; and adding the two or more polymers. In other embodiments, step (a) comprises forming a microemulsion. The microemulsion can be formed by mixing naloxone with a surfactant and a lipophilic enhancer to form a solution; and adding a solvent comprising water, alcohol or a mixture thereof to the solution. 4.1 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1: In Vitro Skin Permeation Study: Penetration of Naloxone from Formulations Utilizing Different Polymer Compositions. FIG. 2: Permeation Result of Naloxone Formulations for the Effect of Drug Loading. FIGs. 3A-3B: Permeation Result of Naloxone Formulations in the Presence of the Surfactant. Fig. 3A displays the results a permeation study comparing the formulations of Ex. 15 and Ex. 18. Fig. 3B is an expanded view of a portion of Fig. 3A around the onset of penetration. FIG. 4: Permeation Result of Naloxone Formulations for the Effects of the Different Surfactants. FIG. 5: Permeation Result of Naloxone Formulations Using Combinational Polymers and Lipophilic Enhancer. FIG. 6: In vitro Dissolution of Different Naloxone Buccal Formulations. FIG. 7: In vivo Dog Pharmacokinetic Profile of Different Naloxone Buccal Formulations. FIG. 8. An IVPT study was conducted, and the data indicated that the addition of a flavoring agent does not affect the permeability of the formulation but enhances the overall palatability of the film. FIG. 9. In vivo Dog Pharmacokinetic Profile of Different Delivery Route. FIG. 10. In vivo Dog Pharmacokinetic Profile Compared to Narcan. {10403/012319-US0/03532073.1} 4.2 DEFINITIONS As used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to “an ingredient” includes mixtures of ingredients, reference to “an active pharmaceutical agent” includes more than one active pharmaceutical agent, and the like. The terms “active agent”, “pharmacologically active agent” and “drug” are used interchangeably herein to refer to a chemical material or compound that includes a desired pharmacological, physiological effect and include agents that are therapeutically effective. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives and analogs of those active agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, inclusion complexes, enantiomers S(-) or R(+), analogs of the active agent (e.g., naloxone). The pharmaceutically active agent of the present disclosure may be in the form of a pharmaceutically-acceptable salt. As used herein, a "salt" is a salt of the present compound which has been modified by making acid or base, salts of the compounds. The salt may be pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately treating a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, {10403/012319-US0/03532073.1} maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66:1-19). In certain embodiments, the film of the present disclosure comprises naloxone in the form of a pharmaceutically-acceptable salt. In certain embodiments, the pharmaceutically-acceptable salt is a hydrocholoride salt (naloxone HCl). The present methods also encompass administering a physiologically functional derivative of the present compound. As used herein, the term “physiologically functional derivative” refers to a compound (e.g., a drug precursor) that is transformed in vivo to yield the present compound or its active metabolite, or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis. Prodrugs are such derivatives, and a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. As used herein, the term “about” or “approximately” as a modifier to a quantity is intended to mean + or - 5% inclusive of the quantity being modified. As used herein, “wt%”, “% w/w” or “% (w/w)” refer to % by weight of the composition. The present agent/composition may be administered therapeutically to achieve a therapeutic benefit (“treating”) or prophylactically to achieve a prophylactic benefit (“preventing”). By therapeutic benefit is meant eradication or amelioration of the disorder or condition being treated, and/or eradication or amelioration of one or more of the symptoms associated with the disorder or condition. By prophylactic benefit is meant prevention or delay of the onset of the condition, and/or prevention or delay of the onset of one or more of the symptoms associated with the condition. In certain embodiments, an effective amount of the present agent/composition to be administered prevents the condition from developing or being exacerbated into more serious conditions. {10403/012319-US0/03532073.1} “Treating” or “treatment” of a state, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder, or condition developing in a person who may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical symptom, sign, or test, thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms or signs. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician. An effective amount of an agent/drug refers to a therapeutically effective amount or a prophylactically effective amount. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. In certain embodiments, since a prophylactic dose is used in subjects prior to or at an earlier stage of a disorder, the prophylactically effective amount is less than the therapeutically effective amount. In certain embodiments, the prophylactically effective amount is similar to, identical to, or more than, the therapeutically effective amount. A therapeutically effective amount of a drug is an amount effective to demonstrate a desired activity of the drug. A therapeutically effective amount may vary depending on the compound, the disorder and its severity and the age, weight, physical condition and responsiveness of the subject to be treated. In certain embodiments, the drug-containing layer, or the reservoir layer or the present composition further comprises a pharmaceutically acceptable carrier, vehicle, excipient and/or diluent. The term “film product” is intended to refer to a self-contained, discrete dosage form that, when administered to a subject for disintegration or dissolution to release the drug(s) for local and/or systemic absorption. The term “oral film” is intended to refer to a self-contained, discrete dosage form that, when administered to a subject orally for disintegration or dissolution to release the drug(s) for local and/or systemic absorption. Some important characteristics of an oral {10403/012319-US0/03532073.1} film include flux rate, lag time and stability. Flux rate relates to the rate at which the oral film delivers naloxone. Lag time relates to the time required for naloxone blood concentration to reach steady state after application of the oral film. Lag time preferably matches naloxone metabolic rate in order to minimize fluctuations in blood concentration between applications of successive oral film. Lastly, stability relates to the amount of impurities that develops within the oral film while in storage. “Molecular weight” of proteins is generally measured in Daltons (Da). 5. DETAILED DESCRIPTION The present disclosure provides a film product containing naloxone, or a pharmaceutically acceptable salt, derivative, or solvate thereof, as an active agent. In certain embodiments, the film product is for treatment or prevention of an opioid overdose. In one or more embodiments, the film comprises at least one polymer (e.g., hydroxyethyl cellulose and/or hydroxypropylmethyl cellulose) or, in certain embodiments, at least two polymers. In certain embodiments, the active ingredient is evenly distributed throughout the film. The even or uniform distribution of the active ingredient is achieved by controlling one or more parameters, and particularly the elimination of air pockets prior to and during film formation and the use of a drying process that reduces aggregation or conglomeration of the components in the film as it forms into a solid structure. The present application further provides methods for producing film products and methods for treating or preventing an opioid overdose. The method may comprise administering the film product to a subject in need. 5.1 Films for the delivery of Naloxone In certain embodiments, film products are film formulations intended for delivery of naloxone or naloxone-based compositions and dissolve after delivery. In certain {10403/012319-US0/03532073.1} embodiments, a pharmaceutically active ingredient that is suitable for transmucosal or oral administration may be contained in the disclosed film product. In one embodiment, the present disclosure provides a naloxone oral dissolving film. In one embodiment, the present disclosure provides a naloxone oral dissolving film for buccal administration. Administration is generally to an oral cavity of a subject, including any portion of the mouth (e.g., oral mucosa, tongue or cheek). Naloxone is an opioid antagonist that reverses or reduce the effects of opioids in the body of a human subject. Naloxone is a synthetic morphinan derivative that is chemically designated of N-allylnoroxymorphone (or 17-allyl-4,5^-epoxy-3,14- dihydroxymorphinan-6-one). The chemical formula of naloxone is C19H21NO4. Naloxone is a racemic mixture of (–)-naloxone (levonaloxone) and (+)-naloxone (dextronaloxone) — two enantiomers, of which only the former is active at the opioid receptor:

In certain embodiments, naloxone is in the form of a pharmaceutically-acceptable salt. In certain embodiments, naloxone is in the form of naloxone HCl. In certain embodiments, naloxone is in the free base form. In certain embodiments, the film product comprises a pharmaceutically acceptable salt, derivative, or solvate of naloxone. In certain embodiments, the naloxone or a pharmaceutically acceptable salt, derivative or solvate thereof is in an amount ranging from about 20-40 wt% or from {10403/012319-US0/03532073.1} about 40-60 wt% relative to total weight of the film product. In certain embodiments, the naloxone or a pharmaceutically acceptable salt, derivative or solvate thereof is in an amount ranging from about 20 – 65 wt%, about 30 – 65 wt%, about 30 – 35 wt%, about 35 – 40 wt%, about 40 – 45 wt%, about 45 – 50 wt%, about 50 – 55 wt%, about 50 – 60 wt%, or about 60 – 65 wt% of the film. In certain embodiments, the naloxone or a pharmaceutically acceptable salt thereof is in an amount of about 55-65 wt% of the film. In certain embodiments, the naloxone or a pharmaceutically acceptable salt thereof is in an amount of about 65 wt % or less of the film. In certain embodiments, the dosage of naloxone or a pharmaceutically acceptable salt, derivative or solvate thereof delivered to the subject via the film of the present application is between about 2 mg to about 4 mg, about 4 mg to about 6 mg, about 6 mg to about 8 mg, about 8 mg to about 10 mg, about 10 mg to about 12 mg, about 12 mg to about 14 mg, about 14 mg to about 16 mg, about 16 mg to about 18 mg, about 18 mg to about 20 mg, about 20 mg to about 22 mg, about 22 mg to about 24 mg, about 24 mg to about 26 mg, about 26 mg to about 28 mg, about 28 mg to about 30 mg. In certain embodiment, the dosage form of naloxone or a pharmaceutically- acceptable salt, derivative or solvate thereof dissolves completely within about 30 seconds to about 1 minute, about 1 minute to about 2 minutes, about 2 minutes to about 3 minutes, about 3 minutes to about 4 minutes, about 4 minutes to about 5 minutes following placement within the oral mucosa of the individual. The naloxone or salt thereof may be present in the film product in combination with another active pharmaceutical ingredient. Suitable active pharmaceutical ingredients for combination with naloxone would be known to those of skill in the art. Oral thin films are thin films containing a pharmaceutically active ingredient which are placed directly in the oral cavity or are placed against the oral mucosa (e.g., on the tongue or cheek) and dissolve there. In particular, they are thin active-ingredient- containing, polymer-based films, which, when applied to a mucosa, in particular the oral mucosa, deliver the active ingredient directly into the mucosa. In one embodiment, the oral thin films are not sticky on the outside. In certain embodiments, the film product {10403/012319-US0/03532073.1} comprises multiple layers. In certain embodiments, the film product further comprises a protective layer. The rich blood supply to the oral mucosa can facilitate a quick transfer of the active ingredient into the bloodstream. This delivery system has the advantage that the active ingredient is absorbed for the most part by the mucosa, and therefore avoids first- pass metabolism. The active ingredient may be dissolved, emulsified (e.g., the film can include a microemulsion) or dispersed in the film. Suitable active ingredients may also be swallowed once the oral thin film has dissolved in the mouth, and thus may be absorbed via the gastrointestinal tract. 5.2 Polymers and Other Components for Film product Polymers In one or more embodiments, the naloxone film product of the present application comprises at least one polymer. In one or more embodiments, the naloxone film product comprises two or more polymers. In certain embodiments, the polymers are water- soluble polymers. Water-soluble polymers comprise chemically different natural or synthetic polymers, the common feature of which is their solubility in water or aqueous media. In certain embodiments, the polymers have a number of hydrophilic groups sufficient for the water-solubility and are not cross-linked. In certain embodiments, the hydrophilic groups may be non-ionic, anionic, cationic and/or zwitterionic. 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 soluble in water, or absorbs water. The materials useful with the present invention may be water soluble at room temperature and other temperatures, such as temperatures exceeding room temperature. Moreover, the materials may be water soluble at pressures less than atmospheric pressure. In certain embodiments, the water soluble polymers are water soluble having at least 20% by weight water uptake or at least 25% by weight water uptake. Films or dosage forms of the {10403/012319-US0/03532073.1} present invention formed from such water soluble polymers are desirably sufficiently water soluble to be dissolvable upon contact with bodily fluids. Examples of suitable polymers include, but are not limited to, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyethylene oxide (PEO), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose (CMC), gelatin, pullulan, sodium alginate, poly(acrylic acid)^^carrageenan, pectin, chitosan, starch and copolymers of any of the foregoing. In certain embodiments, particularly in embodiments in which the film comprises two or more polymers, the two or more polymers can include at least one high molecular weight polymer and at least one low molecular weight polymer. As used herein, the term “low molecular weight polymer” refers to a polymer having a molecular weight below 65,000, and the term “high molecular weight polymer” refers to a polymer having a molecular weight or at least 65,000, i.e., a molecular weight equal to or exceeding 65,000. As used herein, molecular weight is expressed in Daltons or, where appropriate, kilodaltons (kD). In certain embodiments, the high molecular weight polymer is hydroxypropylmethyl cellulose (HPMC). In certain embodiments, the high molecular weight polymer is hydroxyethyl cellulose (HEC). In certain embodiments, the high molecular weight polymer is hydroxypropyl cellulose (HPC). In certain embodiments, the high molecular weight polymer is polyethylene oxide (PEO). In certain embodiments, the high molecular weight polymer is polyvinyl alcohol (PVA). In certain embodiments, the high molecular weight polymer is polyacrylic acid. In certain embodiments, the high molecular weight polymer is polyvinylpyrrolidone (PVP). In certain embodiments, the high molecular weight polymer is selected from the group consisting of HPMC E50 (MW 91,300), HPMC K100LV (MW 164,000), HPMC K100M (MW 1,000,000), HPMC K200M (MW 1,200,000), HEC 250G (MW 300,000), HEC 250HX (MW 1,000,000), HEC 250 HHX (MW 1,300,000), PEO N10 (MW 100,000), PEO N60K (MW {10403/012319-US0/03532073.1} 2,000,000), PEO 303 (MW 7,000,000), PVA 18-88 (MW 130,000), HPC L (MW 95,000), poly(acrylic acid) (MW 450,000), and PVP-K90 (MW 1,300,000). In certain embodiments, the low molecular weight polymer is hydroxypropylmethyl cellulose (HPMC). In certain embodiments, the low molecular weight polymer is hydroxyethyl cellulose (HEC). In certain embodiments, the low molecular weight polymer is hydroxypropyl cellulose (HPC). In certain embodiments, the low molecular weight polymer is polyethylene oxide (PEO). In certain embodiments, the low molecular weight polymer is polyvinyl alcohol (PVA). In certain e embodiments, the low molecular weight polymer is polyacrylic acid. In certain embodiments, the low molecular weight polymer is polyvinylpyrrolidone (PVP). In certain embodiments, the low molecular weight polymer is polyethylene glycol (PEG). In certain embodiments, the low molecular weight polymer is polyvinylpyrrolidone (PVP). In certain embodiments, the low molecular weight polymer is selected from the group consisting of HPMC E3 (MW 20,000), HPMC E6 (MW 40,000), HPMC E15 (MW 52,000), PEG 400 (MW 6,000) PVP K12, PVP K25, and PVP K29/32. In certain embodiments, the proportion of high molecular weight polymer in the two or more polymers is less than about 25% by weight (wt%) relative to the total weight of the film product, for example less than about 20% by weight (wt%), less than about 15% by weight (wt%), less than about 10% by weight (wt%), from about 3% to about 20% by weight (wt%), from about 3% to about 15% by weight (wt%), from about 3% to about 10% by weight (wt%), from about 3% to about 5% by weight (wt%), from about 5% to about 15% by weight (wt%), or from about 5% to about 10% by weight (wt%), for example about 3%, about 5%, about 8%, about 10%, about 12%, about 14%, about 15%, about 16%, about 18%, or about 20% by weight (wt%) relative to the total weight of the film product. In certain embodiments, the proportion of low molecular weight polymer in the two or more polymers is about 45 wt% or less relative to the total weight of the film product. In certain embodiments, the low molecular weight polymer is present in an amount of between about 10% by weight (wt%) to about 45% by weight (wt%) relative {10403/012319-US0/03532073.1} to the total weight of the film product. For example, the low molecular weight polymer can be present in an amount of less than about 45 wt%, less than about 40 wt%, less than about 35% by weight (wt%), less than about 30% by weight (wt%), less than about 25% by weight (wt%), less than about 20% by weight (wt%), from about 5% to about 30% by weight (wt%), from about 10% to about 40% by weight (wt%), from about 10% to about 30% by weight (wt%), from about 5% to about 20% by weight (wt%), from about 10% to about 25% by weight (wt%), from about 15% to about 25% by weight (wt%), for example about 5%, about 7.5%, about 10%, about 15%, about 20% about 25%, or about 30% by weight (wt%), relative to the total weight of the film product. In certain embodiments, the low molecular weight polymer is hydroxypropylmethyl cellulose (HPMC). In certain embodiments, the low molecular weight polymer is hydroxyethyl cellulose (HEC). In certain embodiments, the low molecular weight polymer is polyvinylpyrrolidone (PVP). In certain embodiments, the proportion of high molecular weight polymer in the two or more polymers is less than about 25 wt %, preferably about 20 wt% or less, and the proportion of low molecular weight polymer in the two or more polymers is about 45 wt % or less, preferably about 10 wt% - 45 wt%, relative to the total weight of the film product. In certain embodiments, the total amount of polymers in the film product is up to about 85 wt% of the film. In certain embodiments, the total amount of polymers in the film product is up to about 70 wt% of the film. In certain embodiments, the total amount of polymers in the film product ranges from about 5% to about 25% by weight (wt%), from about 5% to about 10% by weight (wt%), from about 10% to about 15% by weight (wt%), from about 15% to about 20% by weight (wt%), from about 20% to about 25% by weight (wt%), from about 25% to about 30% by weight (wt%), from about 30% to about 35% by weight (wt%), from about 35% to about 40% by weight (wt%), from about 40% to about 45% by weight (wt%), from about 45% to about 50% by weight (wt%), from about 50% to about 55% by weight (wt%), from about 55% to about 60% by weight {10403/012319-US0/03532073.1} (wt%), from about 60% to about 65% by weight (wt%), from about 65% to about 70% by weight (wt%), from about 70% to about 75% by weight (wt%), or from about 75% to about 80% by weight (wt%), from about 80% to about 85% by weight (wt%), relative to the total weight of the film product. In certain embodiments, the total amount of polymers in the film product is about 5 wt %, about 10 wt %, about 15 wt %, about 20 wt %, about 35 wt %, about 30 wt %, about 35 wt %, about 40 wt %, about 45 wt %, about 50 wt %, about 55 wt %, about 60 wt %, about 65 wt %, or about 70 wt % relative to the total weight of the film product. In certain embodiments, the film comprises hydroxypropylmethyl cellulose (HPMC). HPMC is a polymer whose cellulose hydroxyl groups are partly methylated and 2-hydroxypropylated. Several types of HPMC are available differing in the degree of substitution and molecular weight distribution. In certain embodiments, the total amount of hydroxypropyl methylcellulose is less about 70% by weight (wt%) of the film. In certain embodiments, the film comprises one hydroxypropyl methylcellulose (HPMC) polymer. In certain embodiments, the film comprises two hydroxypropyl methylcellulose (HPMC) polymers. In certain embodiments, the film comprises at least one low molecular weight hydroxypropyl methylcellulose (HPMC) polymer having a molecular weight below 65,000. In certain embodiments, the film comprises at least one high molecular hydroxypropyl methylcellulose (HPMC) polymer having a molecular weight of at least 65,000. In certain embodiments, the film comprises a low molecular weight hydroxypropyl methylcellulose (HPMC) polymer and a high molecular weight hydroxypropyl methylcellulose (HPMC) polymer. In certain embodiments, the total amount of hydroxypropyl methylcellulose (HPMC) is about 3-40 wt%, about 10-40 wt%, about 15-40 wt%, about 20-40 wt%, about 20-30 wt%, or about 25-40 wt% of the film. In certain embodiments, the molecular weight of the HPMC can range from about 20,000 to about 2,000,000. In certain embodiments, the molecular weight of the HPMC is about 65,000 or higher (denoted “high molecular weight HPMC”). In certain embodiments, the molecular weight of the HPMC is less than about 65,000 (denoted {10403/012319-US0/03532073.1} “low molecular weight HPMC”). In certain embodiments, the molecular weight of the HPMC is about 1,500,000 or lower. In certain embodiments, the molecular weight of the HPMC is about 1,200,000 or lower. In certain embodiments, the molecular weight of the HPMC is about 1,000,000 or lower. In certain embodiments, the molecular weight of the HPMC is about 500,000 or lower. In certain embodiments, the molecular weight of the HPMC is about 400,000 or lower. In certain e embodiments, the molecular weight of the HPMC is about 300,000 or lower. In certain embodiments, the molecular weight of the HPMC is about 200,000 or lower. In certain embodiments, the molecular weight of the HPMC is about 100,000 or lower. In certain embodiments, the molecular weight of the HPMC is about 65,000 or lower. In certain embodiments, the molecular weight of the HPMC is about 50,000 or lower. In certain embodiments, the molecular weight of the HPMC is about 25,000 or lower. In certain e embodiments, the HPMC is of a series E (HPMC-E, low viscosity grade). In certain embodiments, the HPMC is of a series K (HPMC-K, high viscosity grade). In certain embodiments, the proportion of high molecular weight HPMC polymer in the two or more polymers is less than about 25 wt % or less, preferably about 20 wt% or less, and the proportion of low molecular weight HPMC polymer in the two or more polymers is about 45 wt % or less, preferably about 10 wt% - 45 wt%, relative to the total weight of the film product. In certain e embodiments, at least one polymer comprises polyethylene oxide (PEO). Polyethylene Oxide (also denoted PEO, polyox, polyoxirane, or polyoxyethylene) are high molecular weight water soluble polymers. Non-limiting examples of PEO polymers that can be used in the present disclosure are PEO N10 (MW 100,000), PEO N60 (MW 200,000), PEO N80 (MW 200,000), PEO N750 (MW 300,000), PEO N-3000 (MW 400,000), PEO 205 (MW 600,000), PEO 1105 (MW 900,000), PEO N-12K (MW 1,000,000), PEO N-60K (MW 2,000,000), PEO 301 (MW 4,000,000), and PEO 303 (MW 7,000,000). In certain embodiments the PEO is a low molecular weight polymer {10403/012319-US0/03532073.1} (i.e., has a molecular weight below 65,000). In certain embodiments the PEO is a high molecular weight polymer (i.e., has a molecular weight of at least 65,000). In certain embodiments, polyethylene oxide comprises about 1-25 wt%, about 2- 20 wt%, about 2-10 wt%, about 3-5 wt%, about 5-20 wt%, about 5-15 wt%, about 5-10 wt%, or about 3-20 wt% of the film. In certain embodiments, at least one polymer comprises hydroxyethyl cellulose (HEC). In certain embodiments, the total amount of hydroxyethyl cellulose is about 3-25 wt% of the film. In certain embodiments, the hydroxyethyl cellulose comprises about 20 wt% or more of the film. In certain embodiments, the molecular weight of the hydroxyethyl cellulose can range from about 200,000 to about 1,500,000. In certain embodiments, the molecular weight of the hydroxyethyl cellulose is about 1,300,000 or less. In certain embodiments, the molecular weight of the hydroxyethyl cellulose is about 1,000,000 or less. In certain embodiments, the molecular weight of the hydroxyethyl cellulose is about 500,000 or less. In certain embodiments, the molecular weight of the hydroxyethyl cellulose is about 400,000 or less. In certain embodiments, the molecular weight of the hydroxyethyl cellulose is about 300,000 or less. In certain embodiments, hydroxyethyl cellulose comprises about 3-25 wt%, about 15-24 wt%, about 10-12 wt%, about 12-14 wt%, about 14-16 wt%, about 15-16 wt%, about 16-18 wt%, about 18-20 wt%, about 20-22 wt%, or about 22-24 wt% of the film. In certain embodiments, the amount of naloxone or pharmaceutically-acceptable salt or solvate thereof is about 30 – 65 wt% of the` film, and the total amount of hydroxyethyl cellulose is about 3-25 wt% of the film. In certain embodiments, one or more additional polymers that can also be incorporated into the film product include biodegradable polymers, copolymers, block polymers and combinations thereof. The additional polymers or polymers include but are not limited to poly(glycolic acid) (PGA), poly(lactic acid) (PLA), copolymers of lactide and glycolide referred to as poly(lactic-co-glycolic acid) or poly(lactide-co-glycolide) (PLGA), polydioxanoes, polyoxalates, poly(α-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, {10403/012319-US0/03532073.1} 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 (poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of α-amino acids, copolymers of α-amino acids and caproic acid, copolymers of α-benzyl glutamate and polyethylene glycol, copolymers of succinate and poly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixtures thereof. In certain embodiments, the polymers have the advantage that they are compatible with a large number of pharmaceutically active ingredients and are safe for treatment of a subject. Excipients In certain embodiments, the film of the present disclosure includes one or more pharmaceutically-acceptable excipients. In certain embodiments, the film contains one or more of a penetration enhancer (e.g., a lipophilic enhancer), a plasticizer, a solubilizer, an emulsifier, a sweetening and flavoring agent, a coloring agent, a saliva-stimulating agent, a thickening agent, a stabilizer, a preservative, an antioxidant and a buffering agent. In yet other embodiments, the dosage form includes naloxone or naloxone HCl, at least two polymers, at least one of which is a low molecular weight polymer (MW below 65,000) and at least one of which is a high molecular weight polymer (MW at least 65,000), and at least one of a surfactant, a plasticizer, a penetration enhancer, a solubilizer/emulsifier, a taste modifier, and/or a buffering agent. In particular aspects, the polymer is HPMC, PEO or a combination thereof. In yet other embodiments, the dosage form includes naloxone or naloxone HCl, at least two polymers, at least one of which is a low molecular weight polymer and at least one of which is a high molecular weight polymer, a surfactant and a penetration {10403/012319-US0/03532073.1} enhancer. As used herein, the term “penetration enhancer” denotes a substance that can increase or facilitate the ability of a compound (e.g., a drug) to penetrate through a barrier, e.g., skin. In certain embodiments, the penetration enhancer can be a lipophilic enhancer, i.e., a penetration enhancer that is fat-soluble. A lipophilic enhancer can dissolve in lipids and therefore can better penetrate the skin’s oily outer layer, the stratum corneum, to deliver a compound (e.g., a drug) more effectively. Thus, in certain embodiments, the enhancer enhances accumulated amount of naloxone or salt thereof that is released from the film. In certain embodiments, the surfactant improves the onset time of release of the naloxone or salt thereof from the film. In certain embodiments, the film comprises a microemulsion. In one or more embodiments, the film product can further comprise one or more surfactants. In certain embodiments, the surfactant can facilitate onset time of naloxone penetration or release of the naloxone active ingredient from the film. In certain embodiments, the surfactant a cationic surfactant, an anionic surfactant, a zwitterionic surfactant, or a nonionic surfactant. In certain embodiments, the surfactant is selected from the group consisting of polyoxylglyceride fatty acid ester (including polyoxylglyceride mono-fatty acid esters and polyoxylglyceride di-fatty acid esters), polyoxyethylene-polyglycerin fatty acid esters, glycerol fatty acid esters (including mono, di- and tri-fatty acid ester glycerides), (poly)ethylene glycol fatty acid esters (including mono-fatty acid esters di-fatty acid esters such as polyoxyethylene monostearate, monocaprylate or monolaurate), (poly)propylene glycol fatty acid esters (including mono-fatty acid esters and di-fatty acid esters of propylene glycol), polyoxyethylene alkyl ether such as polyoxyethylene capryl, stearyl or lauryl ether, polyoxyl castor oil, polyoxyl hydrogenated castor oil, polyoxyl hardened castor oil, polysorbates, sorbitan fatty acid esters such as sorbitan monostearate, monocaprylate or monolaurate, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate (Tween), polyoxyethylene alkyl ether polysorbate, sodium lauryl sulfate, polyoxyethylene-polyoxypropylene block copolymers known as “poloxamer”, polyvinyl alcohol (PVA), and polyethylene glycols. {10403/012319-US0/03532073.1} In certain embodiments, the one or more surfactants can include but are not limited to polyoxyl 40 hydrogenated castor oil, caprylocaproyl polyoxyl glycerides (e.g., caprylocaproyl polyoxyl-8 glycerides), glyceryl monocaprylocaprate, sorbitan monooleate, polysorbates (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), dipropylene glycol, poly(propylene glycol), propylene glycol monolaurate, and polyethylene glycol. In certain embodiments, the one more surfactants is present in an amount ranging from about 5% to about 10% by weight (wt%), from about 10% to about 15% by weight (wt%), from about 15% to about 20% by weight (wt%), from about 20% to about 25% by weight (wt%), from about 25% to about 30% by weight (wt%), from about 30% to about 35% by weight (wt%), from about 35% to about 40% by weight (wt%), from about 40% to about 45% by weight (wt%) relative to the total weight of the film product. In certain embodiments, the film product comprises a polyoxylglyceride fatty acid ester. A polyoxylglyceride fatty acid ester comprises a glyceride moiety bonded to a polyethylene glycol (polyoxyl) moiety and one or more fatty acids (including polyoxylglyceride mono-fatty acid esters and polyoxylglyceride di-fatty acid esters). In certain embodiments the polyoxylglyceride fatty acid ester is present in an amount ranging from about 5-25 wt% of the film, about 5-10 wt% of the film, about 10-15 wt% of the film, or about 15-20 wt% of the film, or about 20-25 wt% of the film. The term "fatty acid" as used herein describes aliphatic monocarboxylic acids. A fatty acid can be saturated or unsaturated. For example, aliphatic hydrocarbon chains of known naturally occurring fatty acids are generally unbranched and contain an even number of from about 4 to about 26 carbons. Embodiments of the present disclosure encompass such naturally occurring fatty acids as well as non-naturally occurring fatty acids which may contain an odd number of carbons and/or a non-naturally occurring linkers. Exemplary embodiments include fatty acids having from 6 to 26 carbons, and others include fatty acids having from 6 to 12 carbons or from 12 to 18 carbons in the aliphatic hydrocarbon chain. In still other embodiments, fatty acids can have greater than 24 carbons in the aliphatic hydrocarbon chain. The fatty acids can also {10403/012319-US0/03532073.1} be branched at one or more location along the hydrocarbon chain. In certain e embodiments, the fatty acid chain can be saturated or unsaturated. Suitable saturated fatty acids can be, but are not limited to, those selected from the group consisting of butyric acid (C4), valeric acid (C5), caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C₉), capric acid (C₁₀), lauric acid (C₁₂), myristic acid (C₁₄), pentadecanoic acid (C15), palmitic acid (d^), margaric acid (C17), stearic acid (C1S), arachidic acid (C20), behenic acid (C22), lignoceric acid (C24), and cerotic acid (C26). Suitable unsaturated fatty acids can be, but are not limited to, those selected from the group consisting of oleic acid, erucic acid, nervonic acid, linoleic acid, ^-linolenic acid, arachidonic acid, ^-linolenic acid, eicosapentanoic acid (EPA), docosahexanoic acid (DHA), oleic acid, palmitoleic acid and myristoleic acid. Exemplary fatty acids include, but are not limited to, saturated or unsaturated fatty acid having a chain of 6 to 20 carbons, such as but not limited to caprylic acid, linoleic acid, oleic acid, linolenic acid, stearic acid, isostearic acid and palmitic acid. In an embodiment, the polyoxylglyceride fatty acid ester comprises caprylocaproyl polyoxyl-8 glycerides. In certain e embodiments, the caprylocaproyl polyoxyl-8 glycerides comprise about 10-25 wt% of the film. In certain embodiments, the film comprises a polysorbate. Examples of polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (40) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (60) sorbitan monostearate), and polysorbate 80 (polyoxyethylene (80) sorbitan monooleate). In certain embodiments the polysorbate is about 5-25 wt% of the film, about 5-10 wt% of the film, about 10-15 wt% of the film, or about 15-20 wt% of the film, or about 20-25 wt% of the film. In certain embodiments, the film comprises a polyoxylglyceride fatty acid ester and/or a polysorbate. In certain embodiments, the film product can include caprylocaproyl polyoxyl-8 glycerides and/or polysorbate (e.g., polysorbate 80, polysorbate 20). In certain embodiments, the film comprises caprylocaproyl polyoxyl-8 glycerides and a polysorbate. In certain embodiments, the total amount of caprylocaproyl {10403/012319-US0/03532073.1} polyoxyl-8 glycerides and polysorbate is about 10-25 wt% of the film, for example about 10-20 wt%, about 15-20 wt%, or about 12-20 wt% of the film. In certain embodiments, caprylocaproyl polyoxyl-8 glycerides or polysorbate comprise 15-20 wt% of the film. In certain embodiments, the film further comprises caprylocaproyl polyoxyl-8 glycerides and/or polysorbate 20. In certain embodiments, caprylocaproyl polyoxyl-8 glycerides or polysorbate 20 comprise about 10-25 wt% of the film, for example about 10-20 wt%, about 15-20 wt%, or about 12-20 wt% of the film. In certain embodiments, caprylocaproyl polyoxyl-8 glycerides or polysorbate 20 comprise 15-20 wt% of the film. In certain embodiments, the film comprises polysorbate 80. In certain embodiments, the film comprises polysorbate 80 and sorbitan monooleate. In certain embodiments, polysorbate 80 is present in an amount ranging from 5-20 wt% of the film and sorbitan monooleate is present in an amount ranging from 3-10 wt% of the film. In certain embodiments, the film product can include polysorbate (e.g., polysorbate 80, polysorbate 20) and/or sorbitan monooleate. In certain embodiments the sorbitan monooleate is present in an amount ranging from about 3-10 wt% of the film, about 3-4 wt% of the film, about 4-6 wt% of the film, about 6-8 wt% of the film, or about 8-10 wt% of the film.In certain embodiments, the film product further comprises a plasticizer. The term "plasticizer" as used herein refers to a substance added to a material to produce or promote plasticity and flexibility and to reduce brittleness. Plasticizers impart flexibility to the film of the present disclosure and can affect the release profile of the bioactive agent. Non-limiting examples of suitable plasticizers include alkylene glycols (e.g., propylene glycols and polyethylene glycols of average molecular weights from about 400 to about 6000), glycerin, sorbitol, triacetin, triethyl citrate, castor oil, diethyl phthalate, partially dehydrated hydrogenated glucose syrup, maltitol, maltose, lactitol, xylitol, and erythritol. For example, a plasticizer can be propylene glycol, polyethylene glycol (e.g., PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 3350, PEG 4500, PEG 8000). {10403/012319-US0/03532073.1} In certain embodiments, the plasticizer is propylene glycol, dipropylene glycol and/or polyethylene glycol. In other aspects, the film comprises a solubilizer/emulsifier. In certain embodiments, the solubilizer/emulsifier is polyethoxylated castor oil, sorbitan monolaurate, sorbitan monooleate, polysorbate for example polyethoxylated hydrogenated castor oil. Other emulsifiers include sorbitan monolaurate, sorbitan monopalmitate, and sorbitan monostearate. For instance, sorbitan monolaurate includes sorbitan monolaurate 20 (span 20); sorbitan monopalmitate corresponds to span 40,and sorbitan monostearate corresponds to span 60. In still other aspects, the film comprises a buffering/pH adjusting agent. In certain embodiments, the buffering agent is an organic acid. Examples of buffering agents include, but are not limited to, adipic acid, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic, citric acid monohydrate, dibasic sodium phosphate, diethanolamine, glycine, maleic acid, malic acid, methionine, monobasic sodium phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate, and triethanolamine. In yet other aspects, the film comprises at least one penetration enhancer. In certain embodiments, the film product comprises at least one lipophilic penetration enhancer. In certain embodiments, the at least one lipophilic enhancer is selected from the group consisting of an alkylene glycol fatty acid ester, a fatty acid monoglyceride, a fatty acid diglyceride, a fatty acid triglyceride, a fatty acid, a fatty alcohol (e.g., oleyl alcohol), or a polyoxyalkylene fatty acid ether (e.g., polyoxyethylene 10 oleoyl ether). In certain embodiments, the at least one lipophilic enhancer can include but is not limited to propylene glycol monolaurate, glyceryl monocaprylate, caprylic/capric triglyceride, and oleic acid. {10403/012319-US0/03532073.1} In certain embodiments, the at least one lipophilic enhancer is present in an amount ranging from about 1% to about 3% by weight (wt%), from about 3% to about 6% by weight (wt%), from about 6% to about 9% by weight (wt%), from about 9% to about 12% by weight (wt%), from about 12% to about 15% by weight (wt%), from about 15% to about 18% by weight (wt%), from about 18% to about 21% by weight (wt%), from about 21% to about 24% by weight (wt%), from about 24% to about 27% by weight (wt%), from about 27% to about 30% by weight (wt%) relative to the total weight of the film product. In yet other embodiments, the film product further comprises a taste modifier. The taste modifier can comprise a sweetener and/or a flavorant selected from aspartame, dipotassium glycyrrhetinate, stevia, aspartame, sucralose, thaumatin peppermint oil, synthetic substances or naturally occurring substances, including e.g. vanilla, mint, lemon, lime, orange, menthol and strawberry or a combination thereof. In certain embodiments, the film can comprise one or more additional ingredients, including but not limited to gelatin, lactic acid, maltose, triacetin, and menthol. In certain embodiments, the naloxone composition is naloxone HCl. In certain embodiments, the naloxone composition comprises 65 wt % or less of the film. In certain embodiments, the film comprises a microemulsion. Microemulsions are colloidal systems composed of micron-sized droplets of one immiscible liquid uniformly dispersed within another liquid (e.g., oil in water), facilitated by the presence of appropriate surfactants and co-surfactants. These systems are generally formed through methods such as vigorous agitation or ultrasonic processing and exhibit a relatively stable structural configuration. Microemulsions are thermodynamically stable, fluid, optically clear dispersions of two immiscible liquids such as oil and water. Microemulsions form when a surfactant, or more commonly a mixture of surfactants and cosurfactants, lowers the oil/water interfacial tension to ultra-low values, allowing thermal motions to spontaneous disperse the two immiscible phases {10403/012319-US0/03532073.1} In certain embodiments, the process of preparing the film comprises initially preparing a microemulsion. The microemulsion can be prepared by dissolving naloxone in a surfactant, co-surfactant and penetration enhancer (e.g., a lipophilic enhancer), so as to form a solution. A solvent (typically water and alcohol) are then added, followed by polymers. The solvent is then removed as described herein to form a film. In certain embodiments, the film has a thickness of approximately 2 mils to approximately 10 mils. In one embodiment, the film has a thickness of approximately 2 mils to approximately 4 mils, approximately 4 mils to approximately 6 mils, approximately 6 mils to approximately 8 mils, or approximately 8 mils to approximately 10 mils. In certain embodiments, the film thickness is determined based on the overall size of the film and drug loading capacity of the film. In certain embodiments, the film has a thickness of about 0.01 mm to about 0.15 mm, for example from about 0.02 to about 0.14 mm, from about 0.03 to about 0.13 mm, from about 0.04 to about 0.12 mm, from about 0.05 to about 0.11 mm, from about 0.06 to about 0.10 mm, about 0.01 mm, about 0.02 mm, about 0.03 mm, about 0.04 mm, about 0.05 mm, about 0.06 mm, about 0.07 mm, about 0.08 mm, about 0.09 mm, about 0.10 mm, about 0.11 mm, about 0.12 mm, about 0.13 mm, about 0.14 mm, or about 0.15 mm. 5.3 Controlled Release Films In one or more embodiments, the film product of the present application can be a controlled release film. The term "controlled release" as used herein generally refers to the release of a pharmaceutically active agent (e.g., naloxone) at a pre-selected or desired rate. This rate will vary depending upon the application. Desirable rates include fast or immediate release profiles as well as delayed, sustained or sequential release. Combinations of release patterns, such as initial spiked immediate release followed by lower levels of sustained release of active are contemplated. Pulsed drug releases are also contemplated. The polymers that are chosen for the film products may also be chosen to allow for controlled disintegration of the pharmaceutically active agent (e.g., naloxone). This {10403/012319-US0/03532073.1} may be achieved by providing a substantially water insoluble film that incorporates the pharmaceutically active agent that will be released from the film over time. This may be accomplished by incorporating a variety of different soluble or insoluble polymers and may also include biodegradable polymers in combination. Alternatively, coated controlled release active particles may be incorporated into a readily soluble film matrix to achieve the controlled release property of the active inside the digestive system upon consumption. Films that provide a controlled release of the pharmaceutically active agent are particularly useful for buccal, gingival, sublingual and vaginal applications. The films disclosed herein are particularly useful where mucosal membranes or mucosal fluid is present due to their ability to readily wet and adhere to these areas. The pharmaceutically active agent may be incorporated into the film in a controlled release form. For example, particles of drug 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 drug may also be absorbed on such polymer materials and incorporated into the film product. Other components such as fats and waxes, as well as sweeteners and/or flavors may also be employed in such controlled release film products. 5.4 Preparation of the Film product The present disclosure further provides a method of producing a naloxone buccal film. The method comprises mixing a naloxone composition with at two or more polymers to form a uniform mixture; performing a solvent vapor coating process on the uniform mixture to form a film; and drying the film. In certain embodiments of the method, at least one of the polymers comprises hydroxyethyl cellulose. In certain embodiments of the method, at least one of the polymers comprises hydroxypropylmethyl cellulose. The present disclosure further provides a method of producing a naloxone film, comprising: (a) mixing a naloxone composition with at two or more polymers in a solvent to form a mixture, wherein at least {10403/012319-US0/03532073.1} one polymer has a molecular weight below 65,000, and at least one polymer has a molecular weight of at least 65,000; (b) performing a solvent vapor coating process on the mixture to form a film; and (c) drying the film. In certain embodiments, the total amount of polymers is less than about 70 wt% of the mixture. In other embodiments, the naloxone is about 20 – 65 wt% of the mixture

In certain embodiments of the produced film is dried in an oven at a temperature of approximately 60 - 100° C. In certain embodiments, step (a) comprises mixing naloxone in a solvent comprising water, alcohol or a mixture thereof to form a mixture; optionally adding a surfactant and/or a penetration enhancer; and adding the two or more polymers. In other embodiments, step (a) comprises forming a microemulsion. The microemulsion can be formed by mixing naloxone with a surfactant and penetration enhancer to form a solution; and adding a solvent comprising water, alcohol or a mixture thereof to the solution. In certain embodiments of the method, the produced film is dried to less than about 10% by weight water. Although a variety of different polymers may be used, it is desired to select polymers to provide a desired viscosity of the mixture prior to drying. For example, if the active or other components are not soluble in the selected solvent, a polymer that will provide a greater viscosity is desired to assist in maintaining uniformity. On the other hand, if the components are soluble in the solvent, a polymer that provides a lower viscosity may be preferred. In one or more embodiments, the film disclosed herein is prepared according to the following method: The ingredients of the disclosed compositions were combined by mixing until a uniform mixture is achieved. Specifically, in one or more embodiments, the naloxone or pharmaceutically acceptable salt thereof is mixed with the polymer(s) (e.g., hydroxyethyl cellulose or hydroxypropylmethyl cellulose) to form a uniform mixture. In certain {10403/012319-US0/03532073.1} embodiments, other components (e.g., surfactants, lipophilic enhancers, additives, etc.) can also be added to with the naloxone and polymer(s) to form the uniform mixture. The uniform mixture is then formed into a film by a solvent vapor coating process. The resulting film is then dried. In one or more embodiments, the film is dried in an oven at a temperature of approximately 60-100°C. In one or more embodiments, the film dried to less than about 10% by weight water. In certain embodiments, the film is formed into a sheet prior to drying. After the desired components are combined to form a multi-component matrix, including the polymer, water, and the pharmaceutically active agent (e.g., naloxone) or other components as desired, the combination is formed into a sheet or film, by any method known in the art such as extrusion, coating, spreading, casting or drawing the multi- component matrix. If a multi-layered film is desired, this may be accomplished by co- extruding more than one combination of components which may be of the same or different composition. A multi-layered film may also be achieved by coating, spreading, or casting a combination onto an already formed film layer. Although a variety of different film-forming techniques may be used, it is desirable to select a method that will provide a flexible film, such as reverse roll coating. The flexibility of the film allows for the sheets of film to be rolled and transported for storage or prior to being cut into individual dosage forms. Desirably, the films will also be self-supporting or in other words able to maintain their integrity and structure in the absence of a separate support. Furthermore, the films may be selected of materials that are edible or ingestible. Coating or casting methods are particularly useful for the purpose of forming the films. Specific examples include reverse roll coating, gravure coating, immersion or dip coating, metering rod or meyer bar coating, slot die or extrusion coating, gap or knife over roll coating, air knife coating, curtain coating, or combinations thereof, especially when a multi-layered film is desired. 5.5 Uses of the Film product {10403/012319-US0/03532073.1} The thin films comprising the polymers 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 pharmaceutically active agent is released, which may allow for a 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. The films may be used to orally administer a pharmaceutically active agent. 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. If an adhesive is used, it will desirably be a food grade adhesive that is ingestible and does not alter the properties of the pharmaceutically active agent. Mucoadhesive compositions are particularly useful. 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. In other embodiments, the film may be contacted with the cheek of the mammal. 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. Another use for the films takes advantage of the films to dissolve quickly when introduce to a liquid. A pharmaceutically active agent may be introduced to a liquid by preparing a film, 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. {10403/012319-US0/03532073.1} The films are desirably packaged in sealed, air and moisture resistant packages to protect the active from exposure oxidation, hydrolysis, volatilization and interaction with the environment. In one embodiment, a series of such unit doses are packaged together in accordance with the prescribed regimen or treatment, e.g., a 10-90 day supply, depending on the particular therapy. The individual films can be packaged on a backing and peeled off for use. 5.6 Conditions to be Treated The present disclosure provides methods and film product for treating or preventing an opioid overdose in a subject (e.g., human subject). In one or more embodiments, the opioid overdose is caused by one or more opioids, including by not heroin, fentanyl, morphine, methadone, carfentanil, oxycodone (oxycontin), oxymorphone, buprenorphine, sufentanil, alfentanil, and hydrocodone. In one or more embodiments, a method of treating or preventing an opioid overdose can comprise applying a naloxone film of the present application to the oral mucosa or tongue of the subject in need. The present disclosure further provides a method of treating a subject undergoing an opioid overdose. The method comprises applying a naloxone film product of the present application to the oral mucosa or tongue of the subject. The present disclosure further provides a method of treating opioid dependence in a subject in need thereof. The method comprises applying a naloxone film product of the present application to the oral mucosa or tongue of the subject. The present disclosure further provides a method of treating pain in a subject in need thereof. The method comprises applying a naloxone film product of the present application to the oral mucosa or tongue of the subject. The present disclosure further provides a method of treating a subject exhibiting symptoms of respiratory depression associated with known or suspected opioid overdose. The method comprises applying a naloxone film product of the present application to the oral mucosa or tongue of the subject. {10403/012319-US0/03532073.1} The naloxone film can deliver a therapeutically effective amount of naloxone to the subject. In one or more embodiments, the naloxone film delivers approximately 2 mg to approximately 25 mg of naloxone is delivered from the film to the human subject. In certain embodiments, the naloxone film delivers approximately 2 mg to approximately 4 mg of naloxone, approximately 4 mg to approximately 6 mg of naloxone, approximately 6 mg to approximately 8 mg of naloxone, approximately 8 mg to approximately 10 mg of naloxone, approximately 10 mg to approximately 12 mg of naloxone, approximately 12 mg to approximately 14 mg of naloxone, approximately 14 mg to approximately 16 mg of naloxone, approximately 16 mg to approximately 18 mg of naloxone, approximately 18 mg to approximately 20 mg of naloxone, approximately 20 mg to approximately 22 mg of naloxone, or approximately 22 mg to approximately 25 mg of naloxone is delivered from the film to the human subject. In certain embodiments of the method, about 2 mg - 35 mg of naloxone is delivered from the film to the subject. In certain embodiments of the method, about 2 mg - 25 mg of naloxone is delivered from the film to the subject. In certain embodiments, the subject is a human subject. In certain embodiments, the subject is a non-human animal. In one or more embodiments, the active ingredient (e.g., naloxone composition) is delivered to the subject (i.e., released from the film) within approximately 5 minutes of administration of the film to the subject. More specifically, in certain embodiments, the active ingredient (e.g., naloxone composition) is delivered to the subject and dissolves in the oral mucosa of the subject within approximately 30 seconds, approximately 1 minute, approximately 1 minute and 30 seconds, approximately 2 minutes, approximately 2 minutes and 30 seconds, approximately 3 minutes, approximately 3 minutes and 30 seconds, approximately 4 minutes, approximately 4 minutes and 30 seconds, or approximately 5 minutes of administration of the film to the subject. In one or more embodiments, the active ingredient (e.g., naloxone composition) is released from the film for approximately 16 hours. 5.7 Combination with other active agents {10403/012319-US0/03532073.1} The present film product containing the active agent (e.g., naloxone, or a pharmaceutically acceptable salt, derivative, or solvate thereof) or composition may be administered (or applied) to the subject simultaneously with, before, after, or in a sequence and within a time interval of, the administration of a second active agent(s). By co-administration it is meant either the administration of a single film product containing both the present agent (e.g., naloxone, or a pharmaceutically-acceptable salt, derivative, or solvate thereof) and a second active agent(s), or the administration of the present agent and a second active agent(s) as separate film product within short time periods. The present film product can be combined and administered with a second active agent(s) in separate film product. In certain embodiments, the separate film products are administered simultaneously. In certain embodiments, the separate film products are not administered simultaneously, such as, for example, in a sequential manner, in any order. The present film product may be administered (or applied) to a subject alone, or may be administered (or applied) to a subject in combination with one or more other treatments/agents (a second agent). In certain embodiments, the second agent is opioid receptor antagonist. In certain embodiments, the second agent is an opioid agonist. In certain embodiments, the second agent is an opioid. In certain embodiments, the second agent/treatment is used as adjunctive therapy to the present film product or composition. In certain embodiments, the treatment includes a phase wherein treatment with the second agent/treatment takes place after treatment with the present film product has ceased. In certain embodiments, the treatment includes a phase where treatment with the present film product and treatment with the second agent/treatment overlap. Combination therapy can be sequential, in any order, or can be administered simultaneously. In either case, these drugs and/or therapies are said to be "co- administered." It is to be understood that "co-administered" does not necessarily mean that the drugs and/or therapies are administered in a combined form (i.e., they may be {10403/012319-US0/03532073.1} administered separately (e.g., as separate compositions or formulations) or together (e.g., in the same formulation or composition) to the same or different sites at the same or different times). In certain embodiments, a subject is treated concurrently (or concomitantly) with the present film product and a second agent. In certain embodiments, a subject is treated initially with the present film product, followed by cessation of the present film product treatment and initiation of treatment with a second agent. In certain embodiments, the present film product is used as an initial treatment, e.g., by administration of one, two or three doses, and a second agent is administered to prolong the effect of the present film product, or alternatively, to boost the effect of the present film product. A person of ordinary skill in the art will recognize that other variations of the presented schemes are possible, e.g., initiating treatment of a subject with the present film product, followed by a period wherein the subject is treated with a second agent as adjunct therapy to the present film product treatment, followed by cessation of the present film product treatment. The present compound and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the present pharmaceutically active agent and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. In various embodiments, the therapies (e.g., an film product provided herein and a second agent in a combination therapy) are administered about 0 minutes to about 5 minutes apart, about 5 minutes to about 30 minutes apart, about 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart. In certain {10403/012319-US0/03532073.1} embodiments, the therapies are administered no more than 12 hours apart or no more than 24 hours apart. The second agent can act additively or synergistically with the present pharmaceutically active ingredient. In one embodiment, the film product provided herein is administered concurrently with one or more second agents in the same film product. In another embodiment, a film product provided herein is administered concurrently with one or more second agents in separate film product. In still another embodiment, a film product provided herein is administered prior to or subsequent to administration of a second agent. Also contemplated are administration of a film product provided herein and a second agent by the same or different routes of administration, e.g., oral and parenteral. 5.8 Dosing The present film product may be administered as needed during the course of treatment. In certain embodiments, a subject may be administered 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more of the film product. In certain embodiments, a single dose of the present film product is administered in the present method. In certain embodiments, multiple doses of the present film product (e.g., 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses or more) are administered in the present method. In one embodiment, each dose equates to a single film product. In certain embodiments, the administration of the present film product is continued over a period of up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or longer. In certain embodiments, the present film product is administered once, twice, at least twice, at least three times, at least four times, at least five time, at least six times, at least seven times, at least eight times, at least nine times, or more per treatment. 5.9 Subjects {10403/012319-US0/03532073.1} The subject may be a human. In certain embodiments, the subject is a non-human animal. The non-human animal may be a mammal selected from the group consisting of primates (non-human primates), pigs, rodents, or rabbits and beagle. In an embodiment, the subject is a pig, such as a miniswine. In another embodiment, the subject is a mouse. 5.10 Kits The present disclosure also encompasses an article of manufacture, e.g., a kit. The article of manufacture may contain the present film product in a suitable container with labeling and instructions for use. Optionally, an applicator can be provided in or attached to the container, or separately from the container. Instructions may be packaged with the film product, for example, a pamphlet or package label. The labeling instructions explain how to the present film product, in an amount and for a period of time sufficient to treat or prevent the disorder or condition discussed herein. In certain embodiments, the label includes the dosage and administration instructions, the film product, the clinical pharmacology, drug resistance, pharmacokinetics, absorption, bioavailability, and/or contraindications. This invention will be better understood from the following examples. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative and not limiting. 6. EXAMPLES 6.1 Film Production In the following examples, the compositions of examples 1-18 are film products and the compositions of examples 19-31 are microemulsion film products. The ingredients of inventive compositions in the following tables were combined by mixing until a uniform mixture was achieved. Examples 1-18 were prepared by mixing naloxone in a solvent system (water and/or alcohol), followed by optionally adding a permeating enhancer and/or surfactant(s). Polymers were then added to produce a viscous mixture. Examples 19-31 were prepared by mixing naloxone with a surfactant {10403/012319-US0/03532073.1} and penetration enhancer. A solvent system (water and/or alcohol) was then added, followed by polymers to form a microemulsion. The compositions prepared by the above methods were then formed into a film by solvent vapor coating process. These films were then dried in an oven at the temperature at approximately 60 – 100° C. The films were dried to less than about 10% by weight water. The films were flexible, self-supporting and provided a uniform distribution of the components within the film. For formulations comprising a microemulsion, the microemulsion was applied to a surface in a controlled thickness to form a thin film. The film was subsequently dried and trimmed to achieve the final product. 6.2 Dissolution Study Formulations according to the present application, when dissolution tested in vitro preferably exhibit the following dissolution criteria. The method includes dissolution test performed by using USP Apparatus 5 (Paddle over disk) at 25 rpm in 900 mL of pH4.0 acetate buffer. The amount of dissolved naloxone can be determined conventionally by HPLC. 6.3 Disintegration The disintegration was determined using a disintegrator. Distilled Water at a ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ successive vertical immersion and the time until total disintegration was recorded. 6.4 Film Thickness Micrometer screw (Mitutoyo, Neuss, Germany) was used to determine film thicknesses of oral film samples. 6.5 Swelling Test Study {10403/012319-US0/03532073.1} To mimic oral film oral disintegrating phenomenon, a swelling test study was conducted. 10 ml of distilled water at 37^oC was added into a Petri dish. An oral film of 20×20 mm² was weighed and placed into the water of Petri dish without covering any air bubble. Then, the dish was covered with its lid and put into a 37^oC oven with 30 rpm of shaking speed for 10 min to let the oral film disintegrate slowly. After that, the water was removed with a syringe gently. The dish was dried in an 80^oC oven no less than 10 min. Finally, the appearance of the film in the dish including its dissolution and diffusion results were observed and recorded. 6.6 Skin Permeation Study The skin permeation study was performed by using human cadaver skins mounted on a modified Franz cell systems equipped with a water bath for maintaining the constant temperature at 37^oC. A magnetic stir bar was placed in the receptor chamber to stir constantly for ensuring the solution uniformity. The human cadaver skin stored in -80^oC freezer was thawed and washed in purified water. The epidermis layer of the skin was removed to mimic the mucosal membrane. The skin was cut into a round shape with a radius of 1.6 cm. The skin was then mounted on the Franz cell. Once the pre-cut skin was placed on the donor compartment, the donor compartment and the receptor compartment were clamped together. Phosphate buffer pH 6.5 was added to the marked line with a needled syringe. The testing formulations were then applied onto the skin on the donor compartment. 1 mL of samples were withdrawn at the pre-determined time point and analyzed by the HPLC for the concentration of naloxone. Table 1. Composition of the Invented Formulations with HEC as the Primary Polymer Composition wt /wt % Ingredient {

. Composition wt /wt % Ingredient Ex.1 Ex.2 Ex.3 Ex.4 Ex.5 Ex.6 Ex.7 e,

A formulation comprising hydroxyethyl cellulose (HEC) modified the ductility, softness, and foldability of the film. Invented formulations with HEC are showed in Table 1. For an oral film, Ex.1 and 2 with 22% and 20% of HEC, showed ideal softness property and also could withstand several folds. However, Ex.3 with similar composition but containing only 10% HEC lost its softness and became crispy. Ex.5, which has a similar composition as Ex.4 but without HEC, also became crispy and not as soft as Ex.4. Formulations with higher molecular weight HEC from 1.0 to 1.3 million g/mol were prepared as Ex.6 and 7. However, higher molecular of HEC becomes a sticky property, which might cause oral discomfort. {10403/012319-US0/03532073.1} Table 2. Composition of the Invented Formulations Using Combinations of Polymers Composition wt /wt % Ingredient Ex.8 Ex.9 Ex.10 Ex.11 Ex.12 Ex.13

Table 2 presented above displays formulations of the present application that utilize diverse polymer types characterized by varying molecular weights, concurrently evaluated through skin permeability test. Molecular weights are stratified based on {10403/012319-US0/03532073.1} magnitude, with values below 65,000 denoted as low molecular weight and those equal to or exceeding 65,000 as high molecular weight. The film characteristics derived from the aforementioned examples met the criteria of a smooth, comprehensive surface with notable extensibility. Observations from Ex.8 indicated that drug release occurs at an exceedingly slow rate, when the proportion of high molecular weight film polymers surpasses 45%. In contrast, Ex. 9 to 11 demonstrated that in films with polymer compositions where low molecular weight constitutes over 40%, and high molecular weight is below 25%, the drug penetration was comparatively expeditious. In the instance of Ex.12, even with the utilization of two or more high molecular weight polymers such as HEC, HPC L, and polyethylene oxide, alongside the low molecular weight polymer HPMC E6, the buccal films facilitated drug penetration within the 5 minutes, allow to have fast onset effect. Ex.13 illustrates that, even with only 15% of high molecular weight polymer, fast onset effect could be attained. This indicated fast onset effect for buccal films could be achieved with the polymer composition at approximately 15%. Conclusions can be derived from the above results that less than 25% high molecular weight polymer (e.g., less than 20% high molecular weight polymer) could be achieved to have similar effect, ^^^ ^^^^^!^ "^^^^^^^^^^^^"^^^^^^^^^^^^^^^^^"^^^^^^!^^^^#^^ ^^^^^^^^^^^^^ ^$^^^^^^^^^^ molecular weight polymer was used, the composition should be increased in the range of 10-45%. Fig. 1 shows a line graph displaying the in vitro skin permeation results for naloxone formulations of Ex. 8 – Ex. 13. Table 3: Composition of the Invented Formulations Using Different Drug Loading Composition wt /wt % Ingredient {

Composition wt /wt % Ingredient Ex.14 Ex.15 Ex.16 Ex.17

Buccal films with different drug loading can affect the rate of drug penetrating. In Table 3, examples comprised of 24 to 80% of naloxone hydrochloride are presented. Ex.14 with a drug loading of 24% showed a soft but uneven film appearance was not conducted with further study. Other examples were performed in the in-vitro permeation study to compare the drug loading effect, as Fig. 2 shows. Ex.16 with 65% drug loading exhibited extra 500 %g of penetrating amount than Ex.15 which of 55% drug loading. Ex.17 with 80% of drug loading also showed better penetration than the previous two. However, Ex.17 had an additional 15% increase in drug loading compared to Ex.16 but only increased the penetrating amount by 300 %g. Besides, the structure of Ex.17 was not robust and tended to be fragile. Therefore, the drug loading in subsequent examples is preferably no higher than 65%. Table 4: Composition of the Invented Formulations Using Different Surfactants Composition wt/wt% Ingredient 2

Composition wt/wt% Ingredient Ex.15 Ex.18 Ex.19 Ex.20 Ex.21 Ex.22

Table 4 shows example compositions comprising various surfactants (Ex. 15, 18- 22). Fig. 3A displays the results a permeation study comparing the formulations of Ex. 15 and Ex. 18. Fig. 3B is an expanded view of a portion of Fig. 3A around the onset of penetration. As exemplified in Fig. 3A and 3B, it is observed that formulations with added surfactants (Ex. 18) demonstrate a faster onset time of penetration compared to formulations without surfactants (Ex. 15). This indicated that surfactants have the effect of accelerating the onset time of penetration. In Fig. 4, Ex.20 composed of caprylocaproyl polyoxyl-8 glycerides and polysorbate 80 exhibited the best performance, followed by Ex.19 and Ex.22 with caprylocaproyl polyoxyl-8 glycerides only, and finally Ex.21 with polysorbate 80 and sorbitan monooleate. This indicated that under similar surfactant proportions, the combination of polysorbate 80 and caprylocaproyl polyoxyl-8 glycerides in the formulation (Ex.20) had a synergistic effect compared to caprylocaproyl polyoxyl-8 {10403/012319-US0/03532073.1} glycerides alone (Ex.19 and Ex.22), while the group containing sorbitan monooleate (Ex.21) showed less favorable results. Fig. 6 shows the in vitro dissolution profile of formulations of Ex. 15, 18 and 19, with formulation 19 providing the best results. To confirm the correlation of in vitro assessments, in vivo experiments involving animals were conducted. Pharmacokinetic evaluations were carried out with Example 15, 18, and 19 (Fig. 7). An in vivo dog PK studies was conducted on the invented formulations with high drug loading and microemulsion formulations. As presented in Fig. 7, the formulation with microemulsion (Ex. 19) showed faster onset effect than a formulation without microemulsion (Ex. 18). In Ex 19 naloxone is dissolved in the Caprylocaproyl polyoxyl-8 glycerides, Dipropylene glycol etc to form a microemulsion, while in example 18, naloxone is dissolved in water, followed by addition of the other ingredients, and no microemulsion is formed. Table 5. Microemulsion with Lipophilic Enhancers Composition wt/wt% 2

{10403/012319-US0/03532073.1} Table 5 shows example compositions comprising various lipophilic enhancers (Ex. 23-26) and Fig. 5 shows the corresponding permeation result for these formulations. When microemulsion was loaded with higher drug composition (Ex. 26), as a buccal film, it has the optimal effect to have the fastest onset by a synergistic effect between polysorbate 80, propylene glycol monolaurate, and high drug loading which was the thinnest film (Fig. 5). 6.7 Flavor Agent Adjustment Naloxone tastes very bitter and the excipients used in the formulation do not taste well. This could lead to a patient spitting the film out. Thus, few flavor agents were evaluated to improve patients' willingness to keep the medication in their mouths. The formulations tested are shown below. C^{omposition wt /wt %} Ingredient {

. Lemon flavor - - 3 - - Vanilla flavor 2.5 3 - 2 - 1

An in vitro permeation test (IVPT) study was conducted, and the data is shown in Fig. 8 which indicates that the addition of a flavoring agent does not affect the permeability of the formulation but enhances the overall palatability of the film. 6.8 Additional Animal PK Data An in vivo experiments involving animals were conducted to confirm the onset time of the buccal formulation to different delivery route using Example 22. As presented in Fig. 9, the formulation with microemulsion showed faster onset effect through the buccal delivery. In Fig.10, the buccal delivery showed similar onset time and pharmacokinetic profile as the Narcan, the commercial product. Exemplary products, systems and methods are set out in the following items Item 1. A naloxone buccal film, comprising: (i) a naloxone composition, wherein the naloxone composition is 30 – 65 wt% of the film; and (ii) two or more polymers, wherein at least one of the polymers is hydroxypropyl methylcellulose, and the hydroxypropyl methylcellulose is at least 3 wt% of the film. Item 2. The film of item 1, wherein naloxone composition is naloxone in free base form or a pharmaceutically acceptable salt, derivative, or solvate thereof. {10403/012319-US0/03532073.1} Item 3. The film of item 1 or 2,wherein, as measured using a USP Apparatus 5 at a paddle rotation speed of 25 rpm in 900 mL of a dissolution medium at 37° C., at least 85 wt % of naloxone in a film dissolves within 5 minutes in the dissolution medium, and the dissolution medium is pH 4.0 acetate buffer. Item 4. The film of item 1 or item 2, wherein the two or more polymers are collectively 15-67 wt% of the film. Item 5. The film of any of the preceding items, wherein the two or more polymers include at least one high molecular weight polymer and at least one low molecular weight polymer, wherein a molecular weight below 65,000 denotes a low molecular weight polymer and a molecular weight of at least 65,000 denotes a high molecular weight polymer. Item 6. The film of item 5, wherein the proportion of high molecular weight polymer in the two or more polymers is less than 25 wt % and the proportion of low molecular weight polymer in the two or more polymers is less than 40 wt %. Item 7. The film of any of the preceding items, further comprising one or more surfactants, wherein long chain carbons range between 8 and 18. Item 8. The film of item 7, wherein the surfactants are selected from the group consisting of polyoxyl 40 hydrogenated castor oil, caprylocaproyl polyoxyl-8 glycerides, sorbitan monooleate, polysorbate 80, polysorbate 20, Dipropylene glycol, poly(propylene glycol), and polyethylene glycol. Item 9. The film of any of the preceding items, further comprising: caprylocaproyl polyoxyl-8 glycerides, wherein the caprylocaproyl polyoxyl-8 glycerides comprise 10-20 wt% of the film. {10403/012319-US0/03532073.1} Item 10. The film of item 9, wherein the caprylocaproyl polyoxyl-8 glycerides comprise 15-20 wt% of the film. Item 11. The film of any one of items 1-10, further comprising polysorbate 80. Item 12. The file of any one of items 1-11, further comprising polysorbate or sorbitan monooleate, wherein polysorbate is 5-25 wt% of the film or sorbitan monooleate is 3-10 wt% of the film. Item 13. The film of any of the preceding items, further comprising at least one lipophilic enhancer. Item 14. The film of item 13, wherein the at least one lipophilic enhancer is selected from the group consisting of: propylene glycol monolaurate, glyceryl monocaprylate, caprylic/capric triglyceride, and oleic acid. Item 15. The film of any of the preceding items, wherein the naloxone composition is naloxone HCl. Item 16. The film of any of the preceding items, wherein the naloxone composition comprises 30-65 wt % of the film. Item 17. The film of any of the preceding items, wherein the film comprises a microemulsion. Item 18. A method of treating a subject undergoing an opioid overdose, the method comprising: {10403/012319-US0/03532073.1} applying the naloxone buccal film of item 1 to the oral mucosa or tongue of the subject. Item 19. The method of item 18, wherein about 2 mg - 27 mg of naloxone is delivered from the film to the human subject. Item 20. A method of producing a naloxone buccal film, comprising: mixing a naloxone composition with at two or more polymers to form a uniform mixture, wherein at least one of the polymers comprises hydroxypropyl methylcellulose , and the total usage of hydroxypropyl methylcellulose is 3-40 wt% of the film the naloxone composition is 30 – 65 wt% of the mixture and; performing a solvent vapor coating process on the uniform mixture to form a film; and drying the film. Item 21. The method of item 20, wherein the film is dried to less than about 10% by weight water. Item 22. The method of item 20, wherein the film comprises a microemulsion. Item 23. A naloxone buccal film, comprising: a naloxone composition, wherein the naloxone composition is 30 – 65 wt% of the film; and having greater than 85% release within 5 minutes where it was measured using a USP Apparatus 5 at a paddle rotation speed of 25 rpm in 900 mL of a dissolution medium at 37° C., in the dissolution medium of pH 4.0 acetate buffer. Item 24. The film of item 23, further comprising two or more polymers, wherein at least one of the polymers is hydroxypropyl methylcellulose, and the hydroxypropyl methylcellulose is at least 3 wt% of the film. {10403/012319-US0/03532073.1} Item 25. The film of item 23 or 24, wherein the two or more polymers are collectively 5-70 wt% of the film. Item 26. The film of any one of items 23-25, wherein the two or more polymers include at least one high molecular weight polymer and at least one low molecular weight polymer, wherein a molecular weight below 65,000 denotes a low molecular weight polymer and a molecular weight exceeding 65,000 denotes a high molecular weight polymer. Item 27. The film of item 26, wherein the proportion of high molecular weight polymer in the two or more polymers is less than 25 wt % and the proportion of low molecular weight polymer in the two or more polymers is less than 40 wt %. Item 28. The film of any one of items 23-27, further comprising one or more surfactants, wherein long chain carbons of the surfactants range between 8 and 18. Item 29. The film of item 28, wherein the surfactants are selected from the group consisting of polyoxyl 40 hydrogenated castor oil, caprylocaproyl polyoxyl-8 glycerides, sorbitan monooleate, polysorbate 80, dipropylene glycol, poly(propylene glycol), and polyethylene glycol. Item 30. The film of any one of items 23-29, further comprising: caprylocaproyl polyoxyl-8 glycerides, wherein the caprylocaproyl polyoxyl-8 glycerides comprise 10-20 wt% of the film. Item 31. The film of item 30, wherein the caprylocaproyl polyoxyl-8 glycerides comprise 15-20 wt% of the film. {10403/012319-US0/03532073.1} Item 32. The film of any one of items 23-31, further comprising polysorbate 80. Item 33. The film of any one of items 23-32, further comprising polysorbate or sorbitan monooleate, wherein polysorbate is 5-20 wt% of the film or sorbitan monooleate is 3-10 wt% of the film. Item 34. The film of any one of items 23-33, further comprising at least one lipophilic enhancer. Item 35. The film of item 34, wherein the at least one lipophilic enhancer is selected from the group consisting of: propylene glycol monolaurate, glyceryl monocaprylate, caprylic/capric triglyceride, and oleic acid. Item 36. The film of any one of items 23-35, wherein the naloxone composition is naloxone HCl. Item 37. The film of any one of items 23-36, wherein the naloxone composition comprises 30-55 wt % of the film. Item 38. The film of any one of items 23-37, wherein the film comprises a microemulsion. Item 39. A method of treating a subject undergoing an opioid overdose, the method comprising: applying the naloxone buccal film of any of any one of items 23-38 to the oral mucosa or tongue of the subject. Item 40. The method of item 39, wherein about 2 mg - 27 mg of naloxone is delivered from the film to the human subject. {10403/012319-US0/03532073.1} Item 41. A method of producing a naloxone buccal film, comprising: mixing a naloxone composition with at two or more polymers to form a uniform mixture, wherein at least one of the polymers comprises hydroxypropyl methylcellulose , and wherein the total usage of hydroxypropyl methylcellulose is 3-40 wt% of the film and the naloxone composition is 30 – 65 wt% of the mixture and; performing a solvent vapor coating process on the uniform mixture to form a film; and drying the film. Item 42. The method of item 41, wherein the film is dried in an oven at a temperature of approximately 60 - 100° C. Item 43. The method of item 41 or item 42, wherein the film is dried to less than about 10% by weight water. The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims. Patents, patent applications, and publications are cited throughout this application, the disclosures of which, particularly, including all disclosed chemical structures, are incorporated herein by reference. Citation of the above publications or documents is not intended as an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. All references cited herein are incorporated by reference to the same extent as if each individual publication, patent application, or patent, was specifically and individually indicated to be incorporated by reference. {10403/012319-US0/03532073.1} The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. {10403/012319-US0/03532073.1} Reference

1. Sisson ML, Azuero A, Chichester KR, Carpenter MJ, Businelle MS, Shelton RC, Cropsey KL. Feasibility and acceptability of online opioid overdose education and naloxone distribution: Study protocol and preliminary results from a randomized pilot clinical trial. Contemp Clin Trials Commun. 2023 Apr 5;33: 101 131.

Claims

Reference 1. Sisson ML, Azuero A, Chichester KR, Carpenter MJ, Businelle MS, Shelton RC, Cropsey KL. Feasibility and acceptability of online opioid overdose education and naloxone distribution: Study protocol and preliminary results from a randomized pilot clinical trial. Contemp Clin Trials Commun. 2023 Apr 5;33: 101131. {10403/012319-US0/03532073.1} What is claimed is: 1. A naloxone buccal film, comprising: about 20 – 65 wt% naloxone or a pharmaceutically-acceptable salt or solvate thereof, and two or more polymers, wherein at least one polymer has a molecular weight below 65,000, and at least one polymer has a molecular weight of at least 65,000 and wherein the total amount of polymers is up to about 70 wt% of the film.

2. The film of claim 1, wherein the film has an onset time of release of the naloxone of less than about 10 minutes.

3. The film of claim 1, wherein the film releases more than about 85% of the naloxone in less than about 10 minutes.

4. The film according to claim 1, wherein the polymer is selected from the group consisting of hydroxypropylmethyl cellulose (HPMC), hydroxpropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose (CMC), gelatin, pullulan, sodium alginate, pectin, chitosan, poly(acrylic acid)^^carrageenan, and starch.

5. The film of claim any one of claims 1-4, wherein the total amount of polymers is between about 5 wt% and 70 wt% of the film.

6. The film of claim any one of claims 1-4, wherein the total amount of polymer having a molecular weight below 65,000 is between about 10 wt% and about 45 wt%.

7. The film of claim any one of claims 1-4, wherein the total amount of polymer having a molecular weight of at least 65,000 is less than about 25 wt%, preferably less than about 20%.

8. The film of any one of claims 1-7, comprising at least one HPMC polymer.

9. The film of any one of claims 1-7 comprising at least two HPMC polymers.

10. The film of any one of claims 1-7, comprising at least one HPMC polymer having a molecular weight below 65,000. {10403/012319-US0/03532073.1}

11. The film of any one of claims 1-7, comprising at least one HPMC polymer having a molecular weight of at least 65,000.

12. The film of any one of claims 1-7, comprising at least one HPMC polymer having a molecular weight below 65,000, and at least one HPMC polymer having a molecular weight of at least 65,000.

13. The film of any one of claims 1-12, wherein the at least one polymer having a molecular weight below 65,000 is selected from the group consisting of HPMC E3, HPMC E6, HPMC E15, PEG 400, povidone K12, povidone K25, and povidone K29/32.

14. The film of any one of claims 1-12, wherein the at least one polymer having a molecular weight of at least 65,000 is selected from the group consisting of HPMC E50, HPMC K100LV, HPMC K100M, HPMC K200M, HEC 250G, HEC 250HX, HEC 250 HHX, PEO N10, PEO N60K, PEO 303,PVA 18-88, HPC L, and poly(acrylic acid), and PVP-K90.

15. The film of any one of claims 1-14, comprising at least one HPMC polymer, wherein the total amount of HPMC polymer is about 3 to about 40 wt% of the film.

16. The film of any one of claims 1-15, wherein the total amount of polymers is about 3 to about 70% of the film.

17. The film of any one of claims 1-15, wherein the total amount of polymers is about 5 to about 70% of the film.

18. The film of any one of claims 1-15, wherein the total amount of polymers is about 5 to about 60% of the film.

19. The film of any one of claims 1-18, further comprising at least one of a surfactant, plasticizer, a penetration enhancer, a solubilizer, an emulsifier, a thickening agent, a stabilizer, a preservative, a taste modifier, a sweetening or flavoring agent, a coloring agent, a saliva-stimulating agent, an antioxidant, or a buffering agent. {10403/012319-US0/03532073.1}

20. The film of any one of claims 1-18, comprising at least one surfactant, wherein the surfactant facilitates onset time of naloxone penetration or release.

21. The film of claim 19 or 20, wherein the surfactant a cationic surfactant, an anionic surfactant, a zwitterionic surfactant, or a nonionic surfactant.

22. The film of any one of claims 19-21, wherein the surfactant is selected from the group consisting of polyoxylglyceride fatty acid ester, ethylene glycol fatty acid ester, propylene glycol fatty acid ester, polyoxyl hydrogenated castor oil, polyglycerol fatty acid ester, polysorbate, sorbitan fatty acid ester, polyoxyethylene alkyl ether polysorbate, sodium lauryl sulfate, and a poloxamer.

23. The film of any one of claims 1-22, comprising a polyoxylglyceride fatty acid ester.

24. The film of any one of claims 1-23, comprising a polyoxylglyceride fatty acid ester and a polysorbate.

25. The film of claim 23 or 24, wherein the polyoxylglyceride fatty acid ester comprises caprylocaproyl polyoxyl-8 glycerides.

26. The film of claim 23, wherein the caprylocaproyl polyoxyl-8 glycerides comprise about 10-25 wt% of the film.

27. The film of any one of claims 1-26, comprising caprylocaproyl polyoxyl-8 glycerides and polysorbate in a total amount 15-25 wt% of the film.

28. The film of any one of claims 1-27, comprising at least one lipophilic penetration enhancer.

29. The film of claim 28, wherein the at least one lipophilic penetration enhancer is selected from the group consisting of an alkylene glycol fatty acid ester, a fatty acid monoglyceride, a fatty acid diglyceride, a fatty acid triglyceride, a fatty alcohol, a polyoxyalkylene fatty alcohol ether, and a fatty acid.

30. The film of claim 28 or 29, wherein the at least one lipophilic penetration enhancer is selected from the group consisting of: propylene glycol {10403/012319-US0/03532073.1} monolaurate, glyceryl monocaprylate, caprylic/capric triglyceride, and oleic acid.

31. The film of any one of claims 1-30, comprising a pharmaceutically-acceptable salt of naloxone.

32. The film of claim 31, wherein the pharmaceutically-acceptable salt is a hydrochloride (HCl) salt.

33. The film of any one of claims 1-32, comprising about 30-55 wt % of naloxone or the pharmaceutically-acceptable salt or solvate thereof.

34. The film of any one of claims 1-33, wherein the film has a thickness of about 0.01 mm to about 0.15 mm.

35. The film of any one of claims 1-34, wherein the film comprises a microemulsion.

36. A method of treating opioid overdose in a subject in need thereof, the method comprising: administering a therapeutically-effective amount of the naloxone buccal film of any one of claims 1-35 to an oral mucosa or tongue of the subject.

37. A method of treating opioid dependence in a subject in need thereof, the method comprising: administering a therapeutically-effective amount of the naloxone buccal film of any one of claims 1-35 to an oral mucosa or tongue of the subject.

38. A method of treating pain in a subject in need thereof, the method comprising: administering a therapeutically-effective amount of the naloxone buccal film of any one of claims 1-35 to an oral mucosa or tongue of the subject.

39. A method for treating a subject exhibiting symptoms of respiratory depression associated with known or suspected opioid overdose, the method comprising: administering a therapeutically-effective amount of the naloxone buccal film of any one of claims 1-35 to an oral mucosa or tongue of the subject. {10403/012319-US0/03532073.1}