Medicated plasters

Abstract: Medicated plasters composed of a flexible support and a pressure-sensitive adhesive layer laminated thereon, in which said pressure-sensitive adhesive layer has an exposed surface with pH of 7 or higher and contains one of the following three components: (i) a basic physiologically active agent and an acidic substance, (ii) a salt of a basic physiologically active agent and a basic substance, and (iii) a basic physiolosically active agent and a salt of a basic physiolosically active agent.

Description: This invention relates to a medicated plaster composed of a flexible support and a pressure-sensitive adhesive layer laminated thereon. Medicated plasters are known as a dosage form for percutaneous absorption. Some of these plasters employ as base material a pressure-sensitive adhesive made of an elastomeric or acrylic polymer in order to ensure close adherance to the skin. Plasters of this type, however, are generally low in solubility for medicine. Particularly, it is extremely difficult to keep a medicine in salt form uniformly dissolved; even when uniformly prepared, the medicine tends to become crystallized during storage, thus discouraging its percutaneous absorption. Several techniques are known in which an organic acid is added to the pressure-sensitive adhesive layer containing a medicine for the purpose of (X) improving the releasability of the medicine and its percutaneous absorption (for example, Japanese Patent Kokai No.79820/1988 and No.126119/1987 ), and (Y) preventing the loss of medicine with the passage of time, thus ensuring its stable preservation over long periods ( for example, Japanese Patent Kokai No.193920/1985 and No.100715/1981 ). In any of these techniques, however, no attention is given to the pH of the exposed surface of the pressure-sensitive adhesive layer. The above technique (X) has the problem that the content of medicine frequently declines with the passage of time, and the technique (Y) suffers from poor releasability and percutaneous absorption of the involved medicine in some cases. Thus, plasters combining the features of techniques (X) and (Y) have not been developed yet. EP-A-225005 discloses an analgesic adhesive preparation wherein an analgesic agent in salt form is incorporated into a pressure sensitive adhesive material in the presence of an organic acid. EP-A-209975 discloses an analgesic preparation wherein Diclofenac Sodium and an organic acid are incorporated into an acrylic adhesive. EP-A-276561 discloses a topical analgesic composition comprising piroxam as a basic active ingredient, an alkaline agent and an aqueous adhesive base, said composition having a pH range of from 4.0 to 9.0. Patent Abstracts of Japan, vol.10, no. 49, 26 February 1986 and vol. 12, no. 306, 19 August 1988 disclose pharmaceutical preparations which are obtained by blending an acrylic polymer with basic physiologically active agents and an acid compound. It is the object of the present invention to provide an improved medicated plaster. Said object is achieved by a medicated plaster composed of a flexible support and a pressure-sensitive adhesive laminated thereon, said pressure-sensitive adhesive layer having an exposed surface with a pH in the range of from 7 to 11.5 and containing one of the following three components: (i) a basic physiologically active agent and an acidic substance, (ii) a salt of a basic physiologically active agent and a basic substance, and (iii) a basic physiologically active agent and a salt of a basic physiologically active agent. Figure 1 shows characteristic curves illustrating the concentration change in plasma with the passage of time for the medicines of Examples 1, 9, 13 and 17 and of Comparative Examples 1, 6, 10 and 14. Figures 2, 3, 4 and 5 show characteristic curves illustrating the release rates for the medicines of Examples 1 to 8 and Comparative Examples 1 to 5, for the medicines of Examples 9 to 12 and Comparative Examples 6 to 9 for the medicines of Examples 13 to 16 and Comparative Examples 10 to 13, and for the medicines of Examples 17 to 20 and Comparative Examples 14 to 18, respectively. Figure 6 shows characteristic curves illustrating the concentration change in plasma with the passage of time for the medicines of Examples 27 and 28 and for an oral medicine for comparison. Figure 7 shows characteristic curves illustrating the release rates for the medicines of Example 21 and Comparative Example 22. Figure 8 shows characteristic curves illustrating the concentration change in plasma with the passage of time for the medicines of Examples 29, 30 and 33 and of Comparative Examples 23 and 24. Figure 9 shows characteristic curves illustrating the release rates for the medicines of Examples 29 to 34 and of Comparative Examples 23 to 27. The pressure-sensitive adhesive layer used in this invention serves to hold a basic medicine, and/or a salt thereof and an acidic (and/or basic) substance and to ensure adhesion of the plaster to the skin. Acrylic polymers are suitable materials for the pressure-sensitive adhesive layer of the plaster of this invention in terms of adhesion to the skin and stability of the medicine involved therein. As examples of the acrylic pressure-sensitive adhesive, there may be mentioned polymers composed of at least one alkyl (meth)acrylate having an alkyl group of 4 to 13 carbon atoms [ e.g., butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth)acrylate, undecyl (meth)acrylate, dodecyl (meth)acrylate and tridecyl (meth)acrylate ], and copolymers composed of at least one alkyl (meth)acrylate mentioned above and at least one copolymerizable monomer. Examples of the copolymerizable monomer include the following: (a) carboxyl-containing monomers, such as (meth)acrylic acid, itaconic acid, crotonic acid, maleic acid, fumaric acid and maleic anhydride; and hydroxyl-containing monomers, such as hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate; (b) alkyl (meth)acrylates containing at least one ether linkage in the molecule, such an methoxyethyl (meth)acrylate, ethoxyethyl (meth)acrylate, butoxyethyl (meth)acrylate, tetrahydrofurfuryl (meth)acrylate, methoxyethylene glycol (meth)acrylate, methoxydiethylene glycol (meth)acrylate, methoxypolyethylene glycol (meth)acrylate and methoxypolypropylene glycol (meth)acrylate; (c) monomers represented by the following general formula (I) ( wherein R represents a hydrogen atom or a methyl group, and X represents a radical having at least one nitrogen atom, or nitrogen and oxygen atoms ), including (meth)acrylates containing an alkylaminoalkyl group, such as aminoethyl (meth)acrylate, dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, and tert-butyl (meth)acrylate; and functional acrylic monomers, such as esters of (meth)acrylic acid with urethane, urea and isocyanates (d) monomers represented by the following general formula (II) CH₂=CH-X (II) ( wherein X represents a radical having at least one nitrogen atom, or nitrogen and oxygen atoms ), including vinyl monomers carrying a saturated or unsaturated N-containing heterocyclic ring ( such as vinylcaprolactam, vinylimidazole, vinylmethylimidazole, vinylphenylimidazole, vinylpyrrolidone, vinylmethylpyrrolidone, vinylpiperidone, vinylpyridine, vinylpiperadone, vinylpyrimidine, vinyloxazole, acryloylmorpholine, vinylmorpholine, vinylthiazole, vinylpyrazine, vinylpiperazine and vinylpyrrole ); acrylic monomers containing an amide group [ such as (meth)acrylamide, diemthyl(meth)acrylamide, N-butylacrylamide, tetramethylbutylacrylamide and N-methylol-(meth)acrylamide ); and vinyl monomers such as N-(meth)acryloylamino acids; (e) vinyl monomers, such as (meth)acrylonitrile, vinyl acetate, vinyl propionate, vinyloxazole, styrene, α-methylstyrene and bis(N,N'-dimethylaminoethyl) maleate; and sulfoxy-containing monomers, such as styrenesulfonic acid, allylsulfonic acid, sulfopropyl acrylate, (meth)acryloyloxynaphthalenesulfonic acid, acrylamidomethylpropanesulfonic acid and acryloyloxybenzenesulfonic acid. The above-mentioned alkyl (meth)acrylates and the copolymerizable monomers also include isomers containing linear or branched alkyl groups, isomers in which substituent groups are located at different positions, and various derivatives thereof. Of the monomeric compounds mentioned above, combinations of an alkyl (meth)acrylate with (meth)acrylic acid are preferable in terms of high polymerizability as well as high cohesion and adhesion of the resulting copolymers. Vinyl acetate is preferable in terms of high cohesion of the resulting copolymers. The weight ratio of an alkyl (meth)acrylate to a copolymerizable monomer should preferably be in the range of 50 to 99/50 to 1 to ensure a good balance between cohesion and adhesion to the skin. When an alkyl (meth)acrylate containing at least one ether linkage in the molecule is used to minimize irritation to the skin, the weight ratio between an alkyl (meth)acrylate, an alkyl (meth)acrylate containing at least one ether linkage and a third copolymerizable monomer should preferably be 40 to 80/59 to 10/ 1 to 40. In this case the use of vinyl acetate as the third copolymerizable monomer is preferable in terms of high cohesion of the resulting copolymers. "The third copolymerizable monomer" means a monomer other than the above mentioned monomers. When a water-soluble and latently basic monomer of group (c) and/or (d) is used to ensure good adhesion to the skin as well as high solubility and releasability of the medicine the weight ratio of alkyl (meth) acrylates to said water-soluble monomer should preferably be 50 to 96/50 to 4, more preferably 60 to 90/10 to 30. When said monomer of group (c) and/or (d) is used, a polar monomer of group (a) can be further included in the copolymer in an amount of up to 20 weight %. This serves to improve cohesion, adhesion to the skin and the hydrophilic nature. The use of vinylpyrrolidone as a monomer of group (c) and/or (d) serves to improve cohesion and the hydrophilic nature, and the use of hydroxyethyl (meth)acrylate as a polar monomer of group (a) serves to improve the hydrophilic nature. Examples of pressure-sensitive adhesives of other types are elastomeric polymers ( such as silicone rubber, polyisoprene rubber, polyisobutylene rubber, polybutadiene rubber, styrene-butadiene(or isoprene)-styrene block copolymers and natural rubber), vinyl polymers ( such as polyvinyl alkyl ethers, polyvinyl acetate and a partially saponified product thereof, polyvinyl alcohol and polyvinylpyrrolidone ), cellulose derivatives ( such as methylcellulose, carboxymethylcellulose and carboxypropylcellulose ), polysaccharides ( such as pullulan, dextrin and agar ), polyurethane elastomers, and polyester elastomers. When the pressure-sensitive adhesive used is low in cohesion and part of it is left attached to the skin after peeling off the plaster it is preferred that the polymer composition be subjected to proper chemical crosslinking ( copolymerization with a crosslinkable monomer or addition of an external crosslinker ) or to physical crosslinking ( application of ionizing radiations, such as electron rays or ultraviolet crosslinking ) to such a moderate degree as not to adversely affect the adhesion to the skin. As support to hold the above mentioned pressure sensitive adhesive layer may be used a flexible material that can follow the movements of the skin surface such as a plastic film, nonwoven fabrics, woven fabrics, paper, a metallic foil, and laminated products thereof. Basic medicines and salts thereof used in this invention are those which are physiologically acceptable; particularly those which contain at least one amino or amide group ( of any type ) in the molecule are preferred. The term "base" herein means a Lewis base defined by the Lewis theory ( "Valence and the Structure of Atoms and Molecules" 1923 Gilbert N. Lewis ); hence, basic medicines mean those containing a Lewis base ( or bases ) in the molecule. "Physiologically acceptable" means that that medicine can be safely administered to human bodies. Such basic medicines may be divided into two groups ―― systemic drugs ( those acting systemically, with the active ingredient involved working into blood vessels ), and local drugs ( those acting locally, with no need of the active ingredient working into blood vessels ) ――, and medicines of both types are applicable in the plaster of this invention. Salts of these basic medicines may be of any types ( both organic and inorganic ), such as citrates, succinates, fumarates, maleates, tartrates, hydrochlorides, sulfates and phosphates. Listed below are illustrated examples of salt-form basic medicines to be used in this invention. (1) Hypnotic and sedative agents: Flurazepam hydrochloride; (2) Antipyretic, analgesic and antiphlogistic agents: Cinnolidine hydrochloride, benzidamine hydrochloride, perisoxisal citrate, refetamine hydrochloride, tramadole hydrochloride, dimethothiazine mesylate, buprenorfin hydrochloride or butorphanol tartrate; (3) Stimulating and antihyptonic agents: Methanefetamine hydrochloride; (4) Antiemetics: Meclizine hydrochloride, dl-isoprenaline hydrochloride. diphenidol hydrochloride or betahistine mesylate; (5) Medicines for psyconeurosis: Phenothiazine compounds: chlorpromazine hydrochloride, chlorpromazine hibenzate, triflupromazine hydrochloride. levomepromazine maleate, levomepromazine hydrochloride, perazine maleate, perazine phendizoate, prochlorperazine maleate, trifloperazine maleate. thioridazine hydrochloride, pulphenazine phendizoate, perphenazine maleate, pulphenazine hydrochloride, fluphenazine maleate, fluphenazine hudrochloride, or spiclomazine hydrochloride; Compounds of phenothiazine-like skeletal structure: Flupentixol hydrochloride; Butyrophenone compounds: floropipamide hydrochloride or moperone hydrochloride ; Diphenylmethane compounds: Hydroxydine hydrochloride; Carpipramine compounds: carpipramine hydrochloride, carpipramine maleate or clocapramine hydrochloride; Tricyclic antidepressants: imipramine hydrochloride. desipramine hydrochloride, trimipramine maleate, clomipramine hydrochloride, amitriptyline hydrochloride, nortriptyline hydeochloride, dosulepin hydrochloride, melitracene hydrochloride or lophepramine hydrochloride; Tetracylic antidepressants: mianserin hydrochloride or maprotiline hydrochloride ; MAO inhibitors: safrazine hydrochloride; Benzodiazepine compounds: chlordiazepoxide hydrochloride; Others: methylphenidate hydrochloride or pipradrol hydrochloride; (6) Skeletal muscle relaxants: Pridinol mesylate, eperison hydrochloride or tolperison hydrochloride ; (7) Antispasmodics: Choline blockers: atropine sulfate, scopolamine hydrobromide, dicyclomine hydrochloride. pipethanate hydrochloride, piperidolate hydrochloride, oxyphencyclimine hydrochloride or methixene hydrochloride; Others: papaverine hydrochloride; (8) Antiparkinsonism agents: Piperidene hydrochloride, piperidene lactate, trihexyphenidyl hydrochloride, amantadine hydrochloride, pyroheptin hydrochloride, profenamine hibenzate, profenamine hydrochloride or mazathicol hydrochloride; (9) Antihistaminics: Ethanolamine compounds: diphenhydramine hydrochloride, diphenhydramine salicylate or carbinoxamine maleate; Monoamine compounds: dl-chlorphenilamine maleate or d-chlorphenilamine maleate ; Phenothiazine compounds: alimemazine tartrate; Others: isotipendyl hydrochloride, triprolidine hydrochloride, clemizole hydrochloride, cyploheptadine hydrochloride, homochlorcyclizine hydrochloride, diphenylpyraline hydrochloride, iproheptin hydrochloride, dimethindene maleate or clemastine fumarate; (10) Cardiotonics: dl-Isoproterenol hydrochloride, l-isoproterenol hydrochloride, dopamine hydrochloride, dobutamine hydrochloride, metaraminol tartrate, etilefrin hydrochloride, norfenefrine hydrochloride; (11) Medicines for arrhythmia: Procainamide compounds: procainamide hydrochloride; Xylidine compounds: lidocaine hydrochloride; Kinidin compounds: kinidin sulfate; β-Blocking agents: metoprolol tartrate, propranolol hydrochloride, alprenolol hydrochloride, bufetolol hydrochloride, bupranolol hydrochloride, oxprenolol hydrochloride, indenolol hydrochloride, cartheolol hydrochloride, befnolol hydrochloride, aceptolol hydrochloride, bukumolol hydrochloride, timolol maleate or alotinolol hydrochloride; Others: disopyramide phosphate, mexiretin hydrochloride, verapamil hydrochloride or aprindine hydrochloride; (12) Hypotensive agents: Hydralazine compounds: ekarazine hydrochloride or hydrylazine hydrochloride; Alkaloids : dihydroergotoxine mesylate; Others: guanfacine hydrochloride, clonidine hydrochloride, bunazosine hydrochloride, bunitrolol hydrochloride, prazosin hydrochloride, propranolol hydrochloride, ravetalol hydrochloride, guanabenze acetate, enallapril maleate, guanethidine sulfate, betanidine sulfate or penbutolol sulfate ; (13) Vasoconstrictors: Phenylephrine hydrochloride, methoxamine hydrochloride or dihydroergotamine mesylate ; (14) Coronary vessel vasodilators: Etafenone hydrochloride, oxyfedrine hydrochloride, dilazep hydrochloride, diltiazem hydrochloride, trimetadizine hydrochloride, verapamyl hydrochloride, carbochromen hydrochloride or prenylamine lactate: (15) Peripheral vessel vasodilators: Isoxsuprine hydrochloride, nicametate citrate, nicotinic alcohol tartrate, bamethan sulfate or trazoline hydrochloride; (16) Medicines for other circulatory organs: Nikaldipine hydrochloride, ifenprodil tartrate, pirithioxine hydrochloride, flunaridine hydrochloride, meclofenoxate hydrochloride, moxisylate hydrochloride, brovincamine fumarate, bencyclane fumarate, cinepazide maleate thiapride hydrochloride; (17) Respiration accelerators : Lobeline compounds: lobeline hydrochloride; Dimorpholamine compounds: levallorphan tartrate; Others: dimefline hydrochloride, doxapram hydrochloride or naloxone hydrochloride; (18) Antitussives and expectorants: Centrally acting antitussives: codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, carbetapentane citrate, benproperine phosphate, tipepidine hibenzate, isoaminile citrate, dimemorfan phosphate, oxeladin citrate, evradinone hydrochloride, clobutinol hydrochloride, clofedanol hydrochloride or fominoben hydrochloride ; Other antitussives: noscapine hydrochloride ; Expectorants: L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride, bromhexine hydrochloride, or amproxol hydrochloride; Sympathetic nerve stimulants: dl-epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, isoproterenol sulfate, dl-isoproterenol hydrochloride, orciprenaline sulfate, terbutaline sulfate, salbutanol sulfate, trimetoquinol hydrochloride, clorprenaline hydrochloride, methoxyphenamine hydrochloride, hexoprenaline sulfate, bitolterol mesylate, procaterol hydrochloride, tulobuterol hydrochloride, pirbuterol hydrochloride, fenoterol hydrobromide, formoterol fumarate, clenbuterol hydrochloride or mabuterol hydrochloride; Antiallergic agents: ketotiphen fumarate or azerastine hydrochloride ; (19) Hormones : Clomifene citrate ; (20) Medicines for suppurative diseases ( for external use ): Mafenide acetate ; (21) Analgesic, antipruritic, astringent and antiphlogistic agents; Isothipendyl hydrochloride; (22) Medicines for parasitic dermatosis: Miconazole nitrate, econazole nitrate, iconazole nitrate, sconazole nitrate, oxyconazole nitrate or cloconazole hydrochloride ; (23) Vitamins: Vitamin B₁ compounds: dicethiamine hydrochloride or cycothiamine hydrochloride; (24) Hemostatics: Adrenochromeguanylhydrazone mesylate; (25) Blood clotting inhibitors; Ticropydine hydrochloride; (26) Toxicides and medicines for habitual intoxication: deferoxamine mesylate; (27) Medicines for diabetes Methoformin hydrochloride or buformin hydrochloride; (28) Medicines for malignant tumors : Alkylating agents: nitrogen mustard N-oxide hydrochloride. isoprosulfan tosylate or nimstine hydrochloride; Antimetabolytes: ancitavine hydrochloride; Plant alkaloids: vinblastine sulfate, vincristine sulfate or vindesine sulfate; Cancerocidal antibiotics: daunorubicin hydrochloride or doxorubicin hydrochloide; Others: tamoxifen citrate or procarbazine hydrochloride; (29) Narcotics: Opiate alkaloids: ethylmorphine hydrochloride, morphine hydrochloride, codeine phosphate or dihydrocodeine phosphate ; Coca alkaloids: cocaine hydrochloride; Synthetic narcotics: pethidine hydrochloride or phentanyl citrate; The above-mentioned basic medicines and/or salts thereof may be used in physiologically effective amounts, which are generally in the range of 20 to 5000 µg/cm², preferably 100 to 4000 µg/cm², per unit area of pressure-sensitive adhesive layer. Amounts lower than 20 µg/cm² frequently fail to exhibit satisfactory physiological effects, while amounts higher than 5000 µg/cm² do not show higher effects and cause skin irritation and other troubles in some cases. Normally, these active ingredients are included in pressure-sensitive adhesive in amounts of 0.1 to 50 weight %, preferably 1 to 30 weight %. Conventional pressure-sensitive adhesives are generally low in solubility for medicines; particularly, it is extremely difficult to keep a medicine in salt form uniformly dissolved. Even when it is uniformly dissolved, the salt-form medicine involved is scarcely released in many cases. It is true that medicines in free form can be easily kept uniformly dissolved and satisfactorily released in most cases, compared with those in salt form, but the problem is that the content of medicine tends to decline in some cases as a result of its change with the passage of time during storage. In this invention, these problems are avoided by using a pressure-sensitive adhesive layer having an exposed surface with a pH in the range of from 7 to 11.5 and containing a composition of a basic medicine, a salt thereof, an acidic substance and a basic substance as shown in (i), (ii) and (iii) above. As long as the pH is kept at a level of 7 to 11.5, an acidic or basic substance may be added to the adhesive layer as required. The pH of the exposed surface herein means the value measured by the use of a flat electrode; the pH of waterdrops put on the exposed surface when it nearly comes to equilibrium ( when the pH value remains unchanged for at least 30 seconds ). Since water cannot be included in the pressure-sensitive adhesive layer, the acidic and basic substances added do not serve as so called pH regulator. Unless the pH of the exposed surface is from 7 to 11.5 the medicine involved cannot be sufficiently released to the skin surface and hence its satisfactory percutaneous absorption cannot be achieved. The above-mentioned composition (i) contains an acidic substance, and the compositions (ii) and (iii) each contain a salt of a basic medicine which carries an acid group in the molecule. Hence, an acid is contained besides a basic medicine in each of the compositions, and said acid is effective in preventing the decline of medicine content caused by its change with the passage of time. Any acidic substances that are physiologically acceptable in terms of safety may be used for this purpose, but the use of organic acids (particularly carboxylic acids) is preferred. Typical examples include citric, succinic, tartaric, maleic, fumaric, benzoic, salicylic and lactic acids. The basic substances to be added should be those which are more basic than the medicine used and are physiologically acceptable in terms of safety. These include inorganic bases, such as sodium hydroxide and potassium hydroxide; amines, such as triethanolamine, diethanolamine, triisopropanolamine and diisopropanolamine; and basic amino acids, such as arginine. Such basic substances serve to form a free-base medicine from its salt, thereby facilitating the release of medicine. Suitable amounts of these acidic and basic substances are 0.1 to 10 moles, preferably 0.5 to 5 moles, per mole of the medicine or its salt used. The above-mentioned problems associated with conventional plasters can thus be overcome by the presence of an acid and a basic substance in the pressure-sensitive adhesive layer. Although it is not absolutely clear, it is considered that some intermolecular forces act in the pressure-sensitive adhesive layer among the functional group of the adhesive components, an acid or a basic eliminated from an acidic and/or basic substance, and a free-base physiologically active agent (and an acid) formed from a basic physiologically active agent and/or a salt thereof. These intermolecular forces differ from those observed in solutions in their working mechanism and strength ( forces of various types, for example, those not observed in solutions and those weaker than in solutions ). Presumably this difference serves to eliminate the above-mentioned problems. As is apparent from the foregoing, the medical plasters of this invention containing a basic medicine and/or a salt thereof possess a high releasability of active ingredient and a high percutaneous absorption, with no decline of the medicine content caused by its change with the passage of time. The following examples further illustrate the invention. The parts shown in these examples are all expressed on a weight basis. Preparative Example 1 In a four-necked flask were placed 55 parts of 2-ethylhexyl acrylate, 30 parts of methoxyethyl acrylate, 15 parts of vinyl acetate and 0.3 part of azobisisobutyronitrile. The mixture was heated to a temperature of 60 to 63°C in an inert gas atmosphere to start polymerization, the reaction was continued for ten hours while adjusting the temperature by dropwise addition of 125 parts ethyl acetate, and heating was further continued for two hours at a temperature of 75 to 80°C to complete the reaction, giving a solution of a pressure-sensitive adhesive. Preparative Example 2 In a four-necked flask were placed 95 parts of 2-ethylhexyl acrylate, 5 parts of acrylic acid and 0.2 part of bezoyl peroxide. The mixture was heated to a temperature of 62 to 65°C in an inert gas atmosphere to start polymerization, the reaction was continued for eight hours while adjusting the temperature by dropwise addition of 125 parts ethyl acetate, and heating was further continued for two hours at a temperature of 75 to 80°C to complete the reaction, giving a solution of a pressure-sensitive adhesive. Preparative Example 3 In a four-necked flask were placed 80 parts of isononyl acrylate, 15 parts of 1-vinyl-2-pyrrolidone, 5 parts of 2-hydroxyethyl methacrylate and 66.7 parts of ethyl acetate in an inert gas atmosphere, 0.2 part of azobisisobutyronitrile was added as polymerization initiator. The mixture was heated at a temperature of 62 to 65°C for seven hours with stirring while adjusting the temperature by dropwise addition of 190.4 parts ethyl acetate, and heating was further continued for three hours at a temperature of 75 to 80°C to complete the reaction, giving a solution of a pressure-sensitive adhesive. Preparative Example 4 Three kinds of polyisobutylenes ―― 35 parts VISTANEX MML-80 ( product of Exxon Chemicals Co. Ltd.; viscosity-average molecular weight: 990000 ), 15 parts HIMOL 4H ( product of Nippon Petrochemicals Co. Ltd.; viscosity-average molecular weight: 40000 ) and 50 parts HV-300 ( product of Nippon Petrochemicals Co. Ltd.; viscosity-average molecular weight: 1260 ) ― were dissolved in 50 parts toluene, giving a solution of a pressure-sensitive adhesive. Preparative Example 5 In a four-necked flask were placed 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid. 42.9 parts of ethyl acetate and 0.3 part of azobisisobutyronitrile were further added. The mixture was heated to 65°C in an inert gas atmosphere to start polymerization. The reaction was continued for 18 hours while maintaining the temperature at 65 to 67°C by addition of 107.1 parts ethyl acetate in small portions, and heating was further continued for ten hours at higher temperatures to complete the reaction, giving a solution of an acrylic pressure-sensitive adhesive. Preparative Example 6 VISTANEX MML-80 ( 25 parts ) and HIMOL-4H ( 75 parts ) were dissolved in hexane, giving a solution of a pressure-sensitive adhesive ( solid content: 25 wight % ). Examples 1 through 34, Comparative Examples 1 through 27 Plasters as listed in Tables 1 to 6 were prepared by using the copolymer solutions obtained in the above Preparative Examples 1 to 6. After adding each of the components to a copolymer solution in a prescribed amount, the resulting solution was coated on a polyester liner having a thickness of 75 µm and dried. The dried coating was transferred onto a support listed below. Examples 1-8, 29, 32-34, Comparative Examples 1-5, 23, 24, 27 --- polyester film, (9 µm thick) Examples 9-12, 21-28, 31, Comparative Examples 6-9, 19-22 --- polyethylene film, (30 µm thick) Examples 13-16, Comparative Examples 10-13 --- polyester film (9 µm thick) with ethylene-vinyl acetate copolymer film (20 µm thick) ( vinyl acetate content: 28 weight % ) laminated thereon ( transferred on the ethylene-vinyl acetate copolymer side ) Examples 17-20, Comparative Examples 14-18 --- polyester film(12 µm thick) Example 30, Comparative Examples 25,26 --- polyester film (6 µm thick) with ethylene-vinyl acetate copolyner film(50 µm thick ( vinyl acetate content: 28 weight % ) laminated thereon ( transferred on the ethylene-vinyl acetate copolymer side ) The characteristic features of the medicated plasters obtained in the above Examples and Comparative Examples are shown in Tables 1 to 6 and in Figures 1 to 9. The characteristics shown in Tables 1 to 6 and in Figures 1 to 9 were measured by the methods described below. Surface pH ( Tables 1 to 6 ) The plasters obtained in Examples 1 to 34 and in Comparative Examples 1 to 27 were each cut into a round piece of a diameter of 12 mm, the liner was then peeled off, 0.1 ml of distilled water was added dropwise to the exposed surface, and the pH of the applied water was measured until it came nearly to equilibrium ( when the pH value remained unchanged for at least 30 seconds ). The values shown in the tables are averages of four measurements. Release rate to the skin ( Tables 1 to 4, and 6 ) Round test pieces of a diameter of 30 mm prepared from the plasters obtained in Examples 1 to 20, 29 to 34 and in Comparative Examples 1 to 18, 23 to 27 were each put on the grained back of a rabbit for eight hours, the medicine left therein was measured by extraction with methanol, and the rate of apparent release based on the original content was calculated. The values shown in the tables are average of three measurements. Release rate to the skin ( Table 5 ) Test pieces of 35mm x 40mm in size prepared from the plasters obtained in Examples 21 to 28 and in Comparative Examples 19 to 22 were each put on a human back for 15 hours, the ifenprodil tartrate or ifenprodil left therein was measured by extraction with methanol, and the rate of apparent release based on the original content was calculated. The values shown in the tables are averages of three measurements. Concentration in rat plasma ( Figure 1 ) ( Dopamine hydrochloride ) The plaster obtained in Example 1 was cut into a test piece of such a size that the dose of dopamine hydrochloride was 1 mg per kg of rat body weight. The test piece thus prepared was put on the grained back of the rat and peeled off 24 hours later. Plasma samples were taken out 2, 4, 8, 24 and 30 hours after plaster application, and the medicine concentration in each sample was measured by the usual method. The values shown in Figure 1 are averages of three measurements. A similar test was carried out with the plaster obtained in Comparative Example 1, and the result obtained is also shown in Figure 1. ( Bunitrolol hydrochloride ) The plaster obtained in Example 9 was cut into a test piece of such a size that the dose of bunitrolol hydrochloride was 10 mg per kg rat body weight, and tested in the same way as dopamine hydrochloride. The result obtained is shown in Figure 1. A similar test was carried out with the plaster obtained in Comparative Example 6, and the result is also shown in Figure 1. ( Cinepazide maleate ) The plaster obtained in Example 13 was cut into a test piece of such a size that the dose of cinepazide maleate was 5 mg per kg rat body weight, and tested in the same way as dopamine hydrochloride. The result obtained is shown in Figure 1. A similar test was carried out with the plaster obtained in Comparative Example 10, and the result is also shown in Figure 1. ( Clomifene citrate ) The plaster obtained in Example 17 was cut into a test piece of such a size that the dose of clomifene citrate was 1 mg per kg rat body weight, and tested in the same way as dopamine hydrochloride. The result obtained is shown in Figure 1. A similar test was carried out with the plaster obtained in Comparative Example 14, and the result is also shown in Figure 1. Concentration in human plasma The plasters obtained in Examples 27 and 28 were cut into test pieces of such a size that the amount of medicine involved in each piece was 40 mg. The pieces were put on the upper part of human backs ( four subjects ), and the medicine concentration in plasma was measured by GC-MS 2, 8, 24, 36 and 48 hours later. The detection limit of this method is 200 pg per ml plasma. Figure 6 shows graphs illustrating the averages of measurements obtained. A similar test result obtained when commercial tablets ( active ingredient: 20 mg each ) were orally administered is also shown in Figure 6. Concentration in beagle plasma The plasters obtained in Examples 29, 30 and 33 and in Comparative Example 23 and 24 were cut into test pieces of such a size that the amount of medicine involved in each piece was 50 mg. The pieces thus prepared were put on grained beagle backs, and the concentration of metoprolol in plasma was measured by HPLC 2, 3, 4, 6, 9, 12, 15, 24, 36 and 48 hours later. Three beagles were used for each test group. The averages of measurements obtained are shown in Figure 8. Residue of active agent The plasters obtained in Examples 1 to 21, 29 to 34 and in Comparative Examples 1 to 18, 22 to 27 were stored at 50°C for one, two and three months, and then cut into round samples of a diamter of 30 mm. The amount of medicine left in each sample was measured by exctration with methanol or ethanol, and the residue based on the orignal content was calculated. The result obtained is shown in Figures 2 to 5, 7 and 9. The values in these figures are averages of two measurements. It is apparent from Figures 1 and 8 that the plasters obtained in the Examples show higher concentration in plasma and are stably stored for longer periods, compared with those of the Comparative Examples. Figure 6 also shows that the plasters obtained in Examples 27 and 28 show a higher concentration in plasma and are stably stored for longer periods, compared with commercial tablets. Figures 2 to 5, and 9 show that the plasters obtained in Examples are higher in their residue of involved medicine, compared with those of Comparative Examples 4, 5, 8, 9, 12, 13, 17, 18, 24 and 26 ( which show a high migration rate to the skin ), indicating a high stability in the pressure-sensitive adhesive layer. Figure 7 also shows that the plaster obtained in Example 21 is higher in its residue of involved medicine than that of Comparative Examples 22, indicating an enhanced stability in the pressure-sensitive adhesive layer.

Claims: A medicated plaster composed of a flexible support and a pressure-sensitive adhesive laminated thereon, said pressure-sensitive adhesive layer having an exposed surface with a pH in the range of from 7 to 11.5 and containing one of the following three components: (i) a basic physiologically active agent and an acidic substance, (ii) a salt of a basic physiologically active agent and a basic substance, and (iii) a basic physiologically active agent and a salt of a basic physiologically active agent. The medicated plaster of claim 1, wherein said pressure-sensitive adhesive layer is made of an acrylic pressure-sensitive adhesive. The medicated plaster of claim 2, wherein said acrylic pressure-sensitive adhesive is a copolymer of an alkyl (meth)acrylate and (meth)acrylic acid. The medicated plaster of claim 2, wherein said acrylic pressure-sensitive adhesive is a copolymer prepared from 50 to 99 weight % of an alkyl (meth)acrylate and 50 to 1 weight % of a copolymerizable monomer other than said alkyl (meth)acrylate. The medicated plaster of claim 2, wherein said acrylic pressure-sensitive adhesive is a copolymer of an alkyl (meth)acrylate, an alkyl (meth)acrylate containing at least one ether linkage in the molecule and a third copolymerizable monomer. The medicated plaster of claim 5, wherein said copolymerizable monomer is vinyl acetate. The medicated plaster of claim 5, wherein said acrylic pressure-sensitive adhesive is a copolymer prepared from 40 to 80 weight % of an alkyl (meth)acrylate, 59 to 10 weight % of an alkyl (meth)acrylate containing at least one ether linkage in the molecule and 1 to 40 weight % of a third copolymerizable monomer. The medicated plaster of claim 2, wherein said acrylic pressure-sensitive adhesive is a copolymer of an alkyl (meth)acrylate, a water-soluble monomer represented by the following general formula (I) and/or (II) and a third polar copolymerizable monomer: CH₂= CH-X (II) wherein R represents a hydrogen atom or a methyl group, and X represents a radical having at least one nitrogen atom, or nitrogen and oxygen atoms. The medicated plaster or claim 8, wherein said water-soluble monomer is vinylpyrrolidone. The medicated plaster of claim 8, wherein said polar monomer is hydroxyethyl (meth)acrylate. The medicated plaster of claim 8, wherein said acrylic pressure-sensitive adhesive is a copolymer prepared from 50 to 96 weight % of an alkyl (meth)acrylate, 4 to 50 weight % of said water-soluble monomer represented by the general formula (I) and/or (II) and 0 to 20 weight % of said third polar copolymerizable monomer. The medicated plaster of claim 1, wherein said basic physiologically active agent and/or said salt of a basic physiologically active agent contains at least one amino group in the molecule. The medicated plaster of claim 1, wherein said basic physiologically active agent and/or said salt of a basic physiologically active agent is contained in the pressure-sensitive adhesive layer in an amount of 20 to 5000 µg/cm². The medicated plaster of claim 1, wherein said acidic substance is an organic acid. The medicated plaster of claim 14, wherein said organic acid is an organic carboxylic acid. The medicated plaster of claim 15, wherein said organic carboxylic acid is at least one member selected from the group consisting of citric acid, succinic acid, tartaric acid, maleic acid, fumaric acid, benzoic acid, salicylic acid and lactic acid. The medicated plaster of claim 1, wherein said acidic substance is contained in an amount of 0.1 to 10 moles per mole of said basic physiologically active agent. The medicated plaster of claim 1, wherein the exposed surface of said pressure-sensitive adhesive layer has a pH in the range of from 7 to 9. The medicated plaster of claim 1, wherein said basic physiologically active agent and/or said salt of a basic physiologically active agent is at least one member selected from the group consisting of metoprolol, ifenprodil, dopamine, bunitrolol, cinepazide, clomifene, eperison, propranolol, enallapril, ketotiphen, lidocine and salts thereof.

Inventors: KINOSHITA TAKASHI C O NITTO DE, SUNAMI MASAKI C O NITTO DENKO, YAMANAKA AKIHITO C O NITTO DEN, KINOSHITA, TAKASHI, C/O NITTO DENKO CORPORATION, SUNAMI, MASAKI, C/O NITTO DENKO CORPORATION, YAMANAKA, AKIHITO, C/O NITTO DENKO CORPORATION
Applicants: NITTO DENKO CORP, NITTO DENKO CORPORATION
Application year: 1990
Main classification: A61L15
IPC codes: A61K9, A61L15