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|||||||||||III US00517696A United States Patent (19) 11 Patent Number: 5,176,916 Yamanaka et al. (45) Date of Patent: Jan. 5, 1993

02253 1/1985 Japan. (54) MEDICAL ADHESIVES 245.17 2/1986 Japan . (75) Inventors: Akihito Yamanaka; Saburo Otsuka; 221 121 10/1986 Japan . Yoshifumi Hosaka, all of Ibaraki, Primary Examiner-Thurman K. Page Japan Assistant Examiner-Leon R. Horne 73) Assignees: Nitto Electric Industrial Co., Ltd.; Attorney, Agent, or Firm-Sughrue, Mion, Zinn, Takeda Chemical Industries, Ltd., Macpeak & Seas Osaka, Japan 57) ABSTRACT 21 Appl. No.: 686,383 A medical adhesive comprising a plaster layer contain Apr. 17, 1991 ing the following ingredients, characterized in that the 22 Filed: ingredient (2) is incorporated in a larger amount than the (30) Foreign Application Priority Data ingredient 3. and in an amount not less than 25% by Apr. 18, 1990 (JP Japan ...... 2-104294 weight relative to the total amount of the ingredients C(S), and the plaster layer is a W/O type: 51) Int. Cl...... ------A61F 43/00 a medicinal ingredient, 52 U.S. Cl...... 424/448; 424/449 a hydrophobic polymer having a glass transition tem (58) Field of Search ...... 421/447, 448, 449, 443 perature (Tg) of -65 C. to 35° C. (56) References Cited (3) a percutaneous absorption-promoting agent, U.S. PATENT DOCUMENTS (4) water, and 4.455.146 6/1984 Noda et al...... 424/448 (5) a hydrophilic polymer which is soluble or capable of 4.732,808 3/1988 Krampe et al...... 424/448 Swelling in water; and 4,855, 42 8/1989 Fankhauser et al...... 424/43.4 a medical adhesive which comprises a porous base layer 4.93.905 4/1990 Fankhauser et al...... 424/449 in the plaster layer or in contact with the plaster layer, 4.946.853 8/1990 Bannon et al...... 424/449 which enable stable release of the medicinal ingredient, 4,983,396 1/1991 Boder et al...... 424/4.49 the percutaneous absorption-promoting agents and so FOREIGN PATENT DOCUMENTS on and sustaining of the pharmacological effects over a long period. 0209975 l/1987 European Pat. Off. . 0280737 9/1988 European Pat. Off. . O35900.4 3/1990 European Pat. Off. . 14 Claims, 2 Drawing Sheets

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7 5,176,916 1. 2 This invention relates to an improvement of the adhe MEDICAL ADHESIVES sives using water as a solubilizer as mentioned above. The present invention provides a medical adhesive BACKGROUND OF THE INVENTION exhibiting excellent release and percutaneous absorp This invention relates to a medical adhesive which is 5 tion of the medicinal ingredient, which comprises a base excellent in terms of release and percutaneous and per mainly consisting of a hydrophobic polymer, an effec mucosa (hereinafter when referred to as percutaneous. tive amount of a medicinal ingredient of low solubility the term includes per mucosa unless otherwise speci in said hydrophobic polymer or poor in release from fied) absorption of medicinal ingredients from a prepa said hydrophobic polymer and an effective amount of ration. Ease of producibility and stability of the prepara O percutaneous absorption-promoting agents which are tion are also maintained. admixed with or dispersed throughout said base. For A wide variety of preparations have been developed the purpose of obtaining such an adhesive, a solubilizer as adhesives for topical applications. In recent years, for the medicinal ingredient is normally required. The effective amounts of medicinal ingredients are percutaneous administration has drawn attention as an 15 efficient administration route for of medicines, and generally determined primarily on the basis of the re some adhesives for systemic actions, for example, prep sults of initial studies of physical properties, pharmaco arations of nitroglycerin, isosorbide dinitrate, scopola logical effects, effective concentration in blood and the mine, and estradioi are marketed. Most of the like of the medicinal ingredients, and the effective medicinal ingredients of these marketed preparations amounts are not in general determined taking account are suitable for percutaneous absorption in view of their 20 of the forms and usability of the preparations. This physical properties and levels of effective concentration results in a problem that a stable preparation which in blood. and are relatively easily formed into prepara exhibits the expected pharmacological effect cannot be tions. necessarily obtained in many cases only by incorporat However, medicinal ingredients consisting of hydro 25 ing and mixing an effective amount of said medicinal philic compounds in the form of salts or the like are ingredients, an effective amount of percutaneous ab generally difficult to absorb percutaneously, and even Sorption-promoting agents and the other ingredients. release of the medicinal ingredients from the prepara In the present invention, for example, at least one tions is often difficult in matrix type adhesives in which percutaneous absorption-promoting agent is used. Per the medicinal ingredients are incorporated or dispersed cutaneous absorption-promoting agents are generally in polymers having relatively high hydrophobicity 30 classified into two types, hydrophobic absorption-pro which are in wide use as the bases for adhesives. moting agents and hydrophilic absorption-promoting As one of the means for improving absorbability of agents as mentioned below, and they are normally used medicinal ingredients in such cases release from the Solely or in combination. In some cases, poor compati preparations or percutaneous absorbability of the me 35 bility of the percutaneous absorption-promoting agents dicinal ingredients may be enhanced by increasing the with solubilizers for medicinal ingredients or hydropho fat-solubility of the medicinal ingredients themselves. bic polymers, gives rise to separation of the ingredients For example, the medicinal ingredients may be used during the course of production of the preparations or which have been in advance converted into their free with the lapse of days after production, which results in bases in the base of the preparation; or free bases of the 40 failure to provide the desired adhesives. medicinal ingredients may be formed in the preparation. Below, examples of the combination where compati As another means of improvement, incorporation of bility is poor are given, including the above case. percutaneous absorption-promoting agents may be em a) a hydrophobic absorption-promoting agent and a ployed. Active studies have recently been made of ab hydrophilic absorption-promoting agent; sorption-promoting agents, and a number of absorption 45 b) a hydrophobic absorption-promoting agent and a promoting agents have been reported. Many examples solubilizer for medicinal ingredients; of the adhesives containing absorption-promoting c) a hydrophobic polymer or a solution thereof in an agents are described in, for example, unexamined Japa organic solvent and a hydrophilic absorption-pro nese Patent Application Nos. 24517/1986 and moting agent; and 221 121/1986. However, the solubility of the medicinal 50 d) a hydrophobic polymer or a solution thereof in an ingredients in the base, release thereof from the base, or organic solvent and a solubilizer for medicinal ingre percutaneous absorbability of such adhesives are not dients. satisfactory. As mentioned above, compatibility of each compo For the preparations in which the afore-mentioned nent is critical to feasibility of the preparations for those medicinal ingredients having relatively high hydrophi 55 containing multiple components, and when components licity are incorporated in bases mainly consisting of a of the preparation have poor compatibility, the prepara hydrophobic polymer to exhibit solubility, release and tion lacks stability. percutaneous absorbability of the medicinal ingredients as expected, solubilizers for the medicinal ingredients SUMMARY OF THE INVENTION are normally necessary. As a solubilizer for medicinal 60 An object of the present invention is to provide an ingredients, water is generally selected in view of its adhesive comprising a base mainly composed of a hy low stimulus against the skin. As the examples of such drophobic polymer, in which a medicinal ingredient adhesives in which water is used as a solubilizer, men which is difficult to absorb percutaneously; for exam tion can be made of the adhesives as described in unex ple, a medicinal ingredient having relatively high hy amined Japanese Patent Publication No. 02253/1985, 65 drophilicity, is incorporated and water as a solubilizer is wherein no absorption-promoting agent is contained, further contained, and having satisfactory solubility, permitting relatively easy provision of stable plaster release properties and percutaneous absorption of the layers. medicinal ingredients. 5,176,916 3 4. Another object of the present invention is to provide W/O (water in oil) type or O/W (oil in water) type, and an adhesive as mentioned above which exhibits excel other types. To obtain an adhesive to satisfy the objects lent stability as a preparation and is easily produced. of the present invention in that the adhesive contains The inventors of the present invention have made water. has high shape-retention property and excellent intensive studies for the purpose of solving the before 5 stability during the storage thereof and remains stable mentioned problems, and as a result, obtained the fol during the period from administration to removal lowing findings. thereof, it is required that a hydrophobic polymer, Water used as a solubilizer is inferior in compatibility which is a continuous phase, namely a W/O type, is with a hydrophobic polymer, and use of a large amount selected for the base. of water makes uniform mixture difficult. The present O Hereinbelow, the invention is described in detail. inventors have found that the steps of () incorporating There is no limitation on the medicinal ingredient a hydrophilic polymer which is solubie or capable of (ingredient()) to be used for the present invention as long swelling in water for increasing viscosity of a solution as it can display the expected actions through percutan and (2) mixing the solution with a solution of a hydro eous administration. Especially desirable are the drugs 1 phobic polymer in an organic solvent, followed by 5 g of or 1 ml of which can be dissolved in an amount of homogeneous dispersion suppress separation among the less than 10,000 ml, particularly less than 1,000 ml (most respective components in the obtained applicable solu preferably less than 100 ml) of water. Such drugs which tion or the plaster layer obtained by drying same, even come to have the above-mentioned solubility in water if a large amount of water is incorporated, and sufficient as a result of concomitance with an acid or a base are solubility, release and percutaneous absorbability of the 20 medicinal ingredients can be attained. Moreover, the also useful in the present invention. The medicinal in inventors have found that a preparation of particularly gredients preferably have a molecular weight of stable systems can be obtained by incorporating the 50-1,000, more preferably 100-500, hydrophobic polymer as the main component of the More specific examples of such drugs are as follows: base in a proportion of not less than 25% by weight 25 1 general anesthetics relative to the total amount of the below-mentioned barbiturate: thiamylal sodium, thiopental sodium, ingredients - (5) excluding the organic solvent of the pentobarbital sodium. etc.: hydrophobic polymer and further making the plaster other miscellanea; hydrochloride, etc. layer of the finished adhesive a W/O type. 2) hypnotics and sedatives The present invention has been completed on the 30 drugs: flurazepam hydrochloride, basis of the foregoing findings and is summarized as etC, follows: barbiturate drugs: amobarbital sodium, phenobarbi (1) A medical adhesive comprising a plaster layer con tal, pentobarbital calcium, etc.: taining the following ingredients, characterized in other miscellanea: bromovalerylurea, chloral hy that the ingredient is incorporated in a larger amouf drate, etc.; than the ingredient 5) and in an amount not less than 3) antiepileptics 25% by weight relative to the total amount of the hydantoin drugs: phenytoin sodium, ethotoin, etc.; ingredients (1) - (5), and the plaster layer is a w/O type: barbiturate drugs: phenobarbital Sodium, etc.; a medicinal ingredient, other miscellanea: trimethadione, primidone, etho 2) a hydrophobic polymer having a glass transition) Suximide, , sodium valproate, etc.; temperature (Tg) of -65 C. to 35° C., (4) antipyretics, analgesics and antiinflammatory agents (3) a percutaneous absorption-promoting agent, aniline derivative drugs: acetaminophen, phenacetin, (4) water, and etc.; (5) a hydrophilic polymer which is soluble or capable of Salicylic acid drugs: aspirin, sodium salicylate, etc.; swelling in water; and 45 pyrazolone drugs: aminopyrine, antipyrine, sulpy (2) a medical adhesive as described in (l), which com rine, etc.; prises a porous base layer in the plaster layer or in basic inflammatory drugs: mepirizole, tiaramide hy contact with the plaster layer. drochloride, perixazole citrate, etc.; In the adhesive according to the present invention, other miscellanea; diclofenac sodium, anfenac so water is incorporated as a solubilizer in an amount nec 50 dium, buprenorphine hydrochloride, butorphanol essary for making the plaster layer a W/O type. tartrate, eptazocine hydrobromide, etc.; 5 agents for dizziness BRIEF DESCRIPTION OF THE DRAWINGS , difenidol hydrochloride, di-iso FIG. 1 is a graph showing the change in concentra prenaline hydrochloride, etc.; tion in blood of the medicinal ingredient in each adhe- 55 (6) psychotropic drugs SWe, drugs: hydrochloride, FIGS. 2-4 are cross sectional views of the adhesives maleate, hydrochlo of the present invention having a porous base layer, ride, hydrochloride, etc.; wherein 1 is a plaster layer, 2 is a backing layer, 3 is a drugs of phenothiazine-like structures: thiothixene, porous base layer and 4 is a separate liner. 60 flupenthixol hydrochloride, etc.; butyrophenone drugs: floropipamide hydrochloride, DETALED DESCRIPTION OF THE moperone hydrochloride, etc.; INVENTION drugs: carpipramine hydrochloride, As percutaneously absorbable preparations contain hydrochloride, etc.; ing water, for example, ointments, cream preparations, 65 : hydrochloride, lotions, liquid preparations, suspensions, emulsions may hydrochloride, etc.: be used, besides adhesives. These preparations can be antidepressants: hydrochloride, classified into solution types, dispersion types such as hydrochloride, etc.; 5,176,916 5 6 benzodiazepine drugs: chlordiazepoxide hydrochlo hydrochloride. hydro ride. dipotassium clorazepate, etc.; chloride, etc.: other miscellanea; meprobamate, hydro 18 coronary vasodilators chloride. saflazine hydrochloride, etc.: diltiazem hydrochloride. Varapamil hydrochloride, 7 local anesthetics 5 isosorbide dinitrate, nicorandil. etc.: aminobenzoic acid alkamine ester drugs: tetracaine 19 peripheral vasodilators hydrochloride, procaine hydrochloride, etc.: nicametate citrate, nicotinic- tart rate, tolazo other miscellanea: ethyl aminobenzoate, dibucaine line hydrochloride, etc.: hydrochloride, lidocaine hydrochloride, etc.; 20 drugs for arteriosderosis 8 skeletal muscle relaxants 10 simfibrate, etc.: drugs: chlorphenesin carbamate, metho 21 other drugs for circulatory organs carbamol, etc.: nicardipine hydrochloride, ifenprodil tartrate, alkaloid drugs: alcuronium chloride, tubocurarine piperidinocarbamate, cinepazide maleate, thiapride chloride, etc.: hydrochloride, etc.: other miscellanea: suxamethonium chloride, eperi 5 22) respiratory agents sone hydrochloride, etc.; dimorpholamine drugs: dimorpholamine, levallor 9 autonomic nerve drugs phan tart rate. etc.; drugs; chloride, etc.: other miscellanea; lobeline hydrochloride, naloxone inhibitor: bromide, etc.: hydrochloride, etc.; 10 antispasmodics 20 23) antitussives, expectorants blocker: sulfate, hydro central antitussives: codeine phosphate, dextrometh bromide, etc.: orphan hydrobromide, etc.: other miscellanea: papaverine hydrochloride, etc.; other antitussives: noscapine hydrochloride, etc.; 1 l) drugs for Parkinson's desease expectorants: bromhexine hydrochloride, am hydrochloride, hydrochlo broxol hydrochloride, etc.; ride, hydrochloride, hy derivatives: theophylline, diprophylline, drochloride, hydrochloride. levo etc.; sympathetic nerve-stimulants; d)-epinephrine dopa, hydrochloride, etc.; hydrochloride hydrochloride, isoprote 12) antihistaminics ethanolamine compounds: hydro 30 renol sulfate, hydrochlo chloride, maleate, etc.; ride, etc.; - monoamine compounds: d-chlorpheniramine male anti-allergic drugs: fumarate, hy ate, etc.; phenothiazine compounds: , drochloride, etc.: tart rate, etc.: other miscellanea: , etc.; other miscellanea: hydrochloride, clemi 35 24) hormone drugs hydrocortisone, dexamethasone zole hydrochloride, hydrochlo Sodium phosphate, prednisolone, norethisterone, clo ride, fumarate, etc.; miphene citrate, etc.; 13) cardiacs 25 external drugs for suppurative diseases xanthine derivatives: aminophylline, choline theoph Sulfa drugs: mafenide acetate, sulfamethoxazole so ylline, and sodium benzoate, etc.; 40 dium, etc.; antibiotics: tetracycline hydrochloride, sympathomimetic agents: dl-isoproterenol hydro etc.; chloride, hydrochloride, 26) analagenic, antipruritic, astringent antiinflamma hydrochloride, etc.; other miscellanea; methyl tory drugs methyl salicylate, isothipendyl hydrochlo digoxin, etc.; ride, diphenhydramine, prednisolone, ethyl amino 14) antiarrhythmics benzoate, crotamiton, etc.: (3-blockers: hydrochloride, 27 drugs for parasitic dermal diseases hydrochloride, hydrochloride, Salicylic acid, nystatin, econazole nitrate, cloconazole maleate, tart rate, etc.; hydrochloride, etc.; other miscellanea: procainamide hydrochloride, lido 28 vitamins caine hydrochloride, sulfate, ajmaline, 50 vitamin B1: thiamine hydrochloride, cycothiamine verapamil hydrochloride, aprindine hydrochlo hydrochloride, etc.; ride, etc.; vitamin B2: riboflavin, riboflavin sodium phosphate, 15) diuretics etc.; thiazide drugs: ethiazide, hydrochlorothiazide, etc.; vitamin B6: pyridoxine hydrochloride, pyridoxal other miscellanea: acetazolamide, isosorbide, etha 55 phosphate, pyridoxamine phosphate, etc.; crynic acid, etc.; other miscellanea: nicotinic acid, nicotinamide, cal 16 antihypertensives cium pantothenate, pantothenol, panthetin, biotin, ACE inhibitor drugs: captopril, enalapril maleate, ascorbic acid, etc.; delapril hydrochloride, alacepril, (R)-3-(S)-1-car 29 hemostatic drugs boxy-5-(4-piperidyl) pentyl)amino-4-oxo-2,3,4,5- 60 tranexamic acid, ethamsylate, protamine sulfate, etc.; tetrahydro-1,5-benzothiazepine-5-acetic acid, etc.; 30 drugs for treatment of gout hydralazine drugs: ecarazine hydrochloride, hydrala colchicine, allopurinol zine hydrochloride, etc.; (31) antidiabetics other miscellanea: hexamethonium bromide, cloni tolazamide, glymidine sodium, glybuzole, metofor dine hydrochloride, hydrochloride, pro 65 min hydrochloride, buformin hydrochloride, etc.; pranolol hydrochloride, , guanethidine (32) miscellaneous metabolic drugs sulfate, bethanidine sulfate, etc.; orotic acid, azathioprine, lactulose, etc.; 17 vasoconstrictors 33) antineoplastic agents 5,176,916 7 8 alkylating drugs: nitrogen mustard N-oxide hydro ene gums, polyisoprene gums and styrene-butadiene chloride, cyclophophamide, thio-TEPA. nimustine (or-isoprene)-styrene block copolymer guns; poly viny hydrochloride. etc.: antimetabolite drugs: thioino lalkyl ether-type polymers: vinyl-type polymers such as sine, fluorouracil, tegafur, etc.; poly vinyl-acetate and poly vinyl-propionate; and poly plant alkaloids: vinblastine sulfate, vincristine sulfate. urethane elastic bodies may be used in the present in vindesline sulfate, etc.: vention. carcinostatic antibiatics: mitomycin C, daunorubicin Among those, particularly preferred are pressure hydrochloride, aclarubicin hydrochloride, etc.: sensitive adhesive acryl-type copolymers for adhesivity other miscellanea: procarbazine hydrochloride, cis to the skin. Examples of preferred polymers include one platin, etc.; O polymer or two or more polymers of alkyl esters of 34) antibiotics (meth)acrylic acid such as butyl (meth)acrylate, pentyl natural penicillins: benzylpenicillin potassium, etc.: (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)a- semisynthetic penicillins: amoxicillin, amplicillin, crylate, octyl (meth)acrylate, nonyl (meth)acrylate, etc.: decyl (meth)acrylate, undecy (meth)acrylate, dodecyl caphems; cefalexin, cefazolin sodium, etc.: 5 (meth)acrylate and tridecyl (meth)acrylate, or copoly macrollides: erythromycin, kitasamycin tart rate, etc.; mers of one or more species of said esters with a mono chloramphenicols: chloramphenicol, thiamphenicol, mer copolymerizable therewith. etC. Examples of the copolymerizable monomers include tetracycline types: tetracycline hydrochloride, mino functional monomers exemplified by carboxyl group cycline hydrochloride, etc.; 20 containing monomers such as (meth)acrylic acid, ita incomycins: lincomycin hydrochloride, clindamycin conic acid, crotonic acid, maleic acid, maleic anhydride hydrochloride. etc.; and fumaric acid sulfoxyl group-containing monomers aminoglycosides: streptomycin sulfate, kanamycin such as styrenesulfonic acid, allylsulfonic acid, sulfo sulfate, fradiomycin sulfate, gentamycin sulfate, propylacrylate, (meth)acryloyloxynaphthalenesulfonic etC. acid, acrylamidemethylpropanesulfonic acid and other miscellanea: spectinomycin hydrochloride, cy acryloxyloxybenzenesulfonic acid; hydroxyl group closerine, etc.: containing monomers such as hydroxyethyl (meth)a- 35) chemotherapeutic drugs crylate and hydroxypropyl (meth)acrylate; amido sulfisomidine, isoniazid, ethambutol. acyclovin, etc.; group-containing acrylic-type monomers such as (meth 36 narcotics 30 )acrylamide, dimethyl(meth)acrylamide, N-butyla analkaloid drugs: morphine hydrochloride, codeine crylamide, tetramethylbutylacrylate and N-methylol (- phosphate, etc.: meth)acrylamide; alkylaminoalkyl group-containing cocaalkaloid drugs: cocaine hydrochloride. etc.: acrylic-type monomers such as aminoethyl (meth)acry synthetic narcotics: , fentanyl citrate, etc.: late, dimethylaminoethyl (meth)acrylate, diethylamino While the amount of the medicinal ingredient to be ethyl (meth)acrylate and tert-butyl (meth)acrylate, ; incorporated in the present invention is not particularly ether linkage-containing alkyl ester of acrylic acid such limited provided that the medicinal ingredient displays as methoxyethyl (meth)acrylate, ethoxyethyl (meth)a- the desired pharmacological effects, the preferred crylate, butoxyethyl (neth)acrylate, tetrahydrofurfuryl amount is in the range from 0.1 to 50% by weight rela (meth)acrylate, methoxydiethylene glycol (meth)acry tive to the weight of the plaster in which the medicinal 40 late, methoxydiethylene glycol (meth)acrylate and me ingredient is contained, more preferably from 1 to 30% thoxypolypropylene glycol (meth)acrylate; vinyl-type by weight, and is in the range from 20 to 5,000 ug/cm monomers such as N-(meth)acryloylamino acid and per unit area, preferably from 100 to 3,000ug/cm. acrylic-type monomers such as urethane, urea and iso The hydrophobic polymer (ingredient ) to be used in cyanate esters of acrylic acid, and vinyl-type monomers the present invention is the main ingredient constituting 45 exemplified by (meth)acrylonitrile, vinyl acetate, vinyl the continuous phase of the W/O type plaster, which propionate, vinyl pyrrolidone, vinyl pyridine, vinyl contains a medicinal ingredient, percutaneous absorp pyrazine, vinyl piperazine, vinyl piperadone, vinyl py tion-promoting agents, water and a hydrophilic poly rimidine, vinyl pyrrole, vinyl imidazole, vinyl caprolac mer. The hydrophobic polymer is not limited provided tam, vinyl oxazole, vinyl thiazole, vinyl morpholine, that it is capable of imparting the objective adhesives 50 styrene, a-methylstyrene and bis(N,N'-dimethylamino with adhesion to the skin and acting for shape-retention ethylmaleate. of the adhesives. It is extremely important not to lose The afore-mentioned alkyl esters of (meth)acrylic shape-retention in view of the fact that it is difficult for acid and copolymerizable monomers in the present the adhesives of the present invention containing water invention include a variety of isomers in which the alkyl to retain shape. 55 moiety is straight chain or branched chain, and various It is necessary that the hydrophobic polymer is incor isomers which have substituents at different positions, porated in an amount of not less than 25% by weight and their derivatives. relative to the total amount of the ingredients GD , pref. The proportion of the above alkyl ester of (meth)a- erably 25-80% by weight. Where the hydrophobic crylic acid to the copolymerizable monomer in the polymer is incorporated in an amount of less than 25% 60 pressure-sensitive adhesive acryl-type copolymers is by weight, it fails to contain and to retain the other preferably in the range of 50-99/1-50 by weight, which ingredients, especially percutaneous absorption-pro results in a balance of aggregation properties and ad moting agents which are in a liquid form at room tem hesivity to the skin. perature, and water stably, resulting in failure to main Among the above hydrophobic polymers, preferred tain its shape-retention. 65 are polymers having a lower skin-stimulus and excellent As the hydrophobic polymers, pressure-sensitive ad solubility for the drugs, especially copolymers of (meth hesive polymers exemplified by acrylic-type polymers; )acrylic acid alkyl esters, (meth)acrylic acid alkyl esters gum-type polymers such as silicone gums, polyisobutyl containing ether linkage in the molecule and the other 5,176,916 9 10 copolymerizable monomers other set forth above. In Among the aliphatic carboxylic acids, lower alcohol this case, the proportion of the (meth)acrylic acid alkyl esters of the aliphatic carboxylic acids and the aliphatic esters, the (meth)acrylic acid alkyl esters containing alcohols, preferred are lower (C1-5) alcohol esters of the ether linkage in the molecule and the copolymerizable aliphatic monocarboxylic acids, most preferably isopro monomers other than these is in the range of 40-80/- 5 pyl myristate. 59-10/I-40, As the hydrophilic absorption-promoting agents, In cases where the above hydrophobic polymers are mention can be made of, for example, alkanepolyols. likely to leave a paste on the applied site of the skin As the alkanepolyols. for example, lower alkanediols upon removal due to the shortage of aggregation having 2-5 carbon atoms such as ethylene glycol (1,2- strength, and cause soiling on the skin, it is preferable to 10 ethanol), propylene glycol (1,2-propanediol), 1,3- subject the composition to an appropriate chemical propanediol, 1,2-butanediol, 1,3-butanediol, 1,4- crosslinking treatment (copolymerization of the mono butanediol, 2,3-butanediol and 1,5-pentanediol, and mers having crosslinking properties, further addition of lower alkanetriols having 2-5 carbon atoms of glycerine a crosslinking agent, etc.) or physical crosslinking treat may be utilized. Among others, particularly preferred ment (radiation of radioactive rays such as electronic 15 are propylene glycol and 1,3-butanediol. rays causing electrolytic dissociation, crosslinking by Two or more species of the above-mentioned percu ultraviolet rays, etc.) to a degree not impairing the ad taneous absorption-promoting agents can be used in hesive properties. combination, and hydrophobic absorption-promoting In the present invention, the above-mentioned hydro agents and hydrophilic absorption-promoting agents phobic polymers have a glass transition temperature 20 may be used in combination. (Tg) ranging from -65 C. to 35° C., preferably -50 While the amount of the absorption-promoting agents C. to O C. is optional, the preferred total amount is in the range The percutaneous absorption-promoting agents (in from 0.1 to 80% by weight, more preferably from 1 to gredient (3)) to be used in the present invention can be 50% by weight. defined, in brief, as materials which promote release of 25 In the present invention, water (ingredient (4)) is essen the medicinal ingredients from the composition and/or tially incorporated as a solubilizer for the medicinal migration of the medicinal ingredients into the body, ingredients. Examples of these agents include a wide variety of Water is especially selected as an ingredient for the substances improving solubility or dispersibility of the adhesive compositions of the present invention owing medicinal ingredients in the plaster layer, skin keratin 30 to the following advantageous properties set forth be emollient properties and permeation of drugs into skin low. keratin, auxiliaries for permeation of drugs into skin 1) It is a bio-component. keratin, agents for dilation of pores of the skin, Sub 2) It, as a solubilizer, gives a lower stimulus to the skin. stances for changing the surface conditions and the like. 3) It is easy to adjust the pH of the plaster layer to be These percutaneous absorption-promoting agents are 35 brought into contact with the skin to nearly neutral generally classified into hydrophobic absorption-pro by addition of a small amount of inorganic substances. moting agents and hydrophilic absorption-promoting 4) It is less reactive to medicinal ingredients and thus agents. Examples of the hydrophobic absorption-pro able to retain medicinal ingredients stably in the prep moting agents include aliphatic carboxylic acids having aration. 6-20 carbon atoms, preferably 10-20 carbon atoms, 40 5) It eliminates individual differences in the water con their lower alcohol esters, and-aliphatic alcohols having tent of the skin, to enable the adhesives to exhibit 6-20 carbon atoms, preferably 10-20 carbon atoms. pharmacological effects with little variation resulting As the aliphatic carboxylic acids having 6–20 carbon from individual skin differences. atoms, for example, saturated or unsaturated aliphatic Examples of water-containing percutaneously ab monocarboxylic or dicarboxylic acids such as caproic 45 sorbable preparations include ointments, creams, lo acid, caprylic acid, lauric acid, myristic acid, palmitic tions, liquid preparations, suspensions and emulsions acid, stearic acid, arachic acid, obtusilic acid, linderic besides adhesives, which are classified into solution acid, oleic acid, linoleic acid, linolenic acid, arachidonic types and dispersion types exemplified by W/O types acid may be used in the present invention and sebacic (water in oil) and O/W types (oil in water). In order to acid. As the lower alcohol esters of the aliphatic carbox 50 obtain an adhesive containing water, having a high ylic acids having 6-20 carbon atoms, mention can be shape-retention, and excellent in stability not only dur made of, for example, esters of lower alcohol having ing storage but also during the period from administra about 1-5 carbon atoms (e.g. methanol, ethanol, propa tion to removal, which meets the objects of the inven nol, 2-propanol, butanol, pentanol) and the afore-men tion, a hydrophobic polymer which is a continuous tioned aliphatic acids having 6-20 carbon atoms. As the 55 phase, namely, a W/O type, should be selected as a lower alcohol esters of the aliphatic dicarboxylic acids, base. for example, mono- or diester in which one of the car The amount of water to be incorporated is not limited boxyl groups or two of the carboxyl groups thereof as long as it enables the plaster layer to be a W/O type. is(are) esterified may be used. Specific examples of the Not all the medicinal ingredients to be incorporated lower alcohol esters of the aliphatic carboxylic acids 60 need be dissolved in water. That is, a part of the medici having 6-20 carbon atoms include diesters of sebacinic nal ingredients may remain solid in the plaster layer. acid, isopropyl esters of myristic acid, etc. The particularly preferred amount of water is in the As the before-mentioned aliphatic alcohols having range of from 1 to 20% by weight by water content of 6-20 carbon atoms, for example, Saturated or unSatu the plaster layer. If the water content of the plaster rated aliphatic alcohols such as caproyl alcohols, capry 65 layer is less than 1% by weight, release of the medicinal lyl alcohols, capryl alcohols, lauryl alcohols, myristyl ingredients from the preparation tends to be poor, lead alcohols, cetyl alcohols, stearyl alcohols, oleyl alcohols, ing to failure to exhibit expected medicinal effects. On linoleyl alcohols may be used and linolenyl alcohols. the other hand, if the water content is over 20% by 5,176,916 11 12 weight, containing and retaining the medicinal ingredi ylene sorbitan monolaurate, etc.), esters of polyoxyeth ents and percutaneous absorption-promoting agents as yiene sorbitol fatty acid (e.g. polyoxyethylene sorbitol well as water stably in the plaster layer for long periods monolaurate, etc.). esters of polyoxyethylene fatty acid tends to be difficult. (e.g. polyoxyethylene stearate, etc.), polyoxyethylene In the present invention, a solubilizer may be incorpo 5 higher alcohol ethers (e.g. polyoxyethylene lauryl alco rated as an ingredient of the plaster layer, so the medici hol, polyoxyethylene oleyl alcohol, etc.), polyoxyethyl nal ingredient is dissolved more completely in water. As ene alkylaryl ethers (e.g. polyoxyethylene nonyl phe the solubilizers, acidic or basic, inorganic or organic nol, etc.), polyoxyethylene castor oil derivatives (e.g. substances may be used. Examples of the inorganic polyoxyethylene hydrogenated castor oil derivatives acidic substances include hydrochloric acid, sulfuric 10 such as HCO-50, HCO-60, etc.), polyoxyethylenelano acid, nitric acid and phosphoric acid. Examples of the lin alcohol derivatives and block polymer type nonionic organic acidic substances include acetic acid, lactic surfactants (e.g. pluronic, L-62, L-64, F-68, etc.) may be acid, maleic acid, citric acid, succinic acid and tartaric used. While the amount of the nonionic surfactant to be acid. Examples of the inorganic basic substances include incorporated can be optionally selected as a whole pro sodium hydroxide, potassium hydroxide, sodium car vided that HLB is maintained in the range of 5 to 20, it bonate, potassium carbonate, sodium hydrogencarbon is preferably about 0.5-20% by weight, more preferably ate and potassium hydrogencarbonate. Examples of the about 0.5-10% by weight, most preferably about 1-8% organic basic substances include amines such as trietha by weight. nolamine, diethanolamine, triisopropanolamine, diiso The adhesives of the present inventin can be pro propanolamine, etc., and amino acids such as L-argi 20 duced by known means except the process for drying nine. the plaster layer. Drying of the plaster layer is prefera The solubilizers are added to dissolve the medicinal bly conducted so the water content of the plaster layer ingredients in an optional proportion in the plaster after drying amounts to 1-20% by weight, and there layer, and while the amount of the solubilizers to be fore, the drying is conducted at a temperature lower added is dependent upon the amount of a drug to be 25 than that in the conventional drying of the plaster lay incorporated, it is preferably in the range of 0.01 to 30% ers, for a shorter time, for example, at 65-75 C. for by weight, more preferably in the range of 0.1 to 20% about 1-5 minutes. by weight. The plaster layer may contain a trace amount of sol The hydrophilic polymer (ingredient(5)) is a polymer vent from the solution of the adherent compositions. which is soluble or capable of swelling in water, and it 30 In case where the plaster layer is likely to leave a is incorporated to increase the viscosity of water and, in paste on the applied site of the skin upon removal due to some cases, that of the hydrophilic percutaneous ab the shortage of aggregation strength caused by water, sorption-promoting agents, thereby retaining these in percutaneous absorption-promoting agents and a large gredients stably in the plaster layer. Such hydrophilic amount of the other liquid components contained in the polymers include, for example, water-soluble polymers 35 plaster layer induces plasticization of the hydrophobic and water-aborbing polymers. polymers, and deposit soil on the skin, it is preferable to As the water-soluble polymers, natural water-soluble place a porous base layer in the plaster layer or in polymers such as starch types, pullulan types, cellulose contact with the plaster layer. types, tannin types, lignin types, alginic acid, gum ara While there is no particular limitation on the porous bic, gum guar, gum tragacanth and gelatin, and Syn 40 base layer as long as it does not interfere with free diffu thetic polymers such as polyvinyl alcohol types, polyvi sion and migration throughout the plaster layer and nyl ethyleneoxide types, acrylic acid types, maleic an release toward the surface of the skin of the medicinal hydride types, phthalic acid types, acrylamide types, ingredients, percutaneous absorption-promoting agents, polyvinyl pyrrollidones, polyamines, polyelectrolytes, water and the other ingredients, it is also possible to urea types and melamine types may be used in the pres permit the porous base layer to control the above-men ent invention. tioned phenomena. As the water-absorbing polymers, preferred are poly Examples of the porous base layers include sheet mers capable of absorbing water in at least, preferably bases such as non-woven fabrics, woven fabrics, Japa about 50–2,000 times amount their own weight. These nese paper, porous films, pierced films, or the like. compounds include, for example, vinyl acetate-acrylic 50 The thickness of the porous base layer is preferably acid ester copolymer suspensions, polyacrylic acid salt less than that of the plaster layer when the porous base types, polyvinyl alcohol-maleic anhydride crosslinked layer is placed in the plaster layer. A thick porous base copolymers, isobutylene-maleic acid crosslinked co layer may be used as long as release of the medicinal polymers, polyacrylonitrile graft polymer suspensions ingredients is not adversely affected. and starch-acrylic acid graft polymers. 55 When a porous base layer placed in the plaster layer The amount of these hydrophilic polymers to be used is thinner than the plaster layer, three different embodi in the present invention is not particularly limited as ments of preparation constitutions are generally con long as it does not surpass the amount of the hydropho templated depending on the positions of the porous base bic polymer (ingredient (2)), and is preferably in the range layer. That is, (I) an embodiment in which a porous base of about 0.1 to 15% by weight, more preferably about 60 layer 3 is placed in contact with a backing layer 2 on the 0.2 to 5% by weight. side toward the backing layer 2 of a plaster layer 1 The percutaneous preparations of the present inven (FIG. 2), (II) an embodiment in which the porous base tion may incorporate nonionic surfactants to enable layer 3 is placed in contact with the separate-type liner uniform mixing of the respective ingredients, 4 on the side toward a separate-type liner 4 of the plas As the nonionic surfactants, esters of polyoxyethyl ter layer 1 (FIG. 3) and (III) an embodiment in which ene sorbitan fatty acid (e.g. polyoxyethylene sorbitan the porous base layer 3 is placed out of contact with the monooleate, polyoxyethylene sorbitan monostearate, backing layer 2 and the separate-type liner 4 in the polyoxyethylene sorbitan monopalmitate, polyoxyeth plaster layer 1 (FIG. 4). In all of the above-mentioned 5,176,916 13 14 embodiments, the plaster may be embedded in the po a backing layer with the non-woven fabric sheet made rous base layer, whereby aggregation strength is en of polyester laminated thereon at the basis weight of 40 hanced with that of the plaster perse unchanged. In the g/m2 to obtain a medical adhesive of the present inven above embodiments (II) and (III), the plasters are not tion. necessarily required to be embedded in the porous base 5 layers, and the ingredients of the plaster migrate EXAMPLE 2 through the porous base layer due to capillarity. In the same manner as in Example I except that 2 Among the embodiments (I). (II) and (III), the em parts of the purified water was used in place of 30 parts bodiment (I) is desirable in view of efficiency of produc thereof, an adhesive was obtained. tion. The embodiment (1) offers an advantage in that the O porous base layer can be laminated on the backing layer EXAMPLE 3 with a binder or the like. Fifteen parts of compound (I). 20 parts of lactic acid, The medical adhesives of the present invention solely 10 parts of purified water and 1 part of polyacrylic acid can be applied to the skin alone or may be covered with were mixed for dissolution to give a hydrophilic phase. other adhesives having a skin-adhering property, for 15 With a mixture of 20 parts of oleic acid and 50 parts example, surgical tapes, or with bandages after applica of ethyl acetate was mixed for dissolution 34 parts (as tion of the adhesives for prevention of loosening. the solid portion) of a methyl acrylate-2-ethylhexyl Since the medical adhesive of the present invention acrylate copolymer resin emulsion to give a lipophilic comprises the plaster layer of the W/O type wherein phase. the hydrophobic polymer which is the main constituent 20 The thus-obtained hydrophilic phase and lipophilic component of the continuous phase of the plaster and phase were uniformly mixed, applied onto a polyester the hydrophilic polymer are incorporated in appropri separate-type liner of 75 um in thickness so that the ate amounts, and the components have poor compatibil thickness of the plaster after drying became 100 um, ity with the medicinal ingredients, percutaneous absorp and dried at 75° C. for 5 minutes to form a plaster layer tion-promoting agents, water and the other additives 2 5 of a W/O type. can be easily dissolved or dispersed homogeneously. After the plaster layer was adhered by rolling onto a Accordingly, the medical adhesive has the effect that backing layer made of a polyester film of 9 um in thick the medicinal ingredients and percutaneous absorption ness, the separate-type liner was stripped off and a promoting agents can be released stably, and thus, phar nylon woven fabric was adhered by pressing onto the macological effects can be sustained sufficiently over a 30 exposed plaster layer at the basis weight of 25 g/m2, long period. followed by adhesion of the separate-type liner to give Especially, a medical adhesive in which the water a medical adhesive of the present invention. content of the plaster after formation is 1-20% by weight has the effect that the ingredients can be con EXAMPLE 4 tained and retained in the formed preparations for a Twelve parts of timolol maleate, 20 parts of propy long period. lene glycol, 1.5 parts of sodium carbonate, 30 parts of Below, the present invention is described in further purified water, 2 parts of hydroxypropylcellulose and 5 detail by working examples, which are not limiting and parts of polyoxyethylene (15) oleyl ether were mixed can be modified in various ways. Hereinafter, "part for dissolution to give a hydrophilic phase. means "part by weight'. 40 With 25 parts of isopropyl myristate was mixed for dissolution 53 parts (as the solid portion) of a copolymer EXAMPLE 1 solution (B) obtained by conventional polymerization of Fifteen parts of (R)-3-(S)-1-carboxy-5-(4-piperidyl)- 70 parts of acrylic acid 2-ethylhexyl ester and 30 parts pentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiaze of vinylpyrrolidone in ethyl acetate as the solvent to pine-5-acetic acid hereinafter referred to as compound 45 give a lipophilic phase. (I), an angiotensin I transferase inhibitor, 20 parts of The thus-obtained hydrophilic phase and lipophilic propylene glycol, 1.3 parts of sodium hydroxide, 30 phase were uniformly mixed, applied onto a polyester parts of purified water and 1 part of crosslinked acrylic separate-type liner of 75 um in thickness so that the acid. vinyl alcohol copolymer were mixed for dissolu thickness of the plaster after drying became 50 um, and tion, to obtain a hydrophilic phase. 50 dried at 68 C. for 4 minutes to form a plaster layer of a With twenty parts of isopropyl myristate and 5 parts W/O type. of polyoxyethylen sorbitan monooleate was mixed for Two sheets of the plaster layer formed on the sepa dissolution 38 parts (as the solid portion) of the copoly rate-type liner were prepared. After one of the plaster mer solution (A) obtained by polymerizing a mixture of layers was adhered by rolling onto a backing layer 55 parts of acrylic acid 2-ethylhexyl ester, 30 parts of 55 made of a polyester film of 25 um in thickness, the acrylic acid methoxyethyl ester and 15 parts of vinyl separate-type liner was stripped off. Japanese paper was acetate in ethyl acetate as the solvent by a conventional laminated on the exposed surface of the other plaster method to give a lipophilic phase. layer at the basis weight of 20 g/m2, whereon the ex The thus-obtained hydrophilic phase and lipophilic posed surface of the above-mentioned plaster layer phase were uniformly mixed, applied onto a separate 60 adhered by rolling onto the backing layer was adhered type liner made of polyester of 75 um in thickness so by pressure to afford a medical adhesive of the present that the thickness of the plaster after drying became 100 invention. um, and dried at 70° C. for 4 minutes to form a plaster layer of a W/O type. EXAMPLE 5 The plaster layer was adhered by rolling on the side Ten parts of timolol maleate, 15 parts of 1,3-butan of the polyethylene of a polyester film of 25 um in diol, 1.2 parts of potassium hydroxide, 40 parts of puri thickness with the polyethylene of 30 um in thickness fied water and 1 part of polyacrylic acid were mixed for laminated thereon and on the non-woven fabric side of dissolution to give a hydrophilic phase. 5,176,916 15 16 With 20 parts of lauric acid, 4 parts of polyoxyethyl was excluded from the ingredients to be incorporated ene sorbitan monooleate and 3 parts of sorbitan mono resulted in failure. oleate were mixed for dissolution 46 parts (as the solid portion) of a copolymer solution (C) obtained by con COMPARATIVE EXAMPLE 2 ventional polymerization of 93 parts of acrylic acid An attempt to obtain an adhesive in the same manner 2-ethylhexyl ester and 7 parts of acrylic acid in ethyl as in Example 1 except that the copolymer solution (A) acetate as the solvent to give a lipophilic phase. as the solid portion was incorporated in the proportion The thus-obtained hydrophilic phase and lipophilic of 20 parts instead of 38 parts resulted in failure since the phase were uniformly mixed, applied onto a polyester stable plaster layer could not be formed, separate-type liner of 75 um in thickness so that the O thickness of the plaster after drying became 120 um, COMPARATIVE EXAMPLE 3 and dried at 70° C. for 6 minutes to form a plaster layer An adhesive was obtained in the same manner as in of a W/O type. Example 1 except that the propylene glycol and isopro The plaster layer was then adhered by rolling onto a pyl myristate as the percutaneous absorption-promoting backing layer of 6 um in thickness made of a polyester 5 agents were excluded from the ingredients to be incor film to afford a medical adhesive of the present inven porated. t1O. COMPARATIVE EXAMPLE 4 EXAMPLE 6 An adhesive was obtained in the same manner as in Fifteen parts of diclofenac sodium, 20 parts of propy Example 1 except that purified water was excluded lene glycol, 30 parts of purified water and 2 parts of from the ingredients to be incorporated. carboxymethylcellulose sodium were mixed for dissolu tion to give a hydrophilic phase. COMPARATIVE EXAMPLE 5 With 20 parts of isopropyl myristate and 5 parts of An attempt to obtain an adhesive in the same manner polyoxyethylene (60) hydrogenated castor oil was as in Example 1 except that the crosslinked acrylic mixed for dissolution 38 parts (as the solid portion) of a acid-vinyl alcohol copolymer as a hydrophilic polymer copolymer solution (D) obtained by conventional poly was excluded from the ingredients to be incorporated merization of 70 parts of acrylic acid 2-ethylhexyl ester resulted in failure since an adhesive having a uniform and 30 parts of vinyl acetate in ethyl acetate as the and stable plaster layer could not be obtained due to solvent to give a lipophilic phase. separation between the hydrophilic phase and the lipo The thus-obtained hydrophilic phase and lipophilic philic phase in the drying process at 70° C. for 4 min phase were uniformly mixed, applied onto the polyester teS. separate-liner of 75um in thickness so that the thickness COMPARATIVE EXAMPLE 6 of the plaster after drying became 100 um, and dried at 35 70° C. for 5 minutes to form a plaster layer of a W/O An adhesive was obtained in the same manner as in type. Example 3 except that oleic acid as a percutaneous The obtained plaster layer was then adhered by roll absorption-promoting agent was excluded from the ing onto a backing layer made of a polyester film of 25 ingredients to be incorporated. um in thickness to afford a medical adhesive of the 40 present invention. COMPARATIVE EXAMPLE 7 An adhesive was obtained in the same manner as in EXAMPLE 7 Example 3 except that the proportion of the purified Twelve parts of diclofenac sodium, 25 parts of puri water to be incorporated was changed from 10 parts to fied water and 2 parts of crosslinked acrylic acid.- 45 70 parts, but the liquid ingredients blotted on the surface vinylalcohol copolymer were mixed for dissolution to of the plaster layer immediately after preparation. Thus, give a hydrophilic phase. the adhesive was considered to fail to retain the liquid With 20 parts of lauryl alcohol was mixed for dissolu ingredients stably and was not subjected to the animal tion 66 parts (as the solid portion) of a polymer solution tests as shown below. (E) obtained by homogeneous mixing for dissolution of 50 25 parts of VISTANEX MML-80 (viscosity-average COMPARATIVE EXAMPLE 8 molecular weight 990,000) and 75 parts of HIMOL-4H An attempt to obtain an adhesive in the same manner (viscosity-average molecular weight 40,000) in n-hex as in Example 4 except that the copolymer solution (B) ane as the solvent to give a lipophilic phase. was excluded from the ingredients to be incorporated The thus-obtained hydrophilic phase and lipophilic 55 resulted in failure. phase were uniformly mixed, applied onto a polyester separate-type liner of 75 um in thickness so that the COMPARATIVE EXAMPLE 9 thickness of the plaster after drying became 100 um, An adhesive was obtained in the same manner as in and dried at 75 C. for 5 minutes to form a plaster layer Example 5 except that the 1,3-butandiol as a percutane of a W/O type. ous absorption-promoting agent, potassium hydroxide The plaster layer was then adhered by rolling onto a and purified water were excluded from the ingredients backing layer made of a polyester film of 25 um in to be incorporated. thickness to afford a medical adhesive of the present invention. COMPARATIVE EXAMPLE 10 65 An attempt to obtained an adhesive in the same man COMPARATIVE EXAMPLE 1 ner as in Example 6 except that the proportion of the An attempt to obtain an adhesive in the same manner copolymer solution (D) as the solid portion to be incor as in Example 1 except that the copolymer solution (A) porated was changed from 38 parts to 25 parts resulted 5,176,916 17 18 in failure since a stable layer containing medicinal ingre from the blood in accordance with a conventional dient could not be formed. method, and the concentration in blood was quantita tively determined by gas chromatography or high per COMPARATIVE EXAMPLE 1 - formance liquid chromatography. An attempt to obtain an adhesive in the same manner 5 The test results are shown in FIG. 1. Each of the as in Example 7 except that the crosslinked acrylic values indicates the mean value of three samples. acid. vinyl alcohol copolymer which is a hydrophilic polymer was excluded from the ingredients to be incor TABLE porated resulted in failure since an adhesive having a Skin uniform plaster layer could not be obtained due to sepa O Medicina Water content migration ration of the hydrophilic phase from the lipophilic ingredient ( by weight) ratic () phase in the drying process. l Compound () 7. 61.5 EXPERIMENTAL EXAMPLE Compound (I) 0.7 26.5 3. Compound (I) 3.3 47.8 The water contents were quantitatively determined 4 Timolo maleate 8.4 58.9 for the plaster layers of all Examples in which the uni 5 Timolo maleate 12.9 6.3.3 form and stable plaster layers could be prepared, the 6 Diclofenac sodium 6.0 20.8 7 Diclofenac sodium 3. 7.2 plaster layers of Comparative Examples 3, 4, 6 and 9 Comparative and the unstable plaster layer obtained according to Example Comparative Example 7. As far as Comparative Exam 20 3. Compound (I) 5.8 49.2 ple 7 was concerned, the plaster layer from which the 4 Compound (1) s ().0 S3 blotted liquid ingredients were wiped off with filter 6 Compound (I) 3.6 42.5 paper was quantitatively determined for the water con 7 Compound (l) 2.7 tent. Furthermore, for the above-mentioned adhesives G Tinchly naieate s ().() 2.1 other than the adhesive according to Comparative Ex ample 7, animal experiments were conducted. What is claimed is: 1. A medical preparation comprising a plaster layer EXPERIMENTAL EXAMPLE 1 containing the following ingredients: Quantitative determination of the water content (1) a medicinal ingredient in the range of 0.1 to 15% Water was extracted from the pieces of the size of 30 by weight; 5x5 cm (=25 cm) cut out from the adhesives of Ex (2) a hydrophobic polymer in the range of 25 to 80% amples 1-7 and Comparative Examples 3, 4, 6, 7 and 9 by weight, selected from the group consisting of with anhydrous methanol with sufficient care prohibit acrylic polymers, silicone gums, polyisobutylene ing entry of external moisture, and subjected to chroma gums, polyisoprene gums, styrene-butadiene-sty tography to quantitatively determine the water content rene block copolymer gums, styrene-isoprene-sty in the adhesives. rene block copolymer gums, poly vinylalkyl The results of this test are shown in Table 1. In table, ethers, poly vinyl-acetate, poly vinyl-propionate each of the indicated values is the mean value of three and polyurethane elastic bodies, said hydrophobic samples. polymer having a glass transistion temperature 40 (Tg) of -50° C. to 0° C.; EXPERIMENTAL EXAMPLE 2 (3) a percutaneous absorption-promoting agent in the Test of adhesion to rabbits . . . migration property of range of 0.1 to 80% by weight; medicinal ingredient into the skin (4) water in the range of 0.1 to 20% by weight; and, The pieces of the size of 30 mmdb cut out from the (5) a water soluble or water-absorbing polymer in the adhesives of Examples 1-7 and Comparative Examples range of 0.1 to 15% by weight; 3, 4, 6 and 9 were adhered to the skin in the depilated wherein said ingredient (2) constitutes a continuous back of rabbits (male white Japanese native species aged phase of said plaster layer and said ingredients (4) 12 weeks) for 24 hours and stripped off. The residual and (5) are dispersed in said continuous phase of medicinal ingredient was quantitatively determined by ingredient (2). high performance liquid chromatography, and the ap 50 2. A medical preparation as claimed in claim 1 parent migration ratio of the midicinal ingredient to the wherein the solubility of the medicinal ingredient is at skin based on the initial content (hereinafter referred to least 1 g or 1 ml per 10,000 ml of water. briefly as skin-migration ratio) was calculated. 3. A medical preparation as claimed in claim 2, The results of these tests are shown in Table 1. In 55 wherein the medicinal ingredient is selected from the Table, each of the indicated values is the mean value of group consisting of (R)-3-(S)-1-carboxy-5-(4- three samples. piperidyl)pentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5- benzothiazepine-5-acetic acid, timolol maleate and di EXPERIMENTAL EXAMPLE 3 clofenac sodium. Test of adhesion to rats . . . change in concentration in 60 4. A medical preparation as claimed in claim 1, blood of medicinal ingredient wherein the hydrophobic polymer having a Tg of -50 The round pieces cut out from the adhesives were C. to 0°C. is a pressure-sensitive acrylic adhesive poly adhered to the skin in the depilated abdomens of male e. SD rats aged 9 weeks at the dose of the medicinal ingre 5. A medical preparation as claimed in claim 4, dient of 6 mg/rat for compound (I), 10 mg/rat for timo 65 wherein the pressure-sensitive acrylic adhesive polymer lol maleate and 10 mg/rat for diclofenac sodium for 24 comprises (meth)acrylic acid alkyl ester and a copoly hours. Blood was collected at 5, 7 and 24 hours' lapse merizable monomer in a mixing ratio of 50-99/1-50 by after adhesion. The medicinal ingredient was extracted weight. 5,176,916 19 20 6. A medical preparation as claimed in claim 4, ide. acrylic acid, maleic anhydride, phthalic acid, acryl wherein the pressure-sensitive acrylic adhesive polymer amide, polyvinyl pyrrolidones, polyamines, polyelec is a copolymer of (meth)acrylic acid alkyl ester, (meth trolytes, urea and melamine. )acrylic acid alkyl ester containing an ether linkage and 13. A medical preparation as claimed in claim 1, a copolymerizable monomer; the proportion of the 5 wherein the water-absorbing polymer is selected from (meth)acrylic acid alkyl ester, (meth)acrylic acid alkyl the group consisting of vinyl acetate-acrylic acid ester ester containing an ether linkage and a copolymerizable copolymer suspensions, polyacrylic acid salts, polyvi monomer being 40-80/59-10/1-40 by weight. . nyl alcohol-maleic anhydride crosslinked copolymers, 7. A medical preparation as claimed in claim 1, isobutylene-maleic acid crosslinked copolymers, poly wherein the hydrophobic polymer having a Tg of 50 O acrylonitrile graft polymer suspensions and starch-acry C. to 0° C. is crosslinked. lic acid graft polymers, 8. A medical preparation as claimed in claim 1, 14. A medical preparation comprising a plaster layer wherein the percutaneous absorption-promoting agent containing the following ingredients: is at least one species selected from the group consisting (1) a medicinal ingredient in the range of 0.1 to 15% of aliphatic carboxylic acids having 6-20 carbon atoms, 15 their lower alcohol esters, aliphatic alcohols having by weight; W 6-20 carbon atoms and alkanepolyols. (2) a hydrophobic polymer in the range of 25 to 80% 9. A medical preparation as claimed in claim 1, by weight, selected from the group consisting of wherein the hydrophilic polymer soluble or capable of acrylic polymers, silicone guns, polyisobutylene swelling in water is a water-absorbing polymer capable 20 gums, polyisoprene gums, styrene-butadiene-sty of absorbing 50–2,000 times amount its own weight of rene block copolymer gums, styrene-isoprene-sty Water. rene block copolymer gums, poly vinylalkyl 10. A medical preparation as claimed in claim 1, ethers, poly vinyl-acetate, poly vinyl-propionate which comprises a porous base layer in the plaster layer and polyurethane elastic bodies; or in contact with the plaster layer. 25 (3) a percutaneous absorption-promoting agent in the 11. A medical preparation as claimed in claim 1, range of 0.1 to 80% by weight; wherein the porous base layer is placed in contact with (4) water in the range of 0.1 to 20% by weight; and, a backing layer on the side toward the backing layer of (5) a water soluble or water-absorbing polymer in the the plaster layer. range of 0.1 to 15% by weight: 12. A medical preparation as claimed in claim 1, wherein said ingredient (2) constitutes a continuous wherein the water soluble polymer is selected from the phase of said plaster layer and said ingredients (4) and group consisting of starch, pullulan, cellulose, tannin, (5) are dispersed in said continuous phase of ingredient lignin, alginic acid, gum arabic, gum guar. gum traga (2). canth, gelatin, polyvinyl alcohol, polyvinyl ethyleneox 35

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65 UNITED STATES PATENT ANDTRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 5,176,916 DATED January 5, 1993 NVENOR(S); Akihito Yamanaka et al. it is certified that error appears in the above-indentified patent and that said Letters Patent is hereby Corrected as shown below: On the title page, item 73 Assignee: Delete "NITTO ELECTRIC INDUSTRIAL CO., LTD.' and insert --NITTO DENKO CORPORATION--.

Signed and Sealed this Twentieth Day of June, 1995 Attest: (a (eam

BRUCELEHMAN Attesting Officer Commissioner of Patents and Trademarks