WO2008028047A2

WO2008028047A2 - Bioadhesive film drug delivery system

Info

Publication number: WO2008028047A2
Application number: PCT/US2007/077251
Authority: WO
Inventors: Jason M. Vaughn; Michael M. Crowley; Feng Zhang; John J. Koleng; Justin M. Keen; Justin R. Hughey
Original assignee: Lab International Srl
Priority date: 2006-08-30
Filing date: 2007-08-30
Publication date: 2008-03-06
Also published as: WO2008028047A3

Abstract

Disclosed are methods of formulating bioadhesive or mucoadhesive films that include a mixture of polyethylene oxide polymers. The bioadhesive films contain a therapeutic agent and can be used to administer the therapeutic agent to a patient.

Description

BIOADHESIVE FILM DRUG DELIVERY SYSTEM

BACKGROUND

1. Field of the Invention

The present invention relates to bioadhesive films for delivery of a therapeutic agent and methods of their formulation and use. 2. Description of the Relevant Art

Hot-melt extrusion of films to produce pharmaceutical dosage forms has been known for sometime. However to date, no products have been developed by this method that have been approved for commercial use in the United States. This is in part because of the numerous difficulties involved in producing a therapeutic-agent-containing film by hot melt extrusion that does not either result in heat-degradation o f the therapeutic agent or in stability problems for the formulations when stored over time. Even with the use of plasticizers, high temperatures can be required to produce films by hot-melt extrusion. Although antioxidants can be used to retard degradation of the therapeutic agent, damage from high temperature extrusion often cannot entirely be avoided. Also, certain polymers that perform well when extruded, in particular polyethylene oxide, undergo oxidation when subjected to high heat. Such oxidation is undesirable in a pharmaceutical product. U.S. Pat. No. 4,713,243 to Schiraldi et al. discloses bioadhesive hot-melt extruded films and methods of preparing such films. Shiraldi discloses bioadhesive films made by hot- melt extrusion that include 40-95% by weight of hydroxypropylcellulose, 5-60% of a homopolymer of ethylene oxide (PEO), 0-10% of a water- insoluble polymer, a medicament and 2-10% of a glycol plasticizer, such as propylene glycol, polyethylene glycol, polyhydric alcohol, glycerol esters, fatty acid triglycerides, mineral oil, vegetable oil and the like.

U.S. Pat. No. 6,375,963 to Repka et al. also discloses bioadhesive hot-melt extruded films and methods of their preparation. The compositions disclosed in Repka include a water soluble or water swellable thermoplastic polymer, preferably HPC and/or PEO, and a bioadhesive polymer (e.g., an acrylic acid polymer such as polycarbophil (Noveon AA-I) or carbomer (Carbopol 974P or 971P)). Repka et al. however discloses that the compositions do not include a conventional plasticizer or a material which is generally recognized in the art as a plasticizer for extruded films.

U.S. Patent No. 6,072,100 to Mooney et al. describes a medicament delivery system comprising novel extrudable compositions for topical or transdermal drug delivery. The compositions of Mooney include a thermoplastic water-soluble polymer selected from the group consisting of hydroxypropyl cellulose and polyethylene oxide; a water-soluble polymer derived from acrylic acid; medicament; and plasticizer. The water-soluble polymers are preferably hydroxypropyl cellulose and polyethylene oxide. The compositions of Mooney include from about 10% - 80% of a plasticizer.

U.S. Pat. No. 5,700,478 to Biegajski et al. discloses water-soluble pressure-sensitive mucoadhesive films prepared by hot melt extrusion. In particular, Biegajski discloses the use of water-soluble polymers that have been rendered tacky (that is, pressure sensitive) at room temperature by the addition of a water-soluble plasticizer that is miscible with the polymer and is a liquid at room temperature.

U.S. Pat. No. 6,585,997 to Moro et al. discloses a layered pharmaceutical delivery device for the administration of pharmaceuticals or other active compounds to mucosal surfaces. The device may also be used by itself without the incorporation of a therapeutic agent. The device includes a water-soluble adhesive layer, a non-adhesive, bioerodable backing layer and one or more pharmaceuticals if desired in either or both layers. Upon application, the device adheres to the mucosal surface, providing protection to the treatment site and localized drug delivery. The "residence time", the length of time the device remains on the mucosal surface before complete erosion, can be regulated by modifications of the backing layer.

U.S. Pat. No. 6,159,498 to Tapolsky et al. discloses a water-soluble, bioerodable pharmaceutical delivery device for application to mucosal surfaces. The device comprises an adhesive layer and a non-adhesive backing layer, and the pharmaceutical may be provided in either or both layers. Upon application, the device adheres to the mucosal surface, providing drug delivery and protection to the treatment site.

SUMMARY OF THE INVENTION Disclosed herein are methods of formulating bioadhesive or mucoadhesive film. In some embodiments, the bioadhesive films include a therapeutic agent and may be used to administer the therapeutic agent to a patient. In some embodiments, a bioadhesive film includes: greater than about 40% by weight of polyethylene oxide polymers, wherein the polyethylene oxide polymers comprise at least 5% high molecular weight polyethylene oxide having an average molecular weight in the range of about 1,000,000 to about 10,000,000 and at least 5% low molecular weight polyethylene oxide having an average molecular weight of less than about 900,000, and a pharmaceutically effective amount of a therapeutic agent; wherein the bioadhesive film has a thickness of less than about 6 mm and has a contact surface area of at least about 0.2 cm²; wherein the bioadhesive film is smooth and substantially non-tacky at room temperature; wherein the bioadhesive film is mucoadhesive when moistened and placed in contact with a mucosal surface; and wherein the bioadhesive film is formed using a hot-melt extrusion process. In certain embodiments, a method of making a bioadhesive film includes: forming a mixture comprising greater than about 40% by weight of polyethylene oxide polymers, wherein the polyethylene oxide polymers comprise at least 5% high molecular weight polyethylene oxide having an average molecular weight in the range of about 1,000,000 to about 10,000,000 and at least 5% low molecular weight polyethylene oxide having an average molecular weight of less than about 900,000, and a pharmaceutically effective amount of a therapeutic agent; melting the mixture; and permitting the mixture to solidify as a bioadhesive film, wherein the bioadhesive film has a thickness of less than about 6 mm and has a contact surface area of at least about 0.2 cm². In one embodiment, the mixture is melted using hot-melt extrusion. The bioadhesive films may be shaped for use in the buccal, oral, rectal, vaginal, abdominal, cranial, ophthalmic or otic cavity.

In some embodiments, the bioadhesive film results in controlled delivery of the therapeutic agent over a period of not less than 2 hours, 4 hours, 6 hours, or 8 hours. In other embodiments, the bioadhesive film is in an "immediate release" form in which at least 80% of the therapeutic agent is released over a period of 1 hour. DETAILED DESCRIPTION

In an embodiment, bioadhesive films for transmucosal delivery of a therapeutic agent may be formed by hot-melt extrusion. The bioadhesive films may be formed from a composition that includes, but is not limited to: a primary hydrophobic or hydrophilic matrix material; optionally, one or more secondary hydrophobic or hydrophilic matrix materials; optionally, one or more plasticizers, optionally, one or more surfactants or combination thereof; an active agent, preferably a therapeutic agent; and optionally, one or more functional excipients.

Hydrophilic matrix materials include, but are not limited to hydrophilic polymers such as polyethylene oxide (PEO), ethylene oxide-propylene oxide co-polymers, polyethylene- polypropylene glycol (e.g. poloxamer), carbomer, polycarbophil, chitosan, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxyalkyl celluloses such as hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, polyacrylates such as carbomer, polyacrylamides, polymethacrylamides, polyphosphazines, polyoxazolidines, polyhydroxyalkylcarboxylic acids, alginic acid and its derivatives such as carrageenate alginates, ammonium alginate and sodium alginate, starch and starch derivatives, polysaccharides, carboxypolymethylene, polyethylene glycol, natural gums such as gum guar, gum acacia, gum tragacanth, karaya gum and gum xanthan, povidone, gelatin or the like.

Hydrophobic matrix materials include water-insoluble polymers such as acrylic polymer, acrylic copolymer, methacrylic polymer or methacrylic copolymer, including but not limited to Eudragit® LlOO, Eudragit® L100-55, Eudragit® L 30 D-55, Eudragit® SlOO, Eudragit® 4135F, Eudragit® RS, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamine copolymer, polymethyl methacrylate, polymethacrylic acid anhydride, polymethacrylate, polyacrylamide, polymethacrylic acid anhydride and glycidyl methacrylate copolymers, an alkylcellulose such as ethylcellulose, methylcellulose, calcium carboxymethyl cellulose, certain substituted cellulose polymers such as hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate, cellulose acetate butyrate, cellulose acetate phthalate, and cellulose acetate trimaleate, polyvinyl acetate, polyvinyl acetate phthalate, polyester, waxes, shellac, zein, or the like.

For purposes of this disclosure, a matrix material is considered hydrophilic and a polymer is considered to be water-soluble if it is more than sparingly soluble as defined by USP 29 / NF 24, that is if according to USP 29 / NF 24 the compound is classified as "soluble" or "very soluble."

For purposes of this disclosure, a matrix material is considered to be hydrophobic or water-insoluble if it is "sparingly soluble" or "practically insoluble" or "insoluble" as defined by USP 29 / NF 24.

In embodiments when the bioadhesive films are intended to be ingested or placed in contact with a patient, the preferred matrix materials, therapeutic agent, active agent, plasticizer, surfactant, and functional excipients of the present invention will be pharmaceutically acceptable materials, such as those indicated to be generally regarded as safe ("GRAS-certified") or national formulary certified.

In certain embodiments, the bioadhesive film includes greater than 40%, 45%, 50%, 55%, 60%, 65%, 75% or 80% by weight of the primary matrix material. The bioadhesive film may include less than 60%, less than 50%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 10% or less than 5% by weight of the secondary matrix material. Plasticizers, surfactants, or combinations thereof also make up less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 10%, less than 5% or less than 2% by weight of the bioadhesive film. In some embodiments, the bioadhesive film may be composed of mixtures of polyethylene oxides (PEO) having different molecular weights. PEO is useful as both the bioadhesive and the matrix material. For example, high molecular weight PEO polymers (e.g., PEO homopolymers having an average molecular weight greater than 1,000,000) may be used as the adhesive material. Low molecular weight PEO polymers (e.g., PEO homopolymers having an average molecular weight less than 900,000) may be used as the matrix material. In such an embodiment, the use of low-melting point glycerol plasticizers or other bioadhesive polymers (e.g., cross-linked acrylic acid based polymers ) to render the compositions bioadhesive when moistened is not necessary.

In some embodiments, a low molecular weight PEO homopolymer used in a bioadhesive film composition has an average molecular weight of about 100,000 to about 900,000. In certain embodiments, a low molecular weight PEO homopolymer may have an average molecular weight of less than 100,000, less than 200,000, less than 400,000, less than 500,000, less than 600,000, less than 700,000, less than 800,000, or less than 900,000.

In some embodiments, a high molecular weight PEO homopolymer used in a bioadhesive film composition has an average molecular weight of about 1,000,000 to about 10,000,000. In certain embodiments, a high molecular weight PEO homopolymer may have an average molecular weight of greater than 1,000,000, greater than 2,000,000, greater than 3,000,000, greater than 4,000,000, greater than 5,000,000, greater than 6,000,000, greater than 7,000,000, greater than 8,000,000, or greater than 9,000,000. In some embodiments, the bioadhesive film includes greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, or greater than 90%by weight of one or more PEO homopolymers.

In alternate embodiments, a PEO homopolymer may be combined with a secondary bioadhesive polymer. Bioadhesive polymers include, but are not limited to: polyethylene oxide copolymer, Poloxamer, cross-linked acrylic acid based polymers (e.g., Carbopol® polymers, polycarbophil (Noveon), ), chitosan, , co-polymer of methyl vinyl ether and maleic acid or anhydride (Gantrez), acrylic polymer, polyacrylic polymer, sodium alginate, alginic acid, carrageenan, hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), copolymers of these polymers, combinations thereof, their salts and others known to one of ordinary skill in the art to improve the bioadhesive properties of the film compositions. The bioadhesive film that includes a PEO homopolymer may include greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60% or greater than 70% by weight of the secondary bioadhesive polymer. In certain embodiments, the compositions are substantially free of any cross-linked acrylic acid-based polymers (e.g., Carbopol® polymers).

In other embodiments, the compositions include less than 40% by weight of hydroxypropyl cellulose. Compositions that include PEO homopolymer as the primary matrix material may further include one or more secondary hydrophobic or hydrophilic polymers, or a mixture thereof, in an amount less than 50%, less than 40% by weight, less than 35%, less than 30%, less than 25%, less than 20% or less than 10% by weight of the film composition. Plastidzers In preferred embodiments, a plasticizer is also included in the oral dosage form.

Plasticizers interact with the hydrophobic matrix material resulting in a lower viscosity of the mixture during extrusion or molding. The result is that extrusion or injection molding of the oral dosage form can occur at lower temperatures, thereby reducing the possibility of thermally degrading the therapeutic agent. The most suitable plasticizers are those that lower the glass transition temperature (Tg) of the hydrophobic matrix material. Plasticizers suitable for use with the compositions and methods disclosed herein include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils (e.g., castor oil, rape oil, and sesame oil), small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol) (e.g., poly(ethylene glycol polymers having a molecular weight of less than about 100,000), citrate ester-type plasticizers, triacetin, propylene glycol, phthalate esters (e.g., dimethyl phthalate, diethyl phthalate, dibutyl phthalate, diethylhexyl phthalate, and diisononyl phthalate), and glycerin. Such plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate, monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, triethylenetetramine and 2-amino-2-methyl-l,3-propanediol.

In some embodiments, plasticizers may be "solid-state" plasticizers, that is, compounds that are solids at room temperature. Such plasticizers have a melting point greater than 22 ⁰C, greater than 25 ⁰C, greater than 30 ⁰C, greater than 35 ⁰C, greater than 4O⁰C, greater than 5O⁰C, greater than 55 ⁰C or greater than 7O⁰C. Examples of solid state plasticizers include, but are not limited to, PEG 3350, PEG 4000, and Poloxamer 407. Exdpients

In addition to a hydrophilic matrix material and a therapeutic agent, compositions may also include one or more excipients such as lubricants, thermal lubricants, antioxidants, buffering agents, alkalinizing agents, disintegrants, binders, diluents, sweeteners, chelating agents, colorants, flavorants, surfactants, solubilizers, wetting agents, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic materials, absorption enhancers, preservatives, absorbents, cross-linking agents, bioadhesive polymers, retardants, pore formers, osmotic agents and fragrance.

Lubricants or thermal lubricants useful as an excipient include, but are not limited to fatty esters, glyceryl monooleate, glyceryl monostearate, wax, carnauba wax, beeswax, vitamin E succinate, and a combination thereof.

As used herein, the term "antioxidant" is intended to mean an agent that inhibits oxidation and thus is used to prevent the deterioration of preparations by oxidation due to the presence of oxygen free radicals or free metals in the composition. Such compounds include, by way of example and without limitation, ascorbic acid (Vitamin C), ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), hypophophorous acid, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, vitamin E and its derivatives, propyl gallate and others known to those of ordinary skill in the art.

Binders are ingredients added to mixtures to provide adhesive qualities during and after formation of an oral dosage. Examples of binders include, but are not limited to: waxes such as beeswax; carnauba wax; microcrystalline wax and paraffin wax; cetyl palmitate; glycerol behenate; glyceryl palmitostearate; glyceryl stearate; hydrogenated castor oil; stearic acid; stearic alcohol; stearate 6000 WLl 644; gelucire 50/13; polyethylene glycols (PEG) such as PEG 2000, PEG 3000, PEG 6000, PEG 8000, PEG 10000, PEG 20000; polyethylene oxide; polypropylene oxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate; acrylate-methacrylate copolymers; polyethylene; polycaprolactone; alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; microcrystalline cellulose; starches; pectins; polylactic acid (PLA); polyglycolic acid (PLGA); polyesters (e.g., shellac); and polysaccharides such as cellulose, tragacanth, gum arabic, guar gum, and xanthan gum.

A buffering agent is used to resist change in pH upon dilution or addition of acid or alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate, salts of inorganic or organic acids, salts of inorganic or organic bases, and others known to those of ordinary skill in the art.

As used herein, the term "alkalizing agent" is intended to mean a compound used to provide alkaline medium for product stability. Such compounds include, by way of example and without limitation, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine and others known to those of ordinary skill in the art.

As used herein, the term "disintegrant" is intended to mean a compound used in solid dosage forms to promote the disruption of a solid mass (layer) into smaller particles that are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre-gelatinized and modified starches thereof, sweeteners, clays, bentonite, microcrystalline cellulose (e.g., Avicel™), carboxymethylcellulose calcium, croscarmellose sodium (e.g., Ac-Di-SoI ®), alginic acid, sodium alginate, cellulose polyacrilin potassium (e.g., Amberlite™), alginates, sodium starch glycolate, gums, agar, guar, locust bean, karaya, pectin, tragacanth, crospovidone and other materials known to one of ordinary skill in the art. A superdisintegrant is a rapidly acting disintegrant. Exemplary superdisintegrants include crospovidone, sodium starch glycolate (e.g., Explotab™, Primojel™), and low substituted HPC.

Exemplary chelating agents include EDTA, polyamines, derivatives thereof, and others known to those of ordinary skill in the art. As used herein, the term "colorant" is intended to mean a compound used to impart color to solid (e.g., tablets) pharmaceutical preparations. Such compounds include, by way of example and without limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide, red, other FD&C dyes and natural coloring agents such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and other materials known to one of ordinary skill in the art. The amount of coloring agent used will vary as desired.

As used herein, the term "flavorant" is intended to mean a compound used to impart a pleasant flavor and often odor to a pharmaceutical preparation. Exemplary flavoring agents or flavorants include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other useful flavors include vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors that have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors will be present in any amount as desired by those of ordinary skill in the art. Particular flavors are the grape and cherry flavors and citrus flavors such as orange.

Surfactants include soaps, synthetic detergents, and wetting agents. Suitable surfactants include cationic surfactants, anionic surfactants, non-ionic surfactants, and amphoteric surfactants. Examples of surfactants include Polysorbate 80; sorbitan monooleate; sodium lauryl sulfate (sodium dodecylsulfate); soaps such as fatty acid alkali metal salts, ammonium salts, and triethanolamine salts; cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene)-b/øcfc- poly(oxypropylene) copolymers; and amphoteric detergents, for example, alkyl β- aminopropionates and 2-alkylimidazoline quaternary ammonium salts; wetting agents such as, glycerin, proteins, and peptides; water miscible solvents such as glycols; and mixtures thereof.

Solubilizers include cyclodextrins, povidone, combinations thereof, and others known to those of ordinary skill in the art. Exemplary absorption enhancers include dimethyl sulfoxide, Vitamin E PGS, sodium cholate and others known to one of ordinary skill in the art.

Exemplary waxes include carnauba wax, beeswax, microcrystalline wax and others known to one of ordinary skill in the art. Preservatives include compounds used to prevent the growth of microorganisms.

Suitable preservatives include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal and others known to those of ordinary skill in the art.

Examples of absorbents include polyvinylpyrrolidone (PVP) (e.g., Polyplasdone™ XL 10); veegum; clays; alginates; alginic acid; carboxymethylcellulose calcium; microcrystalline cellulose (e.g., Avicel™); polacrillin potassium (e.g., Amberlite™); sodium alginate; corn starch; potato starch; pregelatinized starch; modified starch; cellulosic agents; montmorrilonite clays (e.g., bentonite); gums; agar: locust bean gum; gum karaya; pecitin; tragacanth; and other absorbents known in to those of ordinary skill in the art.

In an embodiment, the oral dosage form may include one or more polycarboxylic acids. Polycarboxylic acids include organic compounds that have two or more carboxyl (-COOH) groups and from 2 to 9 carbon atoms in a chain or ring to which the carboxyl groups are attached. The carboxyl groups are not included when determining the number of carbon atoms in the chain or ring (e.g., 1,2,3 propane tricarboxylic acid would be considered to be a C₃ polycarboxylic acid containing three carboxyl groups and 1,2,3,4 butanetetracarboxylic acid would be considered to be a C₄ polycarboxylic acid containing four carboxyl groups). C₂ -Cg polycarboxylic acids include, but are not limited to aliphatic, aromatic, and alicyclic acids, either saturated or olefinically unsaturated, with at least two carboxyl groups per molecule. In some embodiments, aliphatic polycarboxylic acids may include a hydroxyl group attached to a carbon atom alpha to a carboxyl group (an α-hydroxy polycarboxylic acid), α-hydroxy polycarboxylic acids include citric acid (also known as 2-hydroxy- 1,2,3 propane tricarboxylic acid) and tartaric acid. Examples of specific polycarboxylic acids include, but are not limited to, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, malic acid, pimelic acid, nonanedioic acid, dodecanedioic acid, octanedioic acid, phthalic acid, isophthalic acid, terephthalic acid, citraconic (methylmaleic acid), citric acid, tartaric acid, itaconic acid (methylenesuccinic acid), 1,2,3 propane tricarboxylic acid, transaconitic acid (trans- 1-propene- 1,2,3-tricarboxylic acid), 1,2,3,4-butanetetracarboxylic acid, all-cis- 1,2,3,4- cyclopentanetetracarboxylic acid, mellitic acid (benzenehexacarboxylic acid), oxydisuccinic acid (2,2'-oxybis(butanedioic acid) , α-bromoglutaric acid, 3,3-dimethylpentanedioic acid, and 2,4- dicholoropentanedioic acid. Bioadhesive polymers include polyethylene oxide, KLUCEL (hydroxypropylcellulose), CARBOPOL, polycarbophil, GANTREZ, and combinations thereof, and others known to one of ordinary skill in the art.

Retardants are agents that are insoluble or slightly soluble polymers with a Tg above 45⁰C, or above 5O⁰C before being plasticized by other agents in the formulation including other polymers and other excipients needed for processing. The excipients include waxes, acrylics, cellulosics, lipids, proteins, glycols, and the like.

Exemplary pore formers include water soluble polymers such as polyethylene glycol, propylene glycol, and povidone; binders such as lactose, calcium sulfate, calcium phosphate and the like; salts such as sodium chloride, magnesium chloride and the like, poloxamers and combinations thereof and other similar or equivalent materials which are widely known in the art. Examples of poloxamers include, but are not limited to: Pluronic® F-68 (Poloxamer 188),

Pluronic® F87 (Poloxamer 237), Pluronic® F108 (Poloxamer 338), Pluronic® F127 (Poloxamer

407, Lutrol F127) and the like. Pluronic® is a registered tradename for BASF Corporation for block copolymers of ethylene oxide and propylene oxide represented by the chemical structure

HO(C₂H₄θ)_a(C₃H₆O)_b(C₂H₄O)_aH wherein for: (a) Pluronic® F-68, a is 80 and b is 27; (b)

Pluronic® F87, a is 64 and b is 37; (c) Pluronic® F108, a is 141 and b is 44; and Pluronic®

F127, a is 101 and b is 56. The average molecular weights of these block copolymers are 8,400,

7,700, 14,600 and 12,600 for Pluronic® F-68, Pluronic® F-87, Pluronic® F108 and Pluronic® F127, respectively.

Exemplary osmagents or osmotic agents include organic and inorganic compounds such as salts, acids, bases, chelating agents, sodium chloride, lithium chloride, magnesium chloride, magnesium sulfate, lithium sulfate, potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, alpha-d-lactose monohydrate, glucose, combinations thereof and other similar or equivalent materials which are widely known in the art.

As used herein, the term "sweetening agent" is intended to mean a compound used to impart sweetness to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

It should be understood that compounds used as excipients or that are used to modify the oral dosage form, may serve a variety of functions or purposes. Thus, whether a compound named herein is assigned to one or more classifications or functions, its purpose or function should not be considered as being limited to the named purpose or function. Therapeutic agents

Compositions of the present invention preferably comprise an active agent, most preferably a therapeutic agent. Therapeutic agents are drugs or other substances that can be used to treat a disease or condition in a patient or to ameliorate the symptoms of a disease or condition. Patients according to the present invention are mammalian animals in need of treatment, preferably humans, including adult humans and human children.

Compositions include a therapeutically effective amount of one or more therapeutic agents. Preferably, the one or more therapeutic or active agents are present in an amount from about 0.001 mg to about 2,500 mg, preferably 0.01 mg to about 1,000 mg, most preferably 0.1 mg to about 500 mg.

When the active agent is a therapeutic compound, exemplary therapeutic compounds include antibiotics, antihistamines and decongestants, antiinflammatory agents, antiparasitics, antivirals, local anesthetics, antifungal agents, amoebicidal agents, trichomonocidal agents, analgesics, antiarthritis agents, anthiasthmatics, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antineoplastics, antipsychotics, neuroleptics, antihypertensives, antidepressants, hypnotics, sedatives, anxyolitic energizers, anticonvulsants, antiparkinson agents, muscle relaxant agents, antimalarials, hormonal agents, contraceptives, sympathomimetics, diuretics, hypoglycemics, ophthalmics, electrolytes, diagnostic agents and cardiovascular drugs. Examples of therapeutic agents include, but are not limited to dextroamphetamine, methylphenidate, pemoline, imipramine, desipramine, bupropion, venlafaxine, clonidine, guanfacine, paroxitine, citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, sertraline, selegiline, levodopa, phenylalanine, and L-tyrosine.

Representative antibacterial substances include, for example, penicillins: penicillin G and V, penicillinase-resistant penicillin (methicillin, nafcillin, oxacilin, cloxacilin and dicloxacillin), and aminopenicillins: ampicillin, amoxicillin, cyclacillin; carboxy and ureidopenicillines such as carbenicillin, ticarcillin, azlocillin, mezlocillin and piperacilllin; cephalosporins such as the first- generation cephalosporins such as cephalotin, cephalexin, cefazolin, second generation cephalosporins such as cefoxitin, cefaclor, cefuroxime, and third generation cephalosporins such as cefotaxime, ceftriaxone,ceftazidime; beta-lactam antibiotics such as imipenem, aztreonam; sulfonamides such as sulfisoxazole, sulfamethoxazole, sulfadiazine, sulfasalazine and trimethropim-sulfamethoxazole; tetracyclines such as oxytetracycline, methacycline, chlorotetracycline and doxycycline; chloramphenicol, erythromycin, lincomycin, clindamycin, vancomycin, bacitracin; aminoglycoside antiobiotics such as streptomycin, gentamicin, tobramycin, amikacin, kanamycin and neomycin; and quinolones such as nalidixic acid, norfloxacin, ciprofloxacin, cinoxacin, ofloxacin, enoxacin, lomefloxacin, amifloxacin and pefloxacin. Representative antiparasitic compounds include anthelmintics such as ivermectin, mebendazole, albendazole, piperazine, praziquantel, thiabendazole, and dapsone. Representative anti-malarial compounds include chloroquine and its congeners, diaminopyrimidines, mefloquine, primaquine and pyrimethamine. Miscellaneous antiparasitic agents include 8-hydroxyquinolines, metronidazole, quinacrine and paromomycin. Representative antiviral compounds include acyclovir, gancyclovir, pencyclovir, foscarnet, idoxuridine, trifluridine and vidarabine; anti-retroviral compunds such as zidovudine, didadosine, estavudine; and others such as interferon, and amantadine.

Representative antineoplastics include nitrogen mustards such as mechlorethamine chlorambucil, cyclophosphamide; ethylenimines and methylmelamines such as triethylenemelamine, thiotepa, hexamethyl-melamine; alkyl sulfonates such as busulfan; nitrosureas such as carmustine (BCNU), lomustine; dacarbazine; folic acid analogs such as methotrexate; pyrimidine analogs such as fluorouracil, arabinoside cytisine; purine analogs such as mercaptopurine, azathiprine; vinca alkaloids such as vincristine, vinblastine, taxol; etoposide; antibiotics such as actinomycin D, daunorubicin, doxorubicin, bleomycin, mitomycin; cisplatin; hydroxyurea; procarbazine; aminoglutethimide; cisplatin and tamoxifen.

Representative anti-inflammatory and analgesic drugs include cortisone, hydrocortisone, prednisone, prednisolone, betamethasone, dexamethasone and fluorocortisone; salycilates such as salycilic acid, aspirin and diflunisal; pyrazolon derivates such as phenylbutazone and oxyphenbutazone; aminopyridines such as dipyrone, paraaminophenol derivates such as acetaminophen and phenacetin, indomethacin and sulindac; fenamates such as mefenamic acid; tolmetin; propionic acid derivates such as ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen and indoprofen; piroxicam, and diclofenac. Representative opioid analgesics include morphine, codeine, meperidine and nalorphine.

Representative drugs used in the treatment of gout include colchicine, allopurinol, probenecid and sulphinpirazone.

Representative antihistamines and decongestants include the first generation compounds such as diphenhydramine, pirilamine, chlorpheniramine, brompheniramine, promethazine; and second-generation compounds such as astemizole, loratadine and terfenadine. Representative sympathomimetic drugs include epinephrine, amphetamine, ephedrine and norepinephrine.

Representative antiasthmatic drugs include methylxanthines such as theophylline; corticoids such as beclomethasone dipropionate, budesonide, flunisolide, prednisone; bronchodilators such as albuterol, salbutamol, salmetherol, terbutaline; antimuscharinic agents such as ipratopium bromide; and cromolyn sodium.

Representative local anesthetics include benzocaine, procaine, lidocaine, cocaine, tetracaine, bupivacaine and dibucaine.

Representative muscle relaxants and antispasmodic agents include baclofen, succinylcholine, dantrolene, carisoprodol, metaxalone, cyclobenzaprine, diazepan, mephensin, trihexylphenidyl and biperiden. Representative antiparkinson disease compounds include levodopa, carbidopa, benceracide, amantadine, bromocriptine and pergolide.

Representative antidepressant include tricyclic agents such as amitriptyline, imipramine, clomipramine, doxepine; monoamine oxidase inhibitors such as isocoboxazid, phenelzine and tranylcypromine; fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, bupropione and trazodone.

Representative anticonvulsants include hydantoins such as phenytoin, barbiturates and deoxy derivates such as phenobarbital and primidone; carbamazepine, ethosuximide, valproic acid; and benzodiacepines such as diazepam and clonazepam. Representative antipsychotics include chlorpromazine, trifluoperazine, thioridazine, fluphenazine, perphenazine, haloperidol, loxapine, molindone, clozapine, pimozide, risperidone and lithium.

Representative hypnotics and sedatives include barbiturates such as pentobarbital sodium, phenobarbital, secobarbital, thiopental; benzodiazepines such as diazepam, alprazolam, chlordiazepoxide, clonazepam, lorazepam, oxazepam; buspirone,meprobamate, Zolpidem and zoplicone.

Representative hypoglycemic agents include insulin, insulin zinc, isophane insulin, protamine zinc insuline and extended insulin zinc suspension; sulfonylureas such as tolbutamide, chlorpropamide, acetohexamide, glyburide, glipizide, glicazide; biguanides such as phenformin, metformin; ciglitazone, troglitazone, and acarbose.

Representative antidiuretics drugs include inhibitors of carbonic anhydrase such as acetazolamide, chortalidone, indapamine; benzothiadiazides such as chlorothiazide, hydrochlorothiazide; ethacrynic acid, furosemide, bumetanide; aldosterone antagonists such as spironolactone; triamtirene and amiloride.

Representative antihypertensive and cardiovascular drugs include inhibitors of the renin- angiotensin system such as enalapril, lisinopril, ramipril, captopril, perindopril, trandolapril; angiotensin II receptors antagonists such as losartan; calcium channel blockers: nifedipine, amlodipine, nitrendipine, nimodipine, diltiazem, verapamil; simpathocolitic agents; adrenergic antagonists; atenolol, propanolol, nadolol, sotalol, timolol, metropolol, acebutolol, carvedilol; adrenergic agonists; prazosin, fentolamine; centrally acting agents such as methyldopa, clonidine, guanfacine, reserpine; direct arterial and venous vasodilators such as sodium nitroprusside, nitroglicerin, isosorbide 5-mononitrate, isosorbide dinitrate; antiarrithmic agents such as quinidine, procainamide, phenytoin, lidocaine, mexiletine, propafenone, flecainide, encainide, propranolol, acebutolol, amiodarone, sotalol, verapamil and diltiazem; digitalis; and cardiac glycosides such as digoxine, digitoxine, amrinone, and milrinone.

Representative anticoagulants include heparin, dicoumarol; thrombolytic agents such as streptokinase, tissue plasminogen activator (t-PA) urokinase and antiplatelet drugs such as dipyridamole, ticlopidine, and sulfinpyrazone.

Representative prokynetic gastrointestinal drugs include cisapride, domperidone, and metoclopramide .

Representative anti-spasmodic and muscle contractants include atropine, scopolamine, methoescopolamine and oxyphenonium. Representative steroidal drugs include prednisolone, cortisone, Cortisol and triamcinolone; androgenic steroids such as methyltesterone, and fluoxmesterone; estrogenic steroids such as 17β-estradiol, α-estradiol, estriol, α-estradiol-3-benzoate, and 17- ethynylestradiol-3-methyl ether; and progestational steroids such as progesterone, 19-norpregn- 4-ene-3,20-dione, 17-hydroxy-19-nor-17α-pregn-5(10)-ene-20-yn-3-one, 17α-ethynyl-17- hydroxy-5(10)-estren-3-one, and 9β,10α-pregna-4,6-diene-3,20-dione.

Representative ophthalmic agents include pilocarpine, pilocarpine salts such as pilocarpine nitrate, pilocarpine hydrochloride, dichlophenamide, atropine, atropine sulfate, scopolamine and eserine salicylate.

Representative nutritional agents include ascorbic acid, niacin, nicotinamide, folic acid, choline biotin, panthothenic acid, and vitamin B-12, essential amino acids, and essential fats.

Representative electrolytes include calcium gluconate, calcium lactate, potassium chloride, potassium sulfate, sodium chloride, sodium fluoride, ferrous lactate, ferrous gluconate, ferrous sulfate, ferrous fumarate and sodium lactate. The above-mentioned list should not be considered exhaustive and is merely exemplary of the many embodiments considered within the scope of the invention. Many other active compounds can be administered with the device of the present invention.

The therapeutic compound(s) contained within the present device can be formulated as its pharmaceutically acceptable salt(s). As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the therapeutic compound is modified by reacting it with an acid or base as needed to form an ionically bound pair. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Suitable non-toxic salts for basic active agents include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known to those of ordinary skill in the art. The salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and others known to those of ordinary skill in the art. Suitable non-toxic salts for acidic active agents include those derived from an organic amine, an alkali metal hydroxide, an alkali metal alkoxide, a primary amine, a secondary amine, a tertiary amine, a quaternary amine, an aromatic amine, a heterocyclic amine, or an inorganic base. The pharmaceutically acceptable salts may be synthesized from the parent therapeutic compound that contains a basic or acidic moiety by conventional chemical methods. Lists of other suitable salts are found in Remington's Pharmaceutical Sciences, 17^th Ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the relevant disclosure of which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with tissues of human beings and animals and without excessive toxicity, irritation, allergic response, or any other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used in this disclosure, the term vitamin refers to trace organic substances that are required in the diet. For the purposes of the present invention, the term vitamin(s) include, without limitation, thiamin, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B 12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E and vitamin K. Also included within the term vitamin are the coenzymes thereof. Coenzymes are specific chemical forms of vitamins and can include thiamin pyrophosphates (TPP), flavin mononucleotide (FMN), and flavin adenine dinucleotive (FAD). Nicotinamide adenine dinucleotide (AND), Nicotinamide adenine dinucleotide phosphate (NADP), Coenzyme A (CoA), pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B12, lipolysine, 11-cis- retinal, and l^S-dihydroxycholecalciferol. The term vitamin(s) also includes choline, carnitine, and alpha, beta, and gamma carotene.

As used in this disclosure, the term "mineral" refers to inorganic substances, metals, and the like required in the human diet. Thus, the term "mineral" as used herein includes, without limitation, calcium, iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromium, mixtures thereof and others known to those of ordinary skill in the art.

The term "dietary supplement" as used herein means a substance, which has an appreciable nutritional effect when, administered in small amounts. Dietary supplements include, without limitation, such ingredients as bee pollen, bran, wheat germ, kelp, cod liver oil, ginseng, and fish oils, amino-acids, proteins, plant extracts, plant powder, herbs, herbal extracts and powders, vitamins, minerals, combinations thereof and others known to those of ordinary skill in the art.

The amount of therapeutic compound incorporated in each device of the invention will be selected according to known principles of pharmacy. An effective amount of therapeutic compound is specifically contemplated. By the term "effective amount", it is understood that, with respect to, for example, pharmaceuticals, a pharmaceutically effective amount is contemplated. A pharmaceutically effective amount is the amount or quantity of a drug or pharmaceutically active substance which is enough for the required or desired therapeutic response, or in other words, the amount, which is sufficient to elicit an appreciable biological response when, administered to a patient. The appreciable biological response may occur as a result of administration of single or multiple unit doses of an active substance. Depending upon the active substance used and upon the amount of active substance present in a particular device, a unit dose may comprise one or more such devices. As used with reference to a vitamin or mineral, the term "effective amount" means an amount of at least about 10% of the United States Recommended Daily Allowance ("RDA") of that particular ingredient for a patient. For example, if an intended ingredient were vitamin C, then an effective amount of vitamin C would include an amount of vitamin C sufficient to provide 10% or more of the RDA. Typically, where the tablet includes a mineral or vitamin, it will incorporate higher amounts, preferably about 100% or more of the applicable RDA. In addition to therapeutic agents, bioadhesive films can be produced that incorporate other active agents including pesticides, herbicides, insecticides, antioxidants, plant growth instigators, sterilization agents, catalysts, chemical reagents, food products, nutrients, cosmetics, vitamins, sterility inhibitors, fertility instigators, microorganisms, flavoring agents, sweeteners, cleansing agents, and other such compounds for pharmaceutical, veterinary, horticultural, household, food, culinary, agricultural, cosmetic, industrial, cleaning, confectionery, flavoring applications and the like. The active agent can be present in its neutral, ionic, salt, basic, acidic, natural, synthetic, diastereometric, isomeric, enantiomerically pure, racemic, hydrate, chelate, derivative, analog, or other common form. In certain embodiments, the bioadhesive films of the present invention are adapted for controlled delivery of an active or therapeutic agent to the buccal, oral, rectal, vaginal, abdominal, cranial, ophthalmic or otic cavity. For oral, buccal, mucosal, sublingual administration the delivery device may be in the form of a film shaped to fit and conform generally to the intended surface. Similarly, for rectal administration, the delivery device can be included in a film designed for release of a therapeutic compound into the intestines, sigmoid flexure and/or rectum. For dermal, cutaneous, otic, intraperitoneal, ophthalmic and implant applications, the device is a film appropriately shaped for that use. Bioavailability enhancers such as alcohols or other compounds that enhance the penetration of the therapeutic compound from the delivery device into the mucosa may be needed to prepare suitable formulations.

Methods of Formulation

Further provided are methods of producing bioadhesive films. Bioadhesive films may be formed by: mixing a primary matrix materials, one more optional secondary matrix materials and a therapeutic agent, wherein the primary matrix materials comprises greater than 60% of the mixture by weight; melting the mixture; and permitting the mixture to solidify as a film.

For purposes of the present disclosure a mixture is "melted" by applying thermal or mechanical energy sufficient to render the mixture partially or substantially completely molten. For instance, in a mixture that includes a matrix material, "melting" the mixture may include substantially melting the matrix material without substantially melting one or more other materials present in the mixture (e.g., the therapeutic agent and one or more excipients). Generally, a mixture is sufficiently molten, for example, when it can be extruded as a continuous rod, or when it can be subjected to injection molding.

The mixture of the primary matrix material, optional secondary matrix material therapeutic agent, optional plasticizer and/or surfactant and optional functional excipients can be accomplished by any suitable means. Well-known mixing means known to those skilled in the art include dry mixing, dry granulation, wet granulation, melt granulation, high shear mixing, and low shear mixing. In some embodiments the primary matrix material is a polyethylene oxide polymer.

Granulation generally is the process wherein particles of powder are made to adhere to one another to form granules, typically in the size range of 0.2 to 4.0 mm. Granulation is desirable in pharmaceutical formulations because it produces relatively homogeneous mixing of different sized particles.

Dry granulation involves aggregating powders under high pressure. Wet granulation involves forming granules using a granulating fluid or wetting agent that is subsequently removed by drying. Melt granulation is a process in which powders are transformed into solid aggregates or agglomerates while being heated. It is similar to wet granulation except that a binder acts as a wetting agent only after it has melted. All of these and other methods of mixing pharmaceutical formulations are well-known in the art.

Subsequent or simultaneous with mixing, the mixture of hydrophobic matrix material, therapeutic agent, optional plasticizer, and optional functional excipients is melted to produce a mass sufficiently fluid to permit shaping of the mixture and/or to produce melding of the components of the mixture. The melted mixture is then permitted to solidify as a film. The mixture can optionally be shaped or cut into suitable sizes during the melting step or during the solidifying step. In some embodiments, the mixture becomes a homogeneous mixture either prior to or during the melting step. Methods of melting the mixture include, but are not limited to, hot-melt extrusion, injection molding and compression molding. Appropriate melting temperatures include those that result in little or no detectable degradation or oxidation of any of the ingredients of the film, and such appropriate melting temperatures can be determined by those of skill in the art based upon known principles depending on the ingredients. Hot-melt extrusion typically involves the use of an extruder device. Such devices are well known in the art. Such systems include mechanisms for heating the mixture to an appropriate temperature and forcing the melted feed material under pressure through a die to produce a rod, sheet or other desired shape of constant cross-section. Subsequent to or simultaneous with being forced through the die the extrudate can be cut into smaller sizes appropriate for use as an oral dosage form. Any suitable cutting device known to those skilled in the art can be used, and the mixture can be cut into appropriate sizes either while still at least somewhat soft or after the extrudate has solidified. The extrudate may be cut, ground or otherwise shaped to a shape and size appropriate to the desired oral dosage form prior to solidification, or may be cut, ground or otherwise shaped after solidification.

In some embodiments, films of the present invention are hot-melt extruded, for example using a single screw or twin-screw type extruder such as those commonly known to those skilled in the art. The extruder zones and die can be set to any appropriate temperature, typically a temperature between 50 ⁰C and 140 ⁰C, more preferably 70 ⁰C to 130 ⁰C.

Under certain conditions, extrusion of compositions may result in "die-swelling," a phenomenon in which the extrudate swells diametrically after exiting the die. In certain embodiments die-swelling may be desirable, producing an extrudate having greater porosity and thus accelerated release characteristics. In other embodiments, it is desirable to avoid die swelling, thereby producing a more solid composition that has slower therapeutic release and/or is slower to dissolve in a solvent such as aqueous ethanol solutions and/or has a greater hardness value.

Injection molding typically involves the use of an injection-molding device. Such devices are well known in the art. Injection molding systems force a melted mixture into a mold of an appropriate size and shape. The mixture solidifies as least partially within the mold and then is released.

Compression molding typically involves the use of a compression-molding device. Such devices are well known in the art. Compression molding is a method in which the mixture is optionally preheated and then placed into a heated mold cavity. The mold is closed and pressure is applied. Heat and pressure are typically applied until the molding material is cured. The molded film is then released from the mold.

In other embodiments, the bioadhesive films may be prepared by solvent casting.

In some embodiments, the bioadhesive films may be a single layer, or may be part of a composite of two or more layers. In single layer films, the film may be a single substantially homogenous layer, that is, the single layer is formed of a substantially homogenous material.

In some embodiments, a bioadhesive layer is coupled to a backing layer. The backing layer may retard dissolution of the bioadhesive layer. Such backing layers are well known within the art and typically include hydrophobic matrix materials. The backing layer may also include one or more active or therapeutic agents that can be the same as, or different from the therapeutic agents in the bioadhesive layer. In compositions comprising two or more layers, the layers may be coupled to each other by any means known to those of skill in the art, including co-extrusion, lamination and the like. In some embodiments, the backing layer may also act as a bioadhesive layer. In other embodiments, the backing is not bioadhesive.

Bioadhesive films may have a thickness in the range from about 0.1 mm to about 6 mm, more preferably about 0.5 mm to about 2.0 mm. Bioadhesive films may have a contact surface area (i.e., the surface area of the film surface that is placed in contact with the mucosa) of at least

0.2 cm², at least 0.5 cm², at least 1.0 cm², at least 2.0 cm², at least 3.5 cm², at least 5 cm², at least 10 cm² or at least 20 cm².

Either before or after solidification of the film, the film may be cut or otherwise shaped to adapt it for a particular use such as delivery of the therapeutic agent to the buccal, oral, rectal, vaginal, abdominal, cranial, ophthalmic, uterine, nasal, sinus or otic cavity.

Methods of Treatment The described bioadhesive films may be used to treat a patient. Treatment of a patient with a bioadhesive film includes: identifying a patient in need of treatment; providing a bioadhesive film composition of the present invention containing a therapeutic agent; and administering said film composition to the patient.

In certain embodiments, the therapeutic agent is delivered transmucosally, sublingually, or transdermally by use of a bioadhesive film. In further embodiments, absorption occurs for not less than 12 hours, 8 hours, 6 hours, 4 hours or 2 hours. Alternatively, the bioadhesive film may be formulated as an "immediate release'" formulation. As used herein the phase "immediate release" means that at least 80% of the therapeutic agent is released in a period of 1 hour.

In one specific embodiment, the therapeutic agent is an agent for the treatment of attention deficit hyperactivity disorder (ADHD), the patient is in need of treatment for ADHD and the bioadhesive film is one that adheres to the buccal mucosa and results in absorption of the therapeutic agent over a period of not less than 8 hours. The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1 Table I

The mixture described in Table I was wet granulated using isopropyl alcohol. The blend was extruded into a film at process temperatures from 110-130 ⁰C. The resulting film was smooth and not tacky at room temperature, but was mucoadhesive when moistened and placed in contact with a mucosal surface.

Example 2: Table II

The mixture described in Table II was wet granulated using isopropyl alcohol. The resultant granules were dried and blended with the remaining ingredients. The blend was extruded into a film at process temperatures from 110 -140 ⁰C. The resulting film was smooth and not tacky at room temperature, but was mucoadhesive when moistened and placed in contact with a mucosal surface. Example 3:

Table III

The mixture described in Table HI was wet granulated using isopropyl alcohol. The resultant granules were dried and blended with the remaining ingredients. The blend was extruded into a film at process temperatures from 110 - 140 ⁰C. The resulting film was smooth and not tacky at room temperature, but was mucoadhesive when moistened and placed in contact with a mucosal surface.

All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are chemically or physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A bioadhesive film comprising: greater than about 40% by weight of polyethylene oxide polymers, wherein the polyethylene oxide polymers comprise at least 5% high molecular weight polyethylene oxide polymer having an average molecular weight in the range of about 1,000,000 to about 10,000,000 and at least 5% low molecular weight polyethylene oxide polymer having an average molecular weight of less than about 900,000, and a pharmaceutically effective amount of a therapeutic agent; wherein the bioadhesive film has a thickness of less than about 6 mm and has a contact surface area of at least about 0.2 cm²; wherein the bioadhesive film is smooth and substantially non-tacky at room temperature; wherein the bioadhesive film is mucoadhesive when moistened and placed in contact with a mucosal surface; and wherein the bioadhesive film is formed using a hot-melt extrusion process.

2. The bioadhesive film of claim 1, wherein the high molecular weight polyethylene oxide has an average molecular weight between about 3,000,000 and about 5,000,000.

3. The bioadhesive film of claim 1, further comprising a plasticizer.

4. The bioadhesive film of claim 1, wherein the bioadhesive film is substantially free of cross-linked acrylic acid-based polymers.

5. The bioadhesive film of claim 1, further comprising one or more pore formers.

6. The bioadhesive film of claim 1, further comprising one or more surfactants.

7. The bioadhesive film of claim 1, wherein the bioadhesive film further comprises one or more hydrophilic polymers.

8. The bioadhesive film of claim 1, wherein the bioadhesive film further comprises one or more hydrophobic polymers.

9. The bioadhesive film of claim 1, wherein the bioadhesive film is a single, substantially homogenous layer.

10. The bioadhesive film of claim 1, further comprising one or more excipients, wherein excipients comprise colorants, lubricants, thermal lubricants, antioxidants, buffering agents, disintegrants, binders, diluents, sweeteners, chelating agents, flavorants, surfactants, solubilizers, stabilizers, waxes, lipophilic materials, absorption enhancers, preservatives, absorbents, bioadhesive polymers, osmotic agents, and fragrance.

11. The bioadhesive film of claim 1 , wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 8 hours.

12. The bioadhesive film of claim 1, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 6 hours.

13. The bioadhesive film of claim 1, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 4 hours.

14. The bioadhesive film of claim 1, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 2 hours.

15. The bioadhesive film of claim 1, wherein the bioadhesive film delivers at least about 80% of the therapeutic agent over a period of 1 hour.

16. A method of making a bioadhesive film comprising: forming a mixture comprising greater than about 40% by weight of polyethylene oxide polymers, wherein the polyethylene oxide polymers comprise at least 5% high molecular weight polyethylene oxide polymer having an average molecular weight in the range of about 1,000,000 to about 10,000,000 and at least 5% low molecular weight polyethylene oxide polymer having an average molecular weight of less than about 900,000, and a pharmaceutically effective amount of a therapeutic agent; melting the mixture; and permitting the mixture to solidify as a bioadhesive film, wherein the bioadhesive film has a thickness of less than about 6 mm and has a contact surface area of at least about 0.2 cm²; wherein the bioadhesive film is smooth and substantially non-tacky at room temperature; and wherein the bioadhesive film is mucoadhesive when moistened and placed in contact with a mucosal surface.

17. The method of claim 16, wherein the mixture is melted in a hot melt extrusion apparatus.

18. The method of claim 16, wherein the mixture is hot-melt extruded, and wherein the bioadhesive film is co-extruded with a second layer.

19. The method of claim 16, further comprising shaping the bioadhesive film for use in the buccal, oral, rectal, vaginal, abdominal, cranial, ophthalmic or otic cavity.

20. The method of claim 16, wherein the high molecular weight polyethylene oxide has an average molecular weight between about 3,000,000 and about 5,000,000.

21. The method of claim 16, wherein the mixture further comprises a plasticizer.

22. The method of claim 16, wherein the mixture is substantially free of cross-linked acrylic acid-based polymers.

23. The method of claim 16, wherein the mixture further comprises one or more pore formers.

24. The method of claim 16, wherein the mixture further comprises one or more surfactants.

25. The method of claim 16, wherein the mixture further comprises one or more hydrophilic polymers.

26. The method of claim 16, wherein the mixture further comprises one or more hydrophobic polymers.

27. The method of claim 16, wherein the film is a single, substantially homogenous layer.

28. The method of claim 16, wherein the mixture further comprises one or more excipients, wherein excipients comprise colorants, lubricants, thermal lubricants, antioxidants, buffering agents, disintegrants, binders, diluents, sweeteners, chelating agents, flavorants, surfactants, solubilizers, stabilizers, waxes, lipophilic materials, absorption enhancers, preservatives, absorbents, bioadhesive polymers, osmotic agents, and fragrance.

29. The method of claim 16, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 8 hours.

30. The method of claim 16, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 6 hours.

31. The method of claim 16, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 4 hours.

32. The method of claim 16, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 2 hours.

33. The method of claim 16, wherein the bioadhesive film delivers at least about 80% of the therapeutic agent over a period of 1 hour.

34. A bioadhesive film made by the process comprising: forming a mixture comprising greater than about 40% by weight of polyethylene oxide polymers, wherein the polyethylene oxide polymers comprise at least 5% high molecular weight polyethylene oxide polymer having an average molecular weight in the range of about 1,000,000 to about 10,000,000 and at least 5% low molecular weight polyethylene oxide polymer having an average molecular weight of less than about 900,000, and a pharmaceutically effective amount of a therapeutic agent; melting the mixture; and permitting the mixture to solidify as a bioadhesive film, wherein the bioadhesive film has a thickness of less than about 6 mm and has a contact surface area of at least about 0.2 cm²; wherein the bioadhesive film is smooth and substantially non-tacky at room temperature; and wherein the bioadhesive film is mucoadhesive when moistened and placed in contact with a mucosal surface.

35. The method of claim 34, wherein the mixture is melted in a hot melt extrusion apparatus.

36. The method of claim 34, wherein the mixture is hot-melt extruded, and wherein the bioadhesive film is co-extruded with a second layer.

37. The method of claim 34, further comprising shaping the bioadhesive film for use in the buccal, oral, rectal, vaginal, abdominal, cranial, ophthalmic or otic cavity.

38. The method of claim 34, wherein the high molecular weight polyethylene oxide has an average molecular weight between about 3,000,000 and about 5,000,000.

39. The method of claim 34, wherein the mixture further comprises a plasticizer.

40. The method of claim 34, wherein the mixture is substantially free of cross-linked acrylic acid-based polymers.

41. The method of claim 34, wherein the mixture further comprises one or more pore formers.

42. The method of claim 34, wherein the mixture further comprises one or more surfactants.

43. The method of claim 34, wherein the mixture further comprises one or more hydrophilic polymers.

44. The method of claim 34, wherein the mixture further comprises one or more hydrophobic polymers.

45. The method of claim 34, wherein the film is a single, substantially homogenous layer.

46. The method of claim 34, wherein the mixture further comprises one or more excipients, wherein excipients comprise colorants, lubricants, thermal lubricants, antioxidants, buffering agents, disintegrants, binders, diluents, sweeteners, chelating agents, flavorants, surfactants, solubilizers, stabilizers, waxes, lipophilic materials, absorption enhancers, preservatives, absorbents, bioadhesive polymers, osmotic agents, and fragrance.

47. The method of claim 34, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 8 hours.

48. The method of claim 34, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 6 hours.

49. The method of claim 34, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 4 hours.

50. The method of claim 34, wherein the bioadhesive film delivers the therapeutic agent over a period of not less than 2 hours.

51. The method of claim 34, wherein the bioadhesive film delivers at least about 80% of the therapeutic agent over a period of 1 hour.

52. A bioadhesive film comprising a high molecular weight polyethylene oxide and a low molecular weight polyethylene oxide polymer, and a pharmaceutically effective amount of a therapeutic agent; wherein the bioadhesive film has a thickness of less than about 6 mm.

53. A method of making a bioadhesive film comprising forming a mixture comprising greater a high molecular weight polyethylene oxide polymer and a low molecular weight polyethylene oxide polymer; melting the mixture; and permitting the mixture to solidify as a bioadhesive film.

54. A bioadhesive film made by the process of claim 53.