BIOADHESIVE COMPOSITION AND PATCH

Abstract: A bioadhesive composition that adheres suitably to a mucosal surface and is capable of delivering drugs in sustained fashion, and a patch comprising the bioadhesive composition. Methods of using and processes for preparing the bioadhesive composition are also described.

Description: BIOADHESIVE COMPOSITION AND PATCH BACKGROUND OF THE INVENTION Field of the Invention This invention relates to mucosal adhesives. In another aspect this invention relates to compositions that adhere to oral mucosa. In yet another aspect this invention relates to methods of transmucosal drug 10 delivery. Description of the Related Art Buccal tablets and like devices are known and disclosed for example in U.S. Pat. Nos. 4,740,365 and , c 4,764,378. These devices adhere to mucosal surfaces and dissolve or otherwise disintegrate over time, thus delivering drug into the mouth of the patient in a sustained fashion. It is also known that delivery of drugs across the oral mucosa avoids hepatic first-pass 2 Q inactivation, inactivation by gastro-intestinal fluids, and other modes of inactivation characteristic of oral drug ingestion. Sustained release adhesive bandages, patches, and the like that contain drugs and adhere to mucosal surfaces are known to the art. Polyacrylic acids 25 and polyisobutylenes have been disclosed as components of such adhesives. For example, U.S. Pat. No. 3,339,546 (Chen) discloses a bandage that is said to adhere to moist surfaces of the oral cavity and comprises a medicament and a hydrocolloid incorporated in a natural or synthetic 3 Q gum-like substance. Carboxypoly ethylene (i.e., polyacrylic acid) is among the hydrocolloids disclosed, and polyisobutylene is among the gum-like substances disclosed. U.S. Pat. No. 4,615,6? " (Robinson) discloses a 35 composition including a bioadhesive and a treating agent. The bioadhesive is a water-swellable but water insoluble, fibrous, crosεlinked, carboxy-functional polymer containing (a) a plurality of repeating units of which at least about 80% contain at least 1 carboxy functionality, and (b) about 0.05 to about 1.5% of a cross-linking agent substantially free from polyalkenyl polyether. The _ specifically excluded type of crosslinker is said to be the type used in CARBOPOL™934 resin (commercially available from B. F. Goodrich, Specialty Chemicals and Polymers Division, Cleveland, OH). CARBOPOL™934 resin is psaid to be water soluble and therefore undesirable as a . 0 bioadhesive in the Robinson composition. U.S. Pat. No. 4,253,460 (Chen et al. ) discloses an adhesive composition consisting of a mixture of a hydrocolloid gum, a pressure sensitive adhesive, and a cohesive strengthening agent. The pressure sensitive .- adhesive component can be a mixture of three to five parts of a polyisobutylene with a viscosity average molecular weight of about 36,000 to about 53,000 and one part of an elastomer such as a polyisobutylene with a viscosity average molecular weight of about 1,150,000 to about 20 1,600,000. U.S. Pat. No. 4,740,365 (Yukimatsu et al. ) discloses a sustained-release preparation comprising an active ingredient and a mixture of two polymer components, the first of which comprises one or more polymers selected from polyacrylic acid and a pharmaceutically acceptable salt thereof, and the second being selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, alginic acid, and a pharmaceutically acceptable salt of alginic acid. CARBOPOL™ resins are , n among the polymers said to be suitable members of the first-mentioned class of polymers. U.S. Pat. No. 4,772,470 (Inoue, et al.) discloses an oral bandage comprising a mixture of a polyacrylic acid and a vinyl acetate polymer in a , c compatible state. This bandage is said to exhibit strong adhesion of long duration when applied to oral mucosa or teeth. SUMMARY OF THE INVENTION This invention provides a bioadhesive composition that comprises: 1) a particulate polymeric resin with an average particle size of less than or equal to about 100 μm and comprising at least about 55% by weight of carboxylic acid moieties based on the total weight of the polymeric resin; 10 2) from about 20 parts to about 250 parts by weight of a hydrophobic elastomeric component, based on 100 parts by weight of the resin; and 3) an amount of a drug effective to provide a desired therapeutic result, ,c wherein the resin and the drug are dispersed substantially throughout the elastomeric component, and which composition contains less than about 10% water by weight based on the weight of the polymeric resin, exhibits substantially no instantaneous adhesion to dry skin, and 2 Q adheres to a mucosal surface. A bioadhesive composition of this invention exhibits good adherence to human oral mucosa. In particular embodiments, this invention provides a bioadhesive composition as described above that exhibits a 25 duration of adhesion to human oral mucosa of at least about 6 hours when tested according to the Test Method described in detail below. Also, the drug is released in sustained fashion over a prolonged period to a mucosal surface for, for example, local or systemic treatment. 20 In a preferred embodiment when systemic treatment is desired, the bioadhesive composition has a backing such as a flexible film applied to it. Further, in yet another preferred embodiment the resin is covalently crosslinked wit ' h about 0.75% to about 3 2% by weight, based on the total weight of the resin, of a polyalkenyl polyether. The preferred resin can also be partially neutralized (e.g., up to about 30%) with a base of mono, di- or trivalent metal, or with a polyamine. This invention also provides therapeutic methods. One such method is a method of achieving and/or _ maintaining a therapeutically effective blood level of a drug in a mammal, comprising the steps of: a) adhering a composition of the invention to a mucosal surface of a mammal; and b) allowing the composition to remain adhered -. - for a time sufficient to release the drug such that a therapeutically effective blood level of drug is achieved and/or maintained. Another such method is a method of delivering a drug to a mucosal surface of a mammal or to the vicinity -. j . of a mucosal surface of a mammal to provide a therapeutic effect on or in the vicinity of the mucosal surface, which method comprises the steps of: a) adhering a composition of the invention to the mucosal surface; 20 b) allowing the composition to remain adhered for a time sufficient to release the drug to the mucosal surface or to the vicinity of the mucosal surface to provide the desired therapeutic effect. A composition of the invention can be used to 25 administer drugs εystemically (e.g., across the oral or vaginal mucosa or other mucosal surfaces) or locally (e.g., to the oral or vaginal cavity). A composition of the invention exhibits sustained delivery of basic, acidic, and neutral drugs, and salts thereof and allows 30 the delivery rate to be tailored as desired. In the case of delivery of a drug across the oral mucosa, a composition of the invention can also minimize the loss of a drug to the gastro-intestinal tract. A composition of the invention is also soft and conformable such that it » ς can be worn comfortably by the user. Detailed Description of the Invention The polymeric resin component of a composition of the invention comprises at least about 55% by weight of carboxylic acid moieties based on the total weight of the ,- resin. Suitable carboxylic acid-containing monomers include acrylic acid, maleic acid, itaconic acid, citraconic acid, methacrylic acid, and the like, and combinations thereof. Acrylic acid is preferred. The polymeric resin can also comprise minor amounts (e.g., 10 less than about 20 percent by weight based on the total weight of all monomers in the polymer) of comonomers that are polymerizable with the carboxylic acid-containing monomer, such as methyl vinyl ether, lower alkyl (meth) acrylates, and the like. , Linear polyacrylic acid resins with a molecular weight between about 400,000 and about 5,000,000 have been found to be suitable for use in a composition of the invention. More preferred, however, are crosslinked resins. Most preferred resins include those comprising 2 Q polyacrylic acid with a molecular weight between about 750,000 and about 4,000,000, preferably about 2,000,000 to about 4,000,000, and more preferably about 3,000,000, crosslinked with about 0.75% to about 2% by weight, based on the total weight of the resin, of a polyalkenyl 5 polyether such as an allyl ether of sucrose or an allyl ether of pentaerythritol. Particularly preferred resins of this type include the resins available under the trade designation CARBOPOL™ resin (e.g., CARBOPOL™ resins 910, 934, 934P, 941, 951, and 1342 from B.F. Goodrich Co., Specialty Polymers and Chemical Division, Cleveland, OH). CARBOPOL™ 934P resin is most preferred, as it is generally recognized as acceptable for pharmaceutical applications. Another suitable resin is "polycarbophil" , a material commercially available from A. H. Robins Co., Richmond, Virginia, and described in USP XX as a polyacrylic acid crosslinked with divinylglycol . A polyacrylic acid resin or a crosslinked resin such as those enumerated above can be partially neutralized by a base of an alkali metal, or by a base of a divalent or trivalent metal (e.g., 2n + 2 , Ca + 2 , Mg + 2 , or Al +3 ). Basic polyamines such as Eudragit™E (a copolymer of dimethylaminoethyl methacrylate and neutral methacrylates, available from Rohm Pharma, eiterstadt, Germany) are also suitable for use in neutralizing a resin. In such a resin, up to about 30% of the carboxylic acid moieties in the resin can be neutralized by a base. Preferred bases include Al(OH) 3 and Ca(OH) 2 . The particle size of the resin affects the adhesion of a composition of the invention to mucosal surfaces, the rate of disintegration, and the rate at which a composition releases drug. Proper particle size affords a composition with sufficient surface area of the resin available to provide good adhesion, but not so much that the composition rapidly disintegrates when placed on a mucosal surface, e.g., in the oral cavity. Average particle size can be up to about 100 μm . It is preferred that the resin have an average particle size of between about 1 μm. and about 80 μm, more preferably between about 1 μm and about 30 μ , and most preferably between about 2 μm and about 10 μ . It is desirable to keep the level of moisture low in a bioadhesive composition of the invention. A bioadhesive composition has a water content of less than about 10% by weight, preferably less than about 6%, more preferably less than about 4% by weight, and most preferably less than about 2% by weight based on the total weight of the resin. In order for the composition to have the requisite low water content the resin, prior to incorporation in the composition, is preferably dried to the desired level and protected from ambient moisture. Once the resin is incorporated in a composition of the invention, ambient moisture is no longer generally of concern, as the resin, which is generally hygroscopic, is protected from ambient moisture by the hydrophobic elastomeric component. A composition can be stored for at least several months at ambient humidity without adversely affecting its adhesive properties. By itself, a polymeric resin as described above generally possesses insufficient structural integrity. Such acidic resins can also be irritating to mucosal tissue. Further, a resin alone provides no means of controlled hydration and sustained release of drug. To remedy these deficiencies, the resin is substantially dispersed throughout a hydrophobic elastomeric component. The relative amounts of the polymeric resin and the hydrophobic elastomeric component can affect both the duration of adhesion and the drug release properties of a -_ composition of the invention. Generally a composition of the invention comprises about 20 parts to about 250 parts, preferably about 20 parts to about 150 parts, and most preferably 25 to about 75 parts by weight of a hydrophobic elastomeric component, based on 100 parts by weight of the resin. 20 Suitable elastomeric components preferably are soft such that the ultimate composition can be worn without significant discomfort to the user. Further, they are such that a composition of the invention does not 25 exhibit excessive cold-flow when stored at room temperature. The hydrophobic elastomeric component preferably has a surface energy of less than about 40 dyne/cm and more preferably has a surface energy of less than about 30 dyne/cm. Examples of materials suitable for use in an 30 elastomeric component include: hydrocarbons such as block styrene-butadiene-styrene copolymerε and block styrene-iεoprene-εtyrene copolymers, such as those available from Shell Chemical Co . as Kraton™ rubbers, ,,. polyolefins such as polyisobutylenes , polybutadienes, butyl rubber (a copolymer of isobutylene and isoprene), and isoprene rubbers, e.g., polyisoprene (such as that available as LIR-50 polyisoprene from Arakawa Chemical Co., Chicago, IL and NATSYN™ polyisoprene from Goodyear, Akron, OH); functionalized polyolefins such as functional polyisoprenes, e.g., carboxy-functional polyiεopreneε (such as that available as LIR-410 polyisoprene, also from Arakawa) and hydroxy-functional polyiso-prenes (such as that available aε LIR-506 polyisoprene, Arakawa); and mixtures and blends of two or more of the foregoing. Another claεε of material suitable for use in an elaεtomeric component includeε acrylate elaεtomerε. 10 Suitable acrylate elaεtomerε include polymerε and copolymers comprising at least about 60 percent by weight based on the total weight of all monomers in the polymer of a hydrophobic monomeric acrylic or methacrylic acid _. ς eεter of an alkyl alcohol, the alkyl alcohol containing 4 to 10 carbon atomε. Some εuch elastomers are discloεed in U.S. Pat. No. 4,751,087 (Wick) the disclosure of which is incorporated herein by reference. Particularly suitable are those acrylate copolymers containing A and B Monomers 5n as follows: Monomer A iε a hydrophobic monomeric acrylic or methacrylic acid ester of an alkyl alcohol, the alkyl alcohol containing 4 to 10 carbon atoms, preferably 8 carbon atoms. Exampleε of suitable A Monomers are n-butyl, n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, 2c iεohexyl, iεooctyl, 2-ethyloctyl, and 2-ethylhexyl acrylateε. The moεt preferred A Monomer iε iεooctyl acrylate. Monomer B iε a reinforcing monomer εelected from the group conεiεting of acrylic acid; methacrylic acid; alkyl acrylateε and methacrylateε containing 1 to 3 - n carbon atomε in the alkyl group; acrylamide; methacrylamide; and lower alkyl-substituted acrylamideε (i.e., the alkyl group containing 1 to 4 carbon atomε) εuch aε tertiary-butyl acrylamide. The moεt preferred B Monomer is acrylamide. In such an elastomer, the A , ( . Monomer is preferably present in an amount by weight of about 80 percent to about 98 percent, and the B Monomer is preferably preεent in an amount by weight of about 2 to about 20 percent of the total weight of the monomers in the copolymer. While such acrylate copolymerε per εe are preεsure-εenεitive adheεiveε, when they are incorporated into a compoεition of the invention, the composition exhibits subεtantially no instantaneous adhesion to dry skin. Hydrocarbons are the most preferred materials for use in an elaεtomeric component. Preferred hydrocarbon elastomeric componentε, particularly when the composition is prepared by the solvent casting method set 10 forth in detail below, include polyiεobutylene mixtureε compriεing, baεed on the total weight of the polyisobutylene mixture, from about 5% to about 50% preferably abut 15% to about 25%, and moεt preferably lς about 20% weight of a polyisobutylene with a viscosity average molecular weight between about 500,000 and about 2,500,000, preferably about 1,250,000, and from about 50% to about 95%, preferably about 75% to about 85%, and most preferably about 80%, by weight of a polyisobutylene with _ a viscoεity average molecular weight between about 40,000 and about 100,000, preferably about 53,000. Particularly preferred iε an elaεtomeric component made by the solvent- casting method and consisting of about 80% by weight of VISTANEX™ LM-MH polyisobutylene and about 20% by weight 25 of VISTANEX™ L-100 polyisobutylene. In contrast to solvent-casting processes, the milling procesε (set forth in detail below) can reduce substantially the average molecular weight of the polymers that are used in the procesε. For example, εome preferred 30 polyisobutylene elastomers in embodiments made by the milling proceεε are made from the preferred polymers enumerated above but they have molecular weights somewhat lower than the molecular weight ranges set forth above. Another preferred elastomeric component when the composition is prepared by the milling method is a 35 polyisobutylene mixture made from about 60 to about 100% by weight a polyisobutylene with a viscosity average molecular weight of about 750,000 to about 1,500,000 most preferably about 900,000, and 0% to about 40% of a polyisobutylene with a viscosity average molecular weight of about 40,000 to about 100,000, moεt preferably about 53,000. Further preferred elaεtomeric componentε, particulary for uεe when the milling method is employed, comprise polyisoprene, polybutadiene, or a mixture thereof. Polyisopreneε having molecular weightε of about 500,000 to about 1,200,000, and ixtureε thereof, are suitable. Polybutadieneε having a molecular weight of about 100,000 to about 500,000, and mixtures thereof, are suitable. Mixtures of εuch polyisopreneε and polybuta¬ dieneε are alεo εuitable. A particularly preferred -. _ elaεtomeric component when the compoεition iε prepared by the milling method is made from a mixture of about 20 to about 80 percent by weight, preferably about 50 percent by weight, of a polybutadiene having a molecular weight of about 375,000 and about 20 to about 80 percent by weight, « 0 preferably about 50 percent by weight, of a polyisoprene having a molecular weight of about 760,000. Exemplary εpecific polyiεobutyleneε suitable for use in the above-described elaεtomeric componentε include those commercially available from Exxon Chemical Co., ? - Houston TX, under the trade designation VISTANEX™ polyisobutylene and those commercially available from BASF under the trade designation OPPANOL™ polyisobutylene. Preferred polyisobutyleneε include VISTANEX™ LM-MH polyiεobutylene (viεcoεity average molecular weight about 30 53,000), VISTANEX™ L-80 polyiεobutylene (viεcoεity average molecular weight about 900,000), and VISTANEX™ L-100 polyiεobutylene (viεcoεity average molecular weight about 1,250,000). Exemplary εpecific polyiεoprenes εuitable for uεe include those commercially available from ,- Goodyear, Akron, OH, under the trade deεignation NATSYN T 1 TM polyiεoprene. Preferred polyisoprenes include NATSYN -. T TM 2210 polyisoprene (weight average molecular weight about 760,000) and NATSYN™ 2205 polyisoprene (weight average molecular weight about 955,000). Exemplary specific polybutadienes suitable for use include those commercially available from Polysar, Akron, OH under the trade deεignation TAKTENE™ polybutadiene. Preferred polybutadieneε include TAKTENE™ 1202 polybutadiene (weight average molecular weight about 375,000). For purpoεes of the instant specification and claims, the term viscosity average molecular weight means Flory molecular weight as determined by the method set forth in "Food Chemicals Codex", 3rd Ed. page 469, 1981. National Academy Press, incorporated herein by references. An elastomeric component can also comprise a plasticizer such as mineral oil, silicone oil, corn oil, and the like. A particularly preferred elastomeric component of this type is a mixture comprising mineral oil and linear styrene-isoprene-styrene block copolymer such as that commercially available from Shell Chemical, Houston, TX, under the trade designation KRATON™D 1107 rubber. It is preferred * that an elastomeric component of this type comprise from about 20 percent to about 40 percent, more preferably about 33 percent, by weight of mineral oil and correspondingly from about 60 percent to about 80 percent, more preferably about 67 percent, by weight of the block copolymer. The resin can be substantially uniformly dispersed throughout the elaεtomeric component, or it can be preεent in any εuitable gradient, e.g., a gradient wherein there iε a εubstantially higher concentration of the resin nearer the surface that iε intended to be adhered to a mucosal surface. The term "gradient" aε used herein repreεentε a continuouε or discontinuous variation in concentration acroεε the croεs-sectional thickness of a composition. A bioadhesive composition of the invention also comprises a drug. Drugs that can be delivered include those uεeful for the local treatment of the mouth or throat, or the vaginal cavity, in addition to thoεe useful for systemic treatment via delivery through mucosal tiεεue. They include antiinflammatory drugε, both εteroidal (e.g., hydrocortiεone, predniεolone, triamcinolone) and nonsteroidal (e.g., naproxen, piroxicam); bacterioεtatic agentε (e.g., chlorhexidine, hexylresorcinol) ; antibacterialε (e.g., penicillins εuch as penicillin V, cephalosporins εuch aε cephalexin, erythromycin, tetracycline, gentamycin, εulfathiazole, nitrofurantoin, and quinoloneε εuch aε norfloxacin, 10 flumequine, and ibafloxacin) ; antiprotazoals (e.g., metronidazole) ; antifungals (e.g., nyεtatin); coronary vasodilatorε (e.g., nitroglycerin) ; calcium channel blockerε (e.g., nifedipine, diltiazem) ; bronchodilatorε (e.g., theophylline, pirbuterol, εalmeterol, 15 iεoproterenol) ; enzyme inhibitorε εuch aε collagenaεe inhibitorε, proteaεe inhibitorε, elaεtaεe inhibitorε, lipoxygenaεe inhibitorε (e.g., A64077), and angiotenεin converting enzyme inhibitorε (e.g., captopril, 20 liεinopril); other antihypertenεiveε (e.g., propranolol) ; leukotriene antagoniεtε (e.g., ICI204,219); anti-ulcerativeε εuch aε H2 antagonists; steroidal hormoneε (e.g., progeεterone, testosterone, estradiol); antiviralε and/or immunomodulatorε (e.g., 1-iεobutyl-lH- 2 imidazo[4,5-c]quinolin-4-amine, 1-(2-hydroxy-2-methylpropyl)-lH-imidazo[4,5-c]quinoline- 4-amine, and other compounds disclosed in U.S. Pat. No. 4,689,338, incorporated herein by reference, acyclovir); local anestheticε (e.g., benzocaine, propofol); ^ n cardiotonicε (e.g., digitaliε, digoxin); antituεεiveε (e.g., codeine, dextro ethorphan) ; antihiεtamineε (e.g., diphenhydramine, chlorpheniramine, terfenadine) ; narcotic analgeεicε (e.g., morphine, fentanyl) ; peptide hormoneε (e.g., human or animal growth hormones, LHRH); , c cardioactive productε such as atriopeptides; proteinaceous products (e.g., insulin); enzymes (e.g., anti-plaque enzymes, lyεozyme, dextranase); antinauseants (e.g., εcopolomine) ; anticonvulεants (e.g., carbamazine) ; immunosuppressives (e.g., cyclosporine) ; psychotherapeutics (e.g., diazepam) ; εedativeε (e.g., phenobarbital) ; anticoagulantε (e.g., heparin); analgeεicε (e.g., acetaminophen); antimigraine agentε (e.g., ergota ine, elatonin, su atripan); antiarrhyth ic agentε (e.g., flecainide); antiemetics (e.g., metaclopromide, ondansetron) ; anticancer agents (e.g., methotrexate); neurologic agents such as anxiolytic drugs; hemostaticε; anti-obeεity agents; and the like, as well as pharmaceutically acceptable salts and esters thereof. Preferred drugs include digoxin, heparin, hydromorphone, morphine, melatonin, buprenorphine, and pharmaceutically acceptable salts thereof. A drug is preferably incorporated neat into a composition of the invention. The drug iε preferably preεent in an effective amount, which will depend upon the particular drug used, the intended therapy, and the desired duration of use of a particular individual application of the compoεition containing the drug. Practical limitations on the amount of drug incorporated in a composition are that amount above which the composition begins to lose adhesion to a mucosal surface, and that amount below which a therapeutically effective blood level of drug cannot be achieved and/or maintained. Generally, the preferred range is from about 0.1% to about 25% by weight based on the total weight of the bioadhesive compoεition. Preferably, the drug will be capable of releaεe from the compoεition in a εuεtained faεhion over a prolonged period (i.e., at least about 6 hours and preferably at least about 12 hours). The drug is generally dispersed throughout the elastomeric component. The drug can be substantially uniformly diεperεed, or it can be distributed in any εuitable gradient, e.g., a gradient wherein drug concentration iε greater nearer the surface that is intended to be adhered to a mucosal surface, or a gradient wherein drug concentration is lower nearer the surface that iε intended to be adhered to a mucoεal εurface, in order to achieve the deεired blood-level profile. A compoεition can contain other ingredientε, for example excipientε εuch aε flavorings or flavor-masking agents, dyes, penetration enhancerε, water-εoluble or water-εwellable fibrouε reinforcerε, and the like under circumεtances and in amounts easily determined by those skilled in the art. Penetration enhancers have particular utility when used with drugs such as peptideε and proteinε. Suitable penetration enhancers include anionic surfactants (e.g., εodium lauryl εulfate); cationic surfactantε (e.g., cetylpyridinium chloride); nonionic surfactants (e.g., polysorbate 80, polyoxeyethylene 9-lauryl ether, glyceryl monolaurate) ; lipidε (e.g., oleic acid); bile εaltε (e.g., εodium glycocholate, εodium taurocholate) ; and related compoundε (e.g., εodium tauro-24,25-dihydrofuεidate) . Like the drug diεcuεsed above, such ingredientε can be diεpersed subεtantially uniformly in the compoεition or diεperεed in any suitable gradient therein. A resin useful in a compoεition of this invention can be prepared uεing conventional procedureε and conventional laboratory equipment. For example, εuch resinε can be prepared from acrylic acid and the appropriate croεεlinkerε by methodε well known to those skilled in the art, and disclosed for example in U.S. Pat. No. 2,798,053 (Brown). A commercially available polyacrylic acid resin or a commercially available particulate resin such as the CARBOPOL™ reεinε diεcuεεed above can be used aε received if it is available in an appropriate particle size and with a suitably low water content. Conventional drying methods, preferably using temperatures lesε than about 95°C, and more preferably leεε than about 50°C, can be uεed to dry a reεin to the deεired degree, e.g., leεε than about 2% water content. Further, if it iε deεired to increase or decrease the particle size, a resin can be wet-granulated by first wetting and εtirring with a polar εolvent (e.g., iεopropyl alcohol), drying to the deεired degree (e.g., in a tray oven), and then milling to a powder of the deεired size. Particle size can also be adjusted by other conventional techniques, with the caveat that subεtantial degradation of the resin is to be avoided. To prepare a neutralized resin as discuεεed above, a particulate polyacrylic acid reεin or a particulate covalently croεεlinked reεin can be suεpended by vigorouεly stirring in a water-soluble solvent (e.g., ethanol, isopropyl alcohol, or methanol). To thiε εuεpenεion, an aqueouε εolution containing the polyamine or the deεired base of a metal can be added. Upon vigorous agitation (e.g., shaking overnight in a conventional laboratory shaker) a homogeneous mixture containing the neutralized resin obtains. Drying this mixture, for example by spray drying, affords a free-flowing powder. With high concentrations of base, a spray drying process can become more time consuming than desired, in which case a wet-granulation procesε might be preferred. In such a proceεε, the polyacrylic acid reεin and the baεe can first be mixed as solids, then moistened with a polar solvent (e.g., isopropyl alcohol) and stirred. Under such conditions, it is possible that significant neutralization does not occur. However, when the resulting resin is incorporated into a composition of the invention as described below, and the composition is placed on a moist surface εuch aε a mucoεal εurface, it iε possible that further neutralization occurs in situ. For the purposeε of the inεtant εpecification and claims, a material so made is termed a neutralized resin prior to presumed further in situ neutralization. In any case, the resulting mixture can then be dried to the deεired degree and milled using conventional apparatus to form a powder of the desired particle size. A suitable resin can then be formulated into a composition of the invention by a solvent-casting method that involves dispersing the resin, e.g., with stirring, in a solution of an elastomeric component in a volatile organic εolvent, εuch aε hexane or toluene, to form a reεin/elaεtomeric component/εolvent mixture. A drug and any excipient or other ingredient can be incorporated by firεt adding it and then the reεin, or vice-verεa, to a solution of the elaεtomeric component in a volatile organic solvent. Alternatively, a drug and any excipient or other ingredient can be incorporated by first adεorbing it on the reεin or on an inert εupport εuch aε εilica, abεorbing it into the reεin, or ionically binding it to the reεin. The compoεition can then be made into a sheet. This can be done by coating (e.g., using a knife coater) a εuitable release liner with a uniform thicknesε of a reεin/elaεtomeric component/solvent mixture containing the drug and any excipient or other ingredient and allowing the solvent to be removed without subεtantial foaming or bubbling caused by solvent release, e.g., by evaporation in air or by drying methods well known to thoεe skilled in the art. As an alternative that avoids the use of added solventε, the componentε of a composition can be milled together neat using mill such as a conventional rubber mill (e.g., a two-roll mill). If the elastomeric component compriseε more than one ingredient, theεe ingredientε can be milled together firεt to form a εubεtantially homogeneouε elaεtomeric component. The polymeric reεin and the drug and any excipient or other ingredientε can then be milled with the εubεtantially homogeneouε elaεtomeric component in order to form a εubstantially homogeneous composition of the invention. In εome caεeε it iε neceεεary to heat or cool the rollε in order to aεεure good mixing and in order to facilitate removal of the compoεition from the rollε. The drug and any excipient or other ingredients can be added neat to the polymeric resin prior to milling. Alternatively, they can be adsorbed on the reεin, adεorbed on an inert εupport such as εilica, abεorbed into the reεin, or ionically bound to the reεin by conventional methodε prior to milling. The compoεition can then be made into a εheet by, for example, pressing between two sheets of release liner in a heated platen presε at a pressure of about 35,000 to about 175,000 KPa and at a temperature of about 50°C. The milling method is particularly amenable to the preparation of compositions wherein the resin and/or the drug is distributed throughout the compoεition in a suitable gradient aε deεcribed above. The preferred thickness of the final dry sheet of composition (irrespective of the method of preparation) is from about 0.5 mm to about 5 mm, more preferably from about 1 mm to about 3 mm. Gradient distribution can be carried out by preparing two or more sheetε of differing composition and optionally differing thickness (e.g., in the range from .about 0.20mm to about 1mm) and laminating them together, e.g., between two sheetε of releaεe liner in a heated platen preεε to produce a compoεition with the deεired gradient. Shimε can be uεed to control the final thickness. If deεired, additional polymeric reεin can be spread substantially uniformly on one surface of a sheet of a compoεition. The compoεition can then be preεεed between two εheetε of release liner in order to embed the additional polymeric resin into the composition. Suitable release liners for uεe in the above-deεcribed methodε of preparation include conventional releaεe liners comprising a known sheet material, such as a polyester web, a polyethylene web, or a polyεtyrene web, or polyethylene-coated paper, coated with a εuitable εilicone-type coating such aε Daubert 164-Z (commercially available from Daubert Co., Elmhurst, IL) . If desired, a backing material can then be applied to the compoεition uεing methodε well known to thoεe skilled in the art. The backing material is preferably a flexible film that prevents bulk fluid flow and is inert to the ingredients of the compoεition. In the caεe of a compoεition that containε a drug intended to be delivered acroεs a membrane such aε a mucoεal εurface and intended to have εyεtemic action, the backing iε preferably substantially resistant to the migration of the drug therethrough. In the case of a composition that containε a drug intended to be delivered, e.g., to the oral cavity or the vaginal cavity and/or intended to have local action, the backing can be permeable to the agent to be delivered and can be permeable to εaliva aε well. The backing material can be any of the conventional materialε uεed aε backing for tapes or dressings, such aε polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene propylene diene copolymer, polyurethane, rayon, and the like. Non-woven materialε such aε polyesters, polyolefins, and polyamides can alεo be used. Alεo, a layer of a hydrophobic elaεtomer εuch aε polyiεobutylene can function aε a backing. Preferred backing materialε include an acrylate preεεure-εenεitive adheεive coated polyurethane film εuch aε TEGADERM™ brand εurgical dreεεing (commercially available from the 3M Company, St. Paul, MN). A compoεition with a backing applied thereto can be made into a patch with a backing by die-cutting individual patcheε from the εheet. Alternatively, a patch with no backing can be prepared by die-cutting individual patcheε from a coated releaεe liner prepared by the εolvent method εet forth above or by die-cutting from a sheet of bioadheεive compoεition prepared by preεεing between two εheetε of release liner. A patch can be of any εuitable εize and εhape, e.g., a 1 cm circular diεk. Particular embodimentε of the invention use no backing or a backing that iε substantially permeable to the bodily fluid with which the composition iε in contact (e.g., εaliva). In εuch embodimentε, it iε preferred that the compoεition exhibit εubεtantially no diεintegration over the time period during which the compoεition iε intended to remain adhered to the mucosal surface. This provideε for εuεtained release of the drug over a prolonged period of time. Other particular embodiments of the invention use a backing that is subεtantially impermeable to the bodily fluid with which the composition is in contact. In such embodiments, the backing further protects the composition from subεtantial diεintegration over the time period during which the composition is intended to remain adhered to the mucosal surface. However, even in such embodiments a lack of subεtantial diεintegration of the bioadhesive composition itself can εerve to optimize the delivery of a drug to the mucoεal surface (as opposed to delivery of the drug to the vicinity of the mucoεal εurface, e.g., to the oral cavity). "Substantially no disintegration" as used herein means that a bioadhesive compoεition iε reεiεtant to disintegration εuch that, when the composition having no backing attached thereto is adhered in the oral cavity and tested as set forth in the Test Method below, the composition covers at least about 50% of the area after it is adhered for a designated period of time as is covered by the composition initially. While compoεitionε of the invention adhere to mucoεal surfaces, they exhibit substantially no instantaneouε adheεion to dry εkin. A compoεition or a patch of the invention can therefore be handled by a patient without undue concern that the composition or patch will have itε mucosal adhesive properties compromised by adhering to the εkin or to another dry εurface prior to placement on the mucosa. A compoεition of the invention or a patch made from a composition of the invention can be applied to a mucosal surface, such as the oral mucosa, e.g., the buccal mucosa or gingival mucosa, of a mammal and replaced as _ desired (e.g., aε is necesεary or aε is convenient to the user) with a fresh patch, e.g., to maintain a therapeutically effective blood level of a drug. The opposing surfaces of a composition or a patch with no backing can be adhered to opposing mucoεal εurfaceε, e.g., ln the gum and the cheek or lip, thereby providing added adheεion and a meanε of εimultaneouε drug delivery to two mucosal surfaceε from the εame patch. A compoεition or a patch of the invention exhibits suεtained releaεe of a drug εuch that a therapeutically effective blood level of 15 the drug can be achieved and/or maintained in a mammal for an extended period of time. Alεo, a therapeutic level of drug can be maintained in the vicinity of the mucoεal εurface (e.g., in the oral cavity or the vaginal cavity) if the treatment being effected iε local rather than 2 Q εyεtemic. In particular embodimentε of the invention, a bioadheεive compoεition or a patch will adhere to human oral mucoεa for at leaεt 6 hourε, more preferably for at leaεt 8 hourε, and moεt preferably at leaεt 12 hourε when 25 tested as described below. Test Method For purposes of determining the duration of adhesion of a bioadhesive composition of the invention to , n human oral mucosa, the following method (hereinafter referred to aε the "Teεt Method") is employed aε follows. Step 1. A bioadhesive compoεition iε made into individual patcheε aε followε: An appropriate amount of a εubεtantially εolvent-free sample of the bioadhesive ,*- composition is placed in a two-roll mill and milled at room temperature until a εubεtantially uniform compoεition obtainε. The compoεition iε then preεεed between 2 εheetε of silicone-coated release liner in a double heated platen press at a pressure of 70,000 KPa and a temperature of 50°C to afford the composition in the form of a 1 mm thick εheet. One εheet of the releaεe liner iε removed, and the _ expoεed bioadheεive εurface iε contacted with the adheεive surface of a 20 μm thick polyurethane backing material that has an acrylate presεure-εenεitive adheεive coated thereon, to provide a bioadheεive-coated εheet material. Individual patches are then die cut using a 1 cm 2 circular die. 0 Step 2. A total of εix healthy εubjectε (3 male, 3 female) between the ageε of 25 and 55 yearε who have been otherwise selected randomly are studied. The subjectε faεt for at leaεt 1 h prior to the placement of the patch. c The release liner (if any) of a patch iε removed and the patch iε preεsed into place with a minimal force (i.e., a force sufficient to allow the patch to adhere but not so great as to cause diεcomfort) on the oral mucoεa of a subject [i.e., at the location preεcribed by the 0 inεtructionε (e.g., a package inεert) accompanying the particular patch being tested, or absent such instructions, on the upper gingival mucosa above a canine tooth] and held there for several secondε, care being taken to assure that the expoεed bioadheεive εurface of 5 the patch iε not contacted with moiεt εkin, water, mucouε, or a mucosal surface prior to placement. The data in the exampleε below involve placement on the upper gingival mucosa above a canine tooth. If the patch doeε not adhere to a particular εubject, an attempt is made to adhere a second patch. If the second patch doeε not adhere, that εubject iε diεmiεεed from the εtudy and replaced with another subject selected as set forth above. Once the patch is in place, the subjects engage in the normal activities of daily living, taking care to not forcibly dislodge the patch, e.g., with their tongue, a toothbrush, or while chewing food. If the patch iε forcibly dislodged during the study, a new patch iε placed as described above and the εtudy with reεpect to that εubject iε begun anew. The elapsed time in hours before the patch loεes adhesion as noted by the subject is measured and recorded. The average elapεed time in hourε obεerved for the εix subjects is then determined. Should it be deεired to meaεure diεintegration over a designated period of time by the Test Method, the backing (if any) of the patch iε removed prior to placement of the patch, the area covered by the patch after adheεion for the deεignated period iε noted, and the average area that remainε covered in the six εubjectε iε determined. In one embodiment of the invention, a bioadheεive compoεition exhibitε a duration of adheεion of at leaεt about 6 hourε when teεted according to thiε Teεt Method. For purposes of determining the duration of adhesion of a patch of the invention to human oral mucoεa, whether the patch haε been prepared according to Step 1 of the Teεt Method or otherwiεe. Step 2 of the Teεt Method iε employed. In one embodiment of the invention, a patch of the invention exhibitε a duration of adheεion of at leaεt about 6 hourε when teεted according to Step 2 of the Teεt Method. The procedureε described below set forth non-limiting methodε of preparing partially neutralized reεinε suitable for uεe in a bioadheεive compoεition of the invention. Other methodε can alεo be employed if a partially neutralized reεin iε deεired. Preparative Method 1 CARBOPOL TM ,934 P reεin (200 g) and calcium hydroxide (15 g, particle εize about 25 μm ) were placed in a 5 quart Hobart mixer (Model N-50, Hobart Corp., Troy, OH) and mixed for 5 minuteε at a εetting of 1. Stirring waε continued and iεopropyl alcohol (about 200 mL) waε added dropwise to the mixture over a period of about 5 minutes, resulting in a material of a dough-like consistency. This material was dried overnight in a tray oven at 90°C, and milled in a small mill (Fitzpatrick _ Model J, Fitzpatrick Co., Elmhurst, IL) to afford a reεin b in the form of a powder with a particle size of about 30-50 μ . Preparative Method 2 10 CARBOPOL . T"M" 934 P reεin (10 g) waε added εlowly to ethyl alcohol (500 mL). The reεulting mixture waε stirred vigorouεly with a magnetic stirrer until the resin was homogeneouεly εuεpended. An aqueouε εolution of calcium hydroxide (780 mL of a εolution containing 1 g/L, 780 mg) was added and the mixture waε placed in a εcrew top jar. The jar waε placed in an Eberbach laboratory shaker and shaken overnight at room temperature. The resulting mixture was spray dried using a Buchi Model 190 __ Mini-Spray Drier (Buchi Laboratorieε, Flawil, Switzerland). A free-flowing powder (5 g) reεulted. Preparative Method 3 25 CARBOPOL™934 P reεin (10 g) waε added εlowly to ethyl alcohol (500 mL). The reεulting mixture waε εtirred vigorously until the reεin was homogeneously suspended. An aqueous solution of aluminum hydroxide (0.91 g in 600 mL water) was added, and the mixture waε εtirred and dried aε εet forth in Preparative Method 2. 30 Preparative Method 4 CARBOPOL TM ,934 P resin ( 300 g) and calcium - ς hydroxide (38 g, particle εize about 25 μ ) were placed in a 5 quart Hobart mixer and mixed for about 5 minuteε at a setting of 1. Stirring waε continued and iεopropyl alcohol (about 300 mL) waε added uniformly over a period of about 5 minuteε. The reεulting material waε dried and milled according to Preparative Method 1 to afford a reεin in the form of a powder with a particle εize of about 30-50 μm. The following examples are provided to illuεtrate the invention. They are not intended to limit the invention. All partε and percentageε are by weight unleεε otherwise indicated. When placebo patches were 10 used to determine adheεion to human buccal mucosa, the duration of adhesion representε the length of time that a patch adhered in one person, unlesε it iε indicated that the Teεt Method waε used. 15 EXAMPLE 1 A solution containing a polyiεobutylene with a viεcoεity average molecular weight of about 53,000 (1.6 g, aε 3.2 g of a εtock εolution containing 50% by weight 20 VISTANEX™ LM-MH polyiεobutylene, ' commercially available from Exxon Chemical Co., Houεton, TX, in a 1:1 mixture by volume of hexane and toluene) and a polyiεobutylene with a viεcosity average molecular weight of about 1,200,000 - c (0.080 g, aε 0.4 g of a stock solution containing 20% by * " weight of VISTANEXTML-l00 polyiεobutylene, alεo commercially available from Exxon Chemical Co., in a 1:1 mixture by volume of hexane and toluene) waε prepared. Reεin obtained from Preparative Method 2 (3.0 g) was added with stirring. A 1:1 solution of hexane and toluene (5 30 mL) was added and stirring continued for about 5 minutes. The mixture was then coated using a knife coater onto εilicone-coated releaεe liner at a wet thickneεε of 3.4 mm. The εolvent waε allowed to evaporate. A backing material, TEGADERM™ 1625 brand surgical dressing, waε 35 applied by hand to the expoεed εurface of the coating to provide a composition with a backing material applied thereto. Individual patches were hand-cut from this εheet material with a 1 cm circular die. EXAMPLES 2-4 To prepare the bioadheεive compoεition of EXAMPLE 2, a εolution containing VISTANEX™ L-100 polyiεobutylene (0.35 g aε 1.75 g of a εtock εolution 10 containing 20% VISTANEX™ L-100 polyiεobutylene by weight in a 1:1 mixture by volume of hexane and toluene) and VISTANEX™ LM-MH polyiεobutylene (1.60 g aε 3.2 g of a stock solution containing 50% VISTANEX™ LM-MH polyisobutylene by weight in a 1:1 mixture by volume of - ς hexane and toluene) was prepared. Digoxin (0.05 g) waε added with εtirring. Reεin obtained from Preparative Method 2 (3.0 g) waε added with stirring. A 1:1 mixture by volume of toluene and hexane (5 mL) was added, and stirring was continued for about 5 minuteε. The reεulting - - mixture waε made into patches according to the method of EXAMPLE 1. Similarly, using the same relative amounts of components, resin obtained from Preparative Method 3 waε combined with digoxin and incorporated into a patch of 2 EXAMPLE 3, and reεin obtained from Preparative Method 4 waε combined with digoxin and incorporated into a patch of EXAMPLE 4. The patches of EXAMPLES 2-4 were tested according to the In Vivo Test of Sustained Release described below. 30 In Vivo Test of Sustained Releaεe A patch of the invention waε presεed in place on the buccal mucoεa of a female beagle dog. Blood samples were drawn periodically after the placement of the patch , c and the blood level of the druq was determined by a standard assay for digoxin. Reεultε are εhown in TABLE I, wherein the abεence of an entry indicateε a blood level of drug below the detection limit of the aεsay. TABLE I Blood Levels of Digoxin (ng/mL) Example 10 15 20 The patches adhered for the 24 hour period during which blood εampleε were drawn. TABLE I εhows that the bioavailability of the digoxin is subεtantial for a period of at leaεt 24 h and that digoxin iε delivered in a - c sustained fashion from these bioadhesive compositions of -so the invention. EXAMPLES 5-7 Solutions containing VISTANEX™ L-100 30 polyisobutylene (0.25 g, as 1.25 g of a solution containing 20% VISTANEX™ L-100 polyisobutylene by weight in a 1:1 mixture by volume of hexane and toluene) and VISTANEX™ LM-MH polyiεobutylene ( 1.0 g, aε 2.00 g of a εolution containing 50% VISTANEX' LΓΪ-MH polyiεobutylene 35 by weight in a 1:1 mixture by volume of hexane and toluene) were prepared. The solutions were combined, and theophylline (0.75 g) was added with stirring. Reεinε obtained from Preparative Methods 2, 3, and 4 (3.0 g) were independently added with εtirring. The reεulting mixtureε were made into patches of EXAMPLES 5, 6, and 7, respectively, according to the method set forth in EXAMPLE 1. EXAMPLES 8-14 Using the general method of EXAMPLES 2-4, individual patches comprising the compositionε liεted in TABLE II below, wherein the elaεtomer iε a 1:4 mixture of VISTANEX™ L-100 polyiεobutylene and VISTANEX™ LM-MH polyiεobutylene, were prepared. TABLE II liεtε the reεin used and the amount thereof, the type and amount of drug used, and the amount of elastomer uεed. All amountε are based upon the total weight of the bioadhesive compoεition. TABLE II Example Reεin (%) % Elaεtomer Drug (%) CARBOPOL TM934P 40% Morphine (15%) (45%) C CAARRBBOO:POL™951 40% Morphine (15%) (45%) 10 CCAARRBBOO:POL™910 35% Morphine (15%) (50%) 11 CCAARRIBOPOL™910 40% Morphine (15%) (455 12 CARBOPOL™910 35% Morphine Sulfate (50%) (15%) 13 CARBOPOL™910 40% Morphine Sulfate (45%) (15%) CARBOPOL™910 35'- Morph. (50%) (15%) Patches of EXAMPLES 10, 12, and 14 were tested according to the In Vivo Teεt of Suεtained Releaεe (εet forth in EXAMPLES 2-4 above) with a εtandard aεεay for morphine being employed. The reεultε are εhown in TABLE III. The patcheε adhered throughout the 24 hour period during which blood samples were drawn. TABLE III shows that the bioavailability of morphine, morphine HCl, and morphine sulfate is subεtantial for a period of at leaεt 24 h, and that these drugs are released from these compositionε of the invention in a εuεtained faεhion. EXAMPLES 15-25 Uεing the general method of EXAMPLE 1, 5.0 g εampleε of the bioadhesive compoεitionε εet forth in TABLE IV below were prepared. All amounts are baεed upon the total weight of the bioadheεive compoεition. Individual patcheε were prepared according to the general method of EXAMPLE 1 and remained adhered to human buccal mucoεa for a study period indicated in TABLE IV. The study period was terminated by removing the patch by hand. No entry indicateε that the patch waε adhered but waε removed after a εhort time. Patcheε of EXAMPLES 20 and 24 were teεted for in vivo adhesion in humans according to Step (2) of the Test Method set forth above. The results are shown in TABLE V below. TABLE IV COMPONENT CARBOPOL™910 CARBOPOL™934P CARBOPOL™940 CARBOPOL™941 CARBOPOL™951 CARBOPOL™1342 VISTANEX™LMMH VISTANEX™L100 Study Period 24h 24h 2h 2h 24h COMPONENT EXAMPLE (wt %) 21 22 2^ 2± 25_ CARBOPOL™910 CARBOPOL™934P 50 40 CARBOPOL™941 CARBOPOL™951 40 60 CARBOPOL™1342 60 VISTANEX™LMMH 40 48 48 32 32 VISTANEX™LI00 10 12 12 8 8 Study Period 24h — 20h 24h 4h Subject A B C D E F Average (± σ) 20.2 (+ 7.3) 20.3 (+ 4.2) The data in TABLE V show that these patches of the invention adhere to human oral mucosa for an extended period of time. EXAMPLES 26-29 CARBOPOL™910 resin (lOOg) was placed in a Hobart mixer (Model N-50, Hobart Corp., Troy, OH) and mixed at a εetting of 1 while isopropyl alcohol (100 ml) waε added dropwise over a period of about 5 minutes. The resulting material was dried overnight in a tray oven at 32°C and milled in a small mill (Fitzpatrick Model J, Fitzpatrick Co., Elmhurεt, IL) to afford CARBOPOL™910 reεin with an average particle εize of about 30 μm to 50 μm . Uεing the general method of EXAMPLE 1, and the CARBOPOL™910 resin as processed above, 5.0 g sampleε of the bioadhesive compositionε εet forth in TABLE VI were prepared. All amounts are based upon the total weight of the bioadheεive compoεition. Individual patcheε were prepared according to the general method of EXAMPLE 1 and remained adhered to human buccal mucoεa for a εtudy period of about 20 hourε. The study period was terminated by removing the patch by hand. TABLE VI Example Uεing the general method of EXAMPLE 1, 5.0 g εampleε of the compoεitionε εet forth in TABLE VII below were prepared. All amountε are baεed upon the total weight of the bioadheεive compoεition. The polyacrylic acid εamples were purchased from Polysciences, Inc., Warrington, PA. Individual patches were prepared according to the general method of EXAMPLE 1 and remained adhered to human buccal mucosa for a study period of about 4 hours. The study period was terminated by removing the patch by hand. TABLE VII Example % Polyacrylic A solution (5.0 g) containing 70% by weight toluene, 10% by weight mineral oil, and 20% by weight of Kraton™D 1107 rubber waε prepared. Polycarbophil (Biomimeticε, Inc., Lexington, MA) was added over a period of about 5 minutes with stirring. Patches were made from the resulting mixture as deεcribed in EXAMPLE 1. The patches remained strongly adhered to human buccal mucosa for a εtudy period of εeveral minuteε. The εtudy period waε terminated by removing the patch by hand. EXAMPLES 34 and 35 A copolymer of 96% by weight iεooctylacrylate and 4% by weight acrylamide (prepared according to the method of Example 2 of U.S. Pat. No. 4,751,087 (Wick), the entire diεcloεure of which iε incorporated herein by reference) waε diεsolved in a 90:10 (V/V) solution of ethyl acetate in methanol in an amount sufficient to prepare a 30% by weight solution of the copolymer. To an aliquot of the solution was added with stirring polycarbophil (Biomimeticε, Inc., Lexington, MA) in an amount εufficient to prepare the compoεitionε εet forth in TABLE VIII below. TABLE VIII Example % Elaεtomer % polycarbophil 34 25 75 35 20 80 The compoεitionε of TABLE VIII were made into patcheε according to the general method of EXAMPLE 1. The patcheε remained adhered εtrongly to human buccal mucoεa for a εtudy period of about 2 hours. The εtudy period waε terminated by removing the patch by hand. EXAMPLES 36-43 Compoεitions were prepared by milling the components liεted in TABLE IX at room temperature in a two-roll mill (Reliable Mill Model 3216, Rubber and Plaster Machine Company, North Bergen, NJ) according to the general method set forth below. The lower molecular weight component of the elastomer was added to the mill and milled until it waε distributed on the rollers. The higher molecular weight component of the elastomer waε then added as small pieces and milling waε continued until a homogeneouε mixture obtained. The plaεticizer (if any) was then added and the mixture was milled until homogeneous. The particulate polymeric resin was mixed with the drug (if any) to form a uniform mixture. The reεin was then added slowly to the elastomeric component in the mill and thiε mixture waε milled until a uniform compoεition obtained. It waε neceεεary to periodically remove the material from the rollers, form it into a ball and re-mill to ensure a uniform composition. The composition was removed from the mill by εcraping the rollerε. About 15 to 25g of the compoεition waε preεεed at about 70,000 KPa between two 17 cm x 17 cm pieceε of silicone-coated release liner in a platen press heated to about 50°C to afford a laminate comprising a sheet of compoεition about 2 mm thick. Individual patches were cut from the resulting laminate with a die. Compoεitionε were prepared aε deεcribed above uεing the materialε set forth in TABLE IX below . Individual patches were found to adhere to human oral mucosa. * from Biomimeticε, Inc., Lexington, MA ** from Arakawa Chemical, Chicago, IL *** MAZOLA™ Corn Oil ** * ** Dow Corning 200 fluid, 200 cpε EXAMPLES 44-47 Compoεitions were prepared according to the general method set forth in EXAMPLES 36-43 above using the componentε εhown in TABLE X below. TEGADERM™ 1625 εurgical dreεεing waε adhered as a backing to one side of the compoεitionε. * Bio imetics, Inc., Lexington, MA Individual patcheε of the compoεition of EXAMPLE 44 were prepared and placed on the gum of a female beagle dog and blood levelε of the drug were meaεured uεing a εtandard assay. The results are shown below. The patch was removed after 24 hourε Individual patcheε of the compoεition of EXAMPLE 45 were prepared and two patcheε were placed on the gum of a female beagle dog and blood levelε of both eεtradiol and estrone were measured using εtandard aεεays. The resultε are εhown below. The patch waε removed at 24 hourε Individual patcheε of the compoεition of EXAMPLE 46 were prepared and placed on the gum or the cheek of a female beagle dog as indicated below and blood levels of the drug were measured using a standard assay. The resultε are εhown below, where nd deεignateε that no determination of blood level of drug waε made. Digoxin level (ng/mL) Time (hr) Gum Cheek 0.5 <0.1 <0.1 1 <0.1 0.5 2 0.13 0.52 3 0.13 1.3 4 0.45 1.1 5 0.38 1.77 6 0.38 nd 7 0.47 nd The patch waε removed at 8 hourε Individual patcheε of the composition of EXAMPLE 47 were prepared and placed on the inner εurface of the upper lip of a female beagle dog and blood levels of the drug were measured using a standard aεεay. The reεultε are shown below. In all cases, therapeutic levels of the respective drug were observed for a sustained period of time. EXAMPLES 48-53 Compositionε were prepared by milling at room temperature in a two-roll mill (Model Number 53060 Farrell-Birmingham Anεonia CT) with rollers of 15 cm diameter and 30 cm length according to the general method set forth below. The elastomeric component or, in the case of a two-component elastomeric component, the higher molecular weight component, waε added to the mill in portionε and milled until uniform (about 15 minuteε) and rolled into a εheet. The εheet was placed in the mill, and the resin or, in the case of a two-component elastomeric component, the resin and the lower molecular weight component together, were added slowly and milled until a uniform composition obtained. The drug was then added and milling waε continued until the drug waε uniformly diεtributed in the compoεition (about 15 minuteε). The compoεition waε then rolled out of the mill in the form of a εheet by adjusting the space between the rollers such that a εheet of the deεired thickneεε (e.g., 1-2 mm) waε produced. Individual patcheε were cut from the reεulting εheet with a 1 cm circular die. Compoεitionε were prepared aε deεcribed above using the components set forth in TABLE XI below. Using conventional methods, the compoεitionε of EXAMPLES 48, 49, and 50 were found to have uniform drug content throughout the compoεitionε. A patch of the compoεition of EXAMPLE 51 remained adhered to the buccal mucoεa of a female beagle dog for a study period of 24 hours. Patches of the compositionε of EXAMPLES 52 and 53 remained adhered to human buccal mucoεa for a study period of about 8 hours and about 15 hourε, respectively. The study periodε were terminated by removing the patcheε by hand. ω Ol o in Morph ™ L-100 Theophyll Sulfa 48 17 15 49 15 50 10 51 20 20 52 53 20 EXAMPLE 54 A composition waε prepared according to the general method of EXAMPLES 36-43 uεing 60% by weight polycarbophil, 32% by weight VISTANEX™ LMMH polyiεobutylene, and 8% by weight VISTANEX™L-100 polyiεobutylene. A circular patch of 1.2 cm diameter waε prepared and placed in the vaginal cavity of a εheep. After a period of about 20 hourε, the patch waε εtill 10 adhering well and waε εlightly εwollen. After a period of about 44 hourε, the patch waε εtill adhering well, but some diεintegration waε obεerved. After a period of about 70 hourε, the patch waε εtill adhering but it was soft and swollen. The patch was removed by gentle scraping with a 15 εpatula. EXAMPLE 55 A multi-layer gradient compoεition waε prepared 20 aε followε: An approximately εquare εheet with an area of about 25 cm 2 of the εolvent-caεt composition of EXAMPLE 15 was prepared. -_ An approximately square εheet with an area of about 25 cm of a compoεition waε prepared by the general milling method of EXAMPLES 48-53 uεing 75% by weight of CARBOPOL™ 934P resin and 25% by weight VISTANEX™L-80 polyisobutylene. __ Aε a backing layer, an approximately εquare εheet with an area of about 25 cm 2 of VISTANEX™L-100 polyiεobutylene waε prepared according to the general method of EXAMPLE 1 (abεent the resin and the backing), by solvent casting the εolution of elastomer at a wet _ ς thicknesε of about 0.5 mm. The three εheetε were stacked with the milled patch in the middle. The stacked compositions were pressed between two sheets of release liner in a heated platen press at 38°C and 35,000 KPa. A 1 cm 2 circular patch was cut from the resulting composition. The patch remained adhered to human gingival mucosa for a study period of about 14 hours. The study period waε terminated by removing the patch by hand. The layerε of the patch showed no sign of de-laminating, and the polyisobutylene backing layer prevented adhesion of the patch to the mucosal surface opposite the gum. EXAMPLES 56-58 Patches were prepared according to the general method of EXAMPLES 48-53 above, using the components εet forth in TABLE XIII below. The above-described patches were independently adhered to a glass slide using double-stick tape and tested for in vitro release of theophylline by immersing the patches in 700 mL of pH 7 buffer solution in a USP Type II dissolution apparatus. Periodically, a 5 mL aliquot of the buffer was removed and analyzed by ultraviolet spectrophotometry (270 nm) for theophylline. Resultε are aε εhown in TABLE XIII below. TABLE XIII The data in TABLE XIII show that theεe compositions of the invention release theophylline in a sustained fashion iji vitro. EXAMPLE 59 A patch was prepared using 20 weight percent NATSYN™2210 polyisoprene (Goodyear, molecular weight about 760,000), 50 weight percent CARBOPOL™934P reεin, and 30 weight percent morphine sulfate, with the sheet of composition being presεed at about 70°C and about 70,000 KPa for about 20 seconds prior to cutting into patches. Morphine sulfate release ii vitro waε determined aε deεcribed above in connection with EXAMPLES 56-58, with the buffer aliquot being analyzed for morphine by the USP method. Reεultε are εhown in TABLE XIV below. The data in TABLE XIV show that the composition of EXAMPLE 59 releaseε morphine sulfate in a sustained fashion i j vitro. EXAMPLE 60 A patch was prepared according to the general method of EXAMPLES 48-53 using 30 weight percent NATSYN™2205 polyisoprene (molecular weight about 955,000) and 70 weight percent CARBOPOL™934P resin. The patch waε adhered to the gingival mucosa of a subject and remained adhered for a study period of about 8 hours, after which time the εtudy period waε terminated and the patch waε removed from the mucosa. EXAMPLE 61 A patch was prepared according to the general method of EXAMPLES 48-53 above uεing 30 weight percent TAKTENE™1202 polybutadiene (Polysar, molecular weight about 375,000) and 70 weight percent CARBOPOL™934P resin. The patch waε placed on the gingival mucoεa of a εubject and remained adhered for a study period of about 7 hours after which time the study period waε terminated and the patch waε removed from the mucosa. EXAMPLES 62-63 Two different embodiments of patches were prepared according to the general method of EXAMPLES 48-53 above, using, respectively, 5 weight percent TAKTENE™1202 polybutadiene (molecular weight about 335,000), 25 weight percent NATSYN™2210 polyiεoprene (molecular weight about 760,000), and 70 weight percent CARBOPOL™934P reεin; and 25 weight percent TAKTENE™1220 polybutadiene, 5 weight percent NATSYN™2210 polyisoprene, and 70 weight percent CARBOPOL™934P resin, with the respective sheets being presεed as described in Example 59 above prior to cutting into patches. The patches were found to adhere to human oral mucosa. EXAMPLE 64 According to the general method of EXAMPLE 1 above, a composition of the invention was prepared uεing 45 weight percent CARBOPOL™934P reεin, 18 weight percent VISTANEX™ L-100 polyisobutylene, 27 weight percent VISTANEX™ LMMH polyisobutylene, and 10 weight percent melatonin. Patches made from this composition were placed on the oral mucosa of dogs and found to provide therapeutically effective blood levelε of melatonin.

Claims: Claimε : 1. A bioadhesive composition that comprises: 1) a particulate polymeric resin with an average particle size of lesε than or equal to about 100 μ and compriεing at least about 55% by weight of carboxylic acid moieties based on the total weight of the polymeric resin; 2) from about 20 parts to about 250 parts by weight of a hydrophobic elastomeric component, 0 based on 100 partε by weight of the resin; and 3) an amount of a drug effective to provide a desired therapeutic result, wherein the resin and the drug are dispersed substantially throughout the elastomeric component, and which 5 composition contains less than about 10% water by weight based on the weight of the polymeric resin, exhibits substantially no instantaneous adhesion to dry skin, and adheres to a mucosal surface. 2. A composition according to Claim 1, wherein 20 the hydrophobic elaεtomeric component comprises a block styrene-butadiene-styrene copolymer, a block styrene- isoprene-styrene copolymer, a polyisobutylene, a polybutadiene, an isoprene rubber, a carboxy-functional __b polyisoprene, a hydroxy-functional polyisoprene, an acrylate elastomer, or a mixture of two or more of the foregoing. 3. A compoεition according to Claim 1, wherein the polymeric resin consiεtε eεεentially of acrylic acid monomer units. 30 4. A composition according to Claim 3, wherein the resin is covalently crosslinked with about 0.75% to about 2% by weight based on the total weight of the resin of a polyalkenyl polyether. 5. A composition according to Claim 1, wherein 35 the elastomeric component is a hydrocarbon. 6. A composition according to Claim 5, wherein the elastomeric component compriseε a polyisoprene with a molecular weight of about 500,000 to about 1,200,000 a polybutadiene with a molecular weight of about 100,000 to about 500,000, or a mixture thereof. 7. A composition according to Claim 1, prepared by a procesε comprising the stepε of: 1) adding to a mill the constituent or constituents of the elastomeric component; 2) milling the constituent or constituents of the elastomeric component to afford a substantially homogeneous elastomeric component; 3) milling the particulate polymeric resin, the drug, and the substantially homogeneous elaεtomeric component from εtep (2) to form a homogeneouε compoεition. 8. A compoεition according to Claim 7, wherein the constituents of the elastomeric component comprise: about 5% to about 50% by weight of a polyisobutylene with a viscosity average molecular weight between about 500,000 and about 2.5 million; and about 50% to about 95% by weight of a polyisobutylene with a viscosity average molecular weight between about 40,000 and about 100,000. 9. A composition according to Claim 7, wherein the constituentε of the elaεtomeric component are selected from the group conεisting of a polyisoprene with a molecular weight of about 500,000 to about 1,200,000, a polybutadiene with a molecular weight of about 100,000 to about 500,000, a mixture of two or more of said polyisoprenes, a mixture of two or more of said polybutadienes, and a mixture of one or more of said polyisoprenes and one or more of said polybutadienes. 10. A composition according to Claim 1, wherein the resin has an average particle size of between about 2 μm and about 10 μm . 11. A composition according to Claim 1, which contains less than about 4% water by weight based on the total weight of the resin. 12. A composition according to Claim 1, wherein the drug is selected from the group consisting of digoxin, heparin, hydromorphone, buprenorphine, theophylline, melatonin, and pharmaceutically acceptable salts thereof. 13. A process for preparing a composition according to Claim 1 in a mill which process comprises the steps of: 1) milling the elastomeric component to afford a substantially homogeneous elastomeric component; 2) milling the particulate polymeric resin, the drug, and the substantially homogeneous elastomeric component from step (1) to form a substantially homogeneouε composition. 14. A method of achieving and/or maintaining a therapeutically effective blood level of a drug in a mammal, which method comprises the stepε of: a) adhering a composition according to Claim 1 to a mucosal surface of a mammal; and b) allowing the composition to remain adhered for a time sufficient to release drug such that a therapeutically effective blood level of drug is achieved and/or maintained. 15. A method of delivering a drug to a mucosal surface of a mammal or to the vicinity of a mucosal surface of a mammal to provide a therapeutic effect on or in the vicinity of the mucosal εurface, which method compriseε the steps of: a) adhering a composition according to Claim 1 to the mucosal surface; b) allowing the composition to remain adhered for a time sufficient to release the drug to the mucosal surface or to the vicinity of the mucosal surface to provide the desired therapeutic effect.

Inventors: BARKHAUS JOAN K, CHEN YEN-LANE, MARECKI NELDA M, SCHERRER ROBERT A, SCHOLZ MATTHEW T, BARKHAUS, JOAN, K., CHEN, YEN-LANE, MARECKI, NELDA, M., SCHERRER, ROBERT, A., SCHOLZ, MATTHEW, T.
Applicants: RIKER LABORATORIES INC, RIKER LABORATORIES, INC.
Application year: 1990
Main classification: A61K9
IPC codes: A61K9, A61K47, A61L15