Patent Publication Number: US-2009238860-A1

Title: Adhesive Patch Less Irritative to Skin

Description:
TECHNICAL FIELD 
     The present invention relates to an adhesive patch less irritative to the skin, particularly, the present invention relates to an adhesive patch containing an active ingredient which causes less skin irritation. More particularly, the present invention relates to an adhesive patch comprising an adhesive base agent and supporting body, which is characterized by containing 3% by mass to 30% by mass of low-molecular-weight polyisobutylene and aluminum hydroxide and/or titanium oxide but not substantially containing water, and a skin irritation reducing agent therefor. The present invention also relates to an adhesive patch comprising an adhesive base agent and supporting body, wherein the adhesive base agent contains thermoplastic rubber and low-molecular-weight polyisobutylene but does not substantially contain water, the patch is characterized by further containing aluminum hydroxide and/or titanium oxide in the adhesive base agent, and a skin irritation reducing agent therefor. 
     BACKGROUND OF THE INVENTION 
     To date, adhesive patches for external use are for example plaster patches, cataplasms, tape patches and the like, which are preparations wherein adhesive polymers containing a drug are directly or indirectly spread over a supporting body such as a flexible fabric, nonwoven fabric or a plastic film and the like. 
     Such adhesive patches for external use cause adverse effects such as generation of stress to the skin during its application, physical action such as pulling the skin and/or hair when removing the patch, chemical action caused by irritating components of raw materials, accumulation of sweat and moisture resulting from the prolonged application, and reddening, rash and the like caused by physiological effect such as sweating, those were the problems to be solved. Major reason for these problems is considered to be destruction of tissues on the surface of the skin caused by stress to the skin during the application of an existing patch and pulling the skin and/or hair when removing the patch. 
     On the other hand, various experiments have been made to solve these problems. For example, a method of opening vent holes in a plaster is disclosed in Patent Literature 1. Also, containing chemicals for preventing rash or reducing skin irritation is disclosed in Patent Literature 2, Patent Literature 3, Patent Literature 4, etc. A method for reducing skin irritation by particular treatment to the base agent is disclosed in Patent Literature 5. Further, adding water-absorbing polymers in order to eliminate physiological factors of rash by sudor, sweating and the like, and physical factors of rash by such as pulling the hair on removing is disclosed in Patent Literature 6. However, in any of these methods, an adhesive patch decreased the adhesion by containing additive components and resulted in unsuitable for practical use, the production process was complicated, and the effect was insufficient. As described above, various methods have been tested; however, they were not for practical use. Consequently, an ideal patch for external use which is not causing rash has yet to be appeared. 
     On the other hand, in transdermal application, skin irritation such as pruritus, flush, rash, pain, eczema, skin inflammation and the like caused by a composition of an adhesive patch or drug itself is rarely recognized, and remedies for those have been desired. Particularly, various researches have been made for application of a patch containing indomethacin, an antiinflammatory analgesic drug, to the skin (see Patent Literature 7 to 9). 
     Incidentally, titanium oxide has been used as a drug additive, such as a coating agent or an ultraviolet absorber; for example, an adhesive patch containing titanium oxide in the supporting body as an inorganic ultraviolet shielding agent has been reported (see Patent Literature 10). Also, it is reported that titanium oxide has effect in such as treating and improving various external injuries, cutaneous diseases and symptoms and the like or effective in improving the skin; therefore, a medical product comprising titanium oxide which is contained in various base agents has been used (see Patent Literature 11). Further, an adhesive patch comprising a styrene-isoprene-styrene block copolymer, an alicyclic saturated hydrocarbon resin, isopropyl myristate, liquid paraffin, titanium oxide, diiron trioxide, dibutylhydroxytoluene, 1-menthol, and indomethacin intermittently laminated with a layer of adhesive agent has been reported as an adhesive patch which reduces generation of dermatopathy, having excellent adhesion and providing high cutaneous absorption (see Patent Literature 12). 
     Furthermore, it has been reported that an obstruction improved adhesive patch can be obtained by containing a metal oxide such as titanium oxide in a matrix for an adhesive patch (see Patent Literature 13), and it has also been reported that an adhesive patch with creaseless film-like supporting body can be obtained by containing a poorly-water-soluble cross-linking agent such as titanium oxide or dry aluminum hydroxide gel in aqueous adhesive layer of the adhesive patch (see Patent Literature 14). 
     Patent Literature 1: Utility model JP-B-58-52251 
     Patent Literature 2: JP-A-58-4721 
     Patent Literature 3: JP-A-60-56911 
     Patent Literature 4: JP-A-60-23312 
     Patent Literature 5: JP-B-59-19528 
     Patent Literature 6: JP No. 2632838 
     Patent Literature 7: JP-A-10-114646 
     Patent Literature 8: JP-A-10-130145 
     Patent Literature 9: JP-A-2001-302502 
     Patent Literature 10: WO 01/068061 
     Patent Literature 11: JP-A-2003-95958 
     Patent Literature 12: JP-A-8-133973 
     Patent Literature 13: JP-A-10-287587 
     Patent Literature 14: JP-A-2003-95929 
     DISCLOSURE OF THE INVENTION 
     Problem to be Solved by the Invention 
     In view of the above circumstances, the present invention has been achieved to provide an adhesive patch for external use wherein rash caused thereby is reduced and a drug itself contained therein has less skin irritation. 
     Means of Solving the Problems 
     The present inventors have made earnest studies to achieve said objective and found that an adhesive base agent containing 3% by mass to 30% by mass of low-molecular-weight polyisobutylene and aluminum hydroxide and/or titanium oxide but not substantially containing water reduces rash, and significantly reduces skin irritation caused by a drug when the drug is contained in the adhesive base agent, and the invention was completed. 
     That is, the present invention relates to an adhesive patch comprising an adhesive base agent and supporting body, characterized by containing 3% by mass to 30% by mass of a low-molecular-weight polyisobutylene and aluminum hydroxide and/or titanium oxide in the adhesive base agent, particularly, the adhesive patch is characterized by not substantially containing water. 
     Further, the present invention relates to an adhesive patch characterized by further comprising a drug in the adhesive base agent which is characterized by containing indomethacin as said drug. 
     Furthermore, the present invention relates to an adhesive patch comprising an adhesive base agent and a supporting body, characterized in that the adhesive base agent does not substantially contain water, and further the adhesive base agent contains thermoplastic rubber, low-molecular-weight polyisobutylene and aluminum hydroxide and/or titanium oxide. 
     Further, the present invention relates to an adhesive patch characterized in that said thermoplastic rubber is a styrene-isoprene-styrene block copolymer, and the content ratio of the thermoplastic rubber and the low-molecular-weight polyisobutylene is from 60:40 to 85:15, preferably from 60:40 to 75:25. 
     Furthermore, the present invention is characterized in that said adhesive patch of the present invention is further containing edetic acid or a salt thereof. 
     More specifically, the present invention relates to the following: 
     (1) An adhesive patch comprising an adhesive base agent and supporting body, characterized in that the adhesive base agent contains 3% by mass to 30% by mass of a low-molecular-weight polyisobutylene and aluminum hydroxide and/or titanium oxide but does not substantially contain water.
 
(2) The adhesive patch according to (1) as above, wherein the content of the low-molecular-weight polyisobutylene is from 6% by mass to 30% by mass.
 
(3) The adhesive patch according to (1) or (2) as above, wherein the content of the low-molecular-weight polyisobutylene is 11% by mass to 30% by mass.
 
(4) The adhesive patch according to any of (1) to (3) as above, wherein the adhesive base agent of the adhesive patch comprises a thermoplastic rubber.
 
(5) The adhesive patch according to (4) as above, wherein the thermoplastic rubber is a styrene-isoprene-styrene block copolymer.
 
(6) The adhesive patch according to (4) or (5) as above, wherein the content ratio of the thermoplastic rubber and the low-molecular-weight polyisobutylene is 60:40 to 75:25.
 
(7) The adhesive patch according to any of (1) to (6) as above, wherein the content of the aluminum hydroxide in the adhesive base agent of the adhesive patch is 0.01% by mass to 10% by mass.
 
(8) The adhesive patch according to any of (1) to (7) as above, characterized by further containing a drug in the adhesive base agent of the adhesive patch.
 
(9) The adhesive patch according to (8) as above, wherein the drug is selected from the group consisting of a nonsteroidal antiinflammatory analgesic drug, a disease-modifying antirheumatic drug, a cytokine blocking drug, a smoking cessation adjuvant, and an antianginal drug.
 
(10) The adhesive patch according to (8) or (9) as above, wherein the drug is at least one selected from indomethacin, ketoprofen, diclofenac sodium, flurbiprofen, felbinac, ibuprofen, suprofen, tiaprofen, loxoprofen, celecoxib, lofecoxib, meloxicam, valdecoxib, nicotine, nitroglycerin, isosorbide dinitrate and the like.
 
(11) The adhesive patch according to any of (8) to (10), wherein the drug is indomethacin.
 
(12) An adhesive patch comprising an adhesive base agent and a supporting body, wherein the adhesive base agent contains thermoplastic rubber and low-molecular-weight polyisobutylene but does not substantially contain water, which is characterized by further containing aluminum hydroxide and/or titanium oxide in the adhesive base agent.
 
(13) The adhesive patch according to (12) as above, wherein the content of the low-molecular-weight polyisobutylene is 6% by mass to 30% by mass.
 
(14) The adhesive patch according to (12) or (13) as above, wherein the content of the low-molecular-weight polyisobutylene is 11% by mass to 30% by mass.
 
(15) The adhesive patch according to (12) or (14) as above, wherein the content ratio of the thermoplastic rubber and the low-molecular-weight polyisobutylene is 60:40 to 75:25.
 
(16) The adhesive patch according to any of (12) to (15) as above, wherein the thermoplastic rubber is a styrene-isoprene-styrene block copolymer.
 
(17) The adhesive patch according to any of (12) to (16) as above, wherein the content of the aluminum hydroxide in the adhesive base agent of the adhesive patch is 0.01% by mass to 10% by mass.
 
(18) The adhesive patch according to any of (12) to (17) as above, characterized by further containing a drug in the adhesive base agent of the adhesive patch.
 
(19) The adhesive patch according to (18) as above, wherein the drug is selected from the group consisting of a nonsteroidal antiinflammatory analgesic drug, a disease-modifying antirheumatic drug, a cytokine blocking drug, a nonsmoking adjuvant, and an antianginal drug.
 
(20) The adhesive patch according to (18) or (19) as above, wherein the drug is at least one selected from indomethacin, ketoprofen, diclofenac sodium, flurbiprofen, felbinac, ibuprofen, suprofen, tiaprofen, loxoprofen, celecoxib, lofecoxib, meloxicam, valdecoxib, nicotine, nitroglycerin, isosorbide dinitrate and the like.
 
(21) The adhesive patch according to any of (18) to (20) as above, wherein the drug is indomethacin.
 
(22) A skin irritation reducing agent in an adhesive patch having an adhesive base agent containing 3% by mass to 30% by mass of low-molecular-weight polyisobutylene relative to total amount of the adhesive base agent and aluminum hydroxide and/or titanium oxide but not substantially containing water.
 
(23) A skin irritation reducing agent in an adhesive patch having an adhesive base agent comprising aluminum hydroxide and/or titanium oxide, further containing thermoplastic rubber and low-molecular-weight polyisobutylene but not substantially containing water.
 
     An adhesive patch of the present invention is an adhesive patch wherein an adhesive base agent is directly or indirectly spread at one surface of a supporting body. 
     For adhesive base agent for the adhesive patch of the present invention, an adhesive base agent comprising thermoplastic rubber is preferable but not specifically limited as long as the adhesive base agent does not substantially contain water. Examples for preferable thermoplastic rubber can include, but as an adhesive component not especially limited to, a high-molecular-weight substances such as polymers of silicone, styrene-isoprene-styrene copolymers, styrene-butadiene copolymers, acrylic polymers, vinyl ether polymers, natural rubbers, polyisoprene polymers, polyurethanes, polyisobutylenes, acrylic acid polymers and the like. Preferable amount of content of these polymer substances contained in an adhesive base agent is 10% by mass to 90% by mass, particularly in the case of what is called diene-based thermoplastic rubber such as a natural rubber, a polyisoprene type, a styrene-isoprene-styrene type, a polyisobutylene type and the like, preferably be 10% by mass to 50% by mass. 
     It should be noted that an adhesive base agent in an adhesive patch of the present invention does not substantially contain water. The term “substantially” used herein means that there is not a step to add water intentionally to an adhesive base agent in the production processes, but not meant to exclude moisture contained in raw materials and the like or moisture absorbed by the adhesive base agent such as sweat and the like during the application. 
     An adhesive base agent of an adhesive patch of the present invention preferably contains low-molecular-weight polyisobutylene in a specified ratio to the total amount of the adhesive base agent. Low-molecular-weight polyisobutylene contained in a specific amount can control keratin layer to be exfoliated when removing the adhesive patch after the application, accordingly, physical irritation by exfoliation can be significantly reduced. 
     Preferable amount of low-molecular-weight polyisobutylene in an adhesive base agent is 3% by mass to 30% by mass, more preferably 6% by mass to 20% by mass. Also, content ratio of an adhesive component, preferably thermoplastic rubber, is preferably 40:60 to 85:15, more preferably 60:40 to 75:25. When the content amount is over 30% by mass, plaster reduces cohesive strength and the plaster residue remains on the skin, while the content amount below 3% by mass increases skin irritation by physical effect produced when the patch is removed. 
     The low-molecular-weight polyisobutylene used herein means molecular weight of 10000 to 60000, and such polyisobutylene exhibits property of very viscous and adhesive semi-solid at normal temperature. 
     Such adhesive base agents can express significant effect of the adhesive patch of the present invention by containing aluminum hydroxide and/or titanium oxide therein. 
     That is, the present invention is characterized by an adhesive base agent which does not contain water but contains preferably thermoplastic rubber as an adhesive component, comprising low-molecular-weight polyisobutylene of molecular weight 10000 to 60000, preferably a molecular weight 10000 to 40000, in an amount of 3% by mass to 30% by mass, preferably 6% by mass to 30% by mass, 11% by mass to 30% by mass, and more preferably 6% by mass to 20% by mass, 11% by mass to 20% by mass relative to total mass of the adhesive base agent, further comprising at least one component selected from the group consisting of aluminum hydroxide and titanium oxide. 
     The adhesive base agent of the present invention contains aluminum hydroxide and/or titanium oxide. The adhesive patch containing such aluminum hydroxide and/or titanium oxide can significantly reduce skin rash when applying the patch to the skin or removing the patch from the skin. Particularly, when an adhesive patch is containing a drug, skin irritation caused by the drug can also significantly be reduced. 
     The content amount of aluminum hydroxide and/or titanium oxide in an adhesive base agent is preferably 0.01% by mass to 10% by mass for each, more preferably 0.1% by mass to 8% by mass, and even more preferably 0.5% by mass to 5% by mass. The content amount 0.01% by mass or less tends to reduce effect of reducing skin rash which is undesirable. To the contrary, the content amount 10% by mass or more reduces cohesion of the plaster and decreases adhesion, which is also undesirable. 
     Aluminum hydroxide and titanium oxide may be contained concurrently or independently; however, combination of both is preferable for a drug particularly indomethacin, an antiinflammatory analgesic drug. 
     In a preferable embodiment of the present invention, an effect of an adhesive patch of the present invention can significantly be produced to reduce causing rash or skin irritation by using an adhesive base agent containing styrene-isoprene-styrene block copolymer as thermoplastic rubber and low-molecular-weight polyisobutylene in the above content amount but not substantially containing water, and further adding aluminum hydroxide and/or titanium oxide to the base agent. 
     In a more preferable embodiment of the present invention, adhesive base agent further comprising edetate is included. The content amount of edetate can be, but not limited to, a range from 0.01% by mass to 5% by mass, preferably from 0.1% by mass to 5% by mass and more preferably from 0.1% by mass to 3% by mass relative to total amount of the adhesive base agent. The edetate used herein can include, but not limited to, various edetate salts such as an alkali metal salt or an alkaline earth metal salt and the like, preferably an alkali metal salt particularly a sodium salt. An example of preferable edetate is disodium edetate. 
     If necessary, an adhesive base agent of the present invention can contain conventionally used tackifier, for example, a rosin type resin, [Ester gum(ARAKAWA CHEMICAL)], Hariester (HARIMA CHEMICAL), Pentalyn (Eastman Chemical), Foral (Eastman Chemical), a terpene type resin, [YS-Resin (YASUHARA CHEMICAL)], Picolyte (Loos &amp; Dilworth), a petroleum resin, [Arkon (ARAKAWA CHEMICAL INDUSTRIES, LTD.), Rigaret (Eastman Chemical), Picolastic (Eastman Chemical), Escorez (Exxon), Wingtack (GOODYEAR), Quintone (ZEON), aphenolicresin, axylene type resin and the like in an amount equal to or less than 50% by mass. 
     However, when for example an acrylic type base agent is used as a polymer substance of an adhesive component, some has sufficient adhesiveness by themselves depending on the properties; therefore, the above tackifier is not necessary in such a case. 
     An adhesive base agent of an adhesive patch of the present invention can contain a drug. Examples of such a drug can include, but not limited to, an anti-inflammatory analgesic drug such as acetaminophen, phenacetin, mefenamic acid, diclofenac sodium, flufenamic acid, aspirin, sodium salicylate, methyl salicylate, glycol salicylate, aminopyrine, alclofenac, ibuprofen, naproxen, flurbiprofen, ketoprofen, amfenac sodium, mepirizole, indomethacin, piroxicam, loxoprofen, tiaprofen, acemetacin, ferbinac, sulindac, etodolac, tolmetin, ampiroxicam, azapropazone, valdecoxib, lofecoxib and the like; a steroidal antiinflammatory drug such as hydrocortisone, triamcinolone, dexamethasone, prednisolone and the like; a vasodilator drug such as diltiazem hydrochloride, pentaerythritol tetranitrate, isosorbide dinitrate, tradipil, nicorandil, nitroglycerin, prenylamine lactate, molsidomine, amyl nitrate, tolazoline hydrochloride, nifedipine and the like; a drug for arrhythmia such as procainamide hydrochloride, lidocaine hydrochloride, propranolol hydrochloride, alprenolol hydrochloride, atenolol, nadolol, metoprolol tartrate, ajmaline, disopyramide, mexiletine hydrochloride and the like; an antihypertensive agent such as ecarazine hydrochloride, indapamide, clonidine hydrochloride, bunitrolol hydrochloride, labetalol hydrochloride, captopril, guanabenz acetate, mebutamate, betanidine sulfate and the like; a cough medication and expectorant such as carbetapentane citrate, cloperastine, oxeladin tannate, clobutinol hydrochloride, clofedanol hydrochloride, noscapine hydrochloride, ephedrine hydrochloride, isoproterenol hydrochloride, clorprenaline hydrochloride, methoxyphenamine hydrochloride, procaterol hydrochloride, tulobuterol hydrochloride, clenbuterol hydrochloride, ketotifen fumarate and the like; an antineoplastic drug such as cyclophosphamide, fluorouracil, tegafur, mitomycin C, procarbazine hydrochloride, doxifluridine, ranimusutine and the like; a topical anesthetic such as ethyl aminobenzoate, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, oxybuprocaine hydrochloride, propitocaine hydrochloride and the like; a hormone drug such as propylthiouracil, thiamazole, metelonon acetate, estradiol, estriol, progesterone and the like; an antihistamine drug such as diphenhydramine hydrochloride, chlorpheniramine maleate, promethazine, cyproheptadine hydrochloride, diphenylpyraline hydrochloride and the like; an anticoagulant drug such as warfarin potassium, ticlopidine hydrochloride and the like; an antispasmodic drug such as atropine methylbromide, scopolamine and the like; a general anesthetic such as thiopental sodium, pentobarbital sodium and the like; a hypnotic-analgesic drug such as bromovalerylurea, amobarbital, phenobarbital and the like; an antiepileptic drug such as phenytoin sodium and the like; a stimulant•analeptic drug such as methamphetamine hydrochloride and the like; an antidinic such as difenidol hydrochloride, betahistine mesylate and the like; a drug for psychoneurosis such as chlorpromazine hydrochloride, thioridazine, meprobamate, imipramine hydrochloride, chlordiazepoxide, diazepam and the like; a skeletal muscle relaxant such as suxamethonium hydrochloride, eperisone hydrochloride and the like; an autonomic drug such as neostigmine bromide, bethanechol chloride and the like; an antiparkinsonism drug such as amantadine hydrochloride and the like; a diuretic drug such as hydroflumethiazide, isosorbide, furosemide and the like; a vasoconstrictor such as phenylephrine hydrochloride and the like; a respiratory stimulant such as lobeline bromide, dimorpholamine, naloxone hydrochloride and the like; a peptic antiulcer drug such as glycopyrronium bromide, proglumide, cetraxate hydrochloride, cimetidine, spizofurone and the like; a cholagogue such as ursodesoxycholic acid, osalmid and the like; a drug for urogenital organ and anus such as hexamine, sparteine, dinoprost, ritodrine hydrochloride and the like; a drug for parasitic skin diseases such as salicylic acid, cyclopiroxolamine, cloconazole hydrochloride and the like; a skin softener such as urea and the like; a vitamin drop such as calcitriol, thiamine hydrochloride, riboflavin sodium phosphate, pyridoxine hydrochloride, nicotinic acid amide, panthenol, ascorbic acid and the like; an inorganic formulation such as calcium chloride, potassium iodide, sodium iodide and the like; a hemostat such as etamsylate and the like; a drug for liver disease such as thiopronine and the like; a drug for habitual toxicosis such as cyanamide and the like; an arthrifuge such as colchicine, probenecid, sulfinpyrazone and the like; an antidiabetic such as tolbutamide, chlorpropamide, glymidine sodium, glypsol, buformine hydrochloride, insulin and the like; an antibiotic such as benzylpenicillin potassium, propicillin potassium, cloxacillin sodium, sodium ampicillin, bacampicillin hydrochloride, carbenicillin sodium, cephaloridine, sodium cefoxitin, erythromycin, chloramphenicol, tetracycline, kanamycin sulfate, cycloserine and the like; a chemotherapeutic drug such as isoniazid, pyrazinamide, ethionamide and the like; a narcotic such as morphine hydrochloride, codeine phosphate, cocaine hydrochloride, pethidine hydrochloride, fentanyl citrate and the like; a disease-modifying antirheumaic drug such as leflunomide, auranofin and the like; a cytokine blocking drug such as infliximab, etanercept, anakinra and the like; a smoking cessation adjuvant such as nicotine and the like; an antianginal drug such as nitroglycerin and the like. 
     A drug preferable to be contained in an adhesive base agent of an adhesive patch of the present invention is a drug which increases skin irritation by itself because an adhesive patch of the present invention can exhibit a significant effect. Examples of such drugs include a nonsteroidal type antiinflammatory analgesic drug such as indomethacin, ketoprofen, flurbiprofen, felbinac, diclofenac, ibuprofen, suprofen and the like. An adhesive patch of the present invention particularly an adhesive patch containing indomethacin exhibits a significant effect. 
     In addition to the above mentioned components, an adhesive patch of the present invention can also contain fillers, antioxidants, cross-linking agents, stabilizers, antiseptics, absorption promoters and the like accordingly. 
     Examples of a preferable antioxidant include tocopherol and ester derivatives thereof, ascorbic acid, ascorbyl stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene, butylhydroxyanisol and the like. 
     Examples of a preferable filler include calcium carbonate, magnesium carbonate, silicate (for example, aluminum silicate, magnesium silicate and the like), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like. 
     Examples of a preferable cross linking agent include organic cross linking agents such as a thermosetting resin (an amino resin, a phenol resin, an epoxy resin, an alkyd resin, unsaturated polyester and the like), an isocyanate compound, a block isocyanate compound, and inorganic cross linking agents such as metal or a metal compound and the like. 
     Examples for a preferable antiseptic include ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate and the like, and examples of a preferable ultraviolet absorbing agent include p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amine-acid compounds, imidazoline derivatives, pyridine derivatives, dioxane derivatives and the like. 
     Examples of a preferable absorption promoter include terpene oil such as d-limonene; and aliphatic acid esters such as glycerin monolaurate, glycerin monooleate, diethyl sebacate; aliphatic acids such as azone, pirotiodecane, oleic acid, lauric acid, myristic acid or derivatives thereof and the like. 
     Supporting body used in an adhesive patch of the present invention is selected from an elastic or non-elastic supporting body such as a film or sheet, for example, polyethylene, polypropylene, polybutadiene, an ethylene-vinyl acetate copolymer, polyvinylchloride, polyester (for example, polyethylene terephthalate(PET)), nylon, polyurethane and the like, or a porous body and a foamed body thereof, and paper, cloth, nonwoven fabric, woven fabric (including knitted fabric) and the like. Particularly, when the adhesive patch is applied to a highly mobile region of the body such as the joint, rash or skin irritation can be reduced by using woven fabric or nonwoven fabric which is elastic as a supporting body. 
     An adhesive patch of the present invention can be easily produced by a conventionally known method. For example, to produce a tape patch which has rubber-type adhesive agent as a base, firstly mix a base and other components such as softener and tackifier on heating at 120-160° C. by using a mixing machine such as a kneader, mixer and the like, subsequently adjust the mixture for formation of adhesive layer by adding and mixing medicinal properties at a temperature not thermally decompose the medicinal properties. The mixture can then be directly spread over a film as a supporting body to form an adhesive layer, or the mixture can be spread over a release coated paper or film and place a supporting body thereon to transfer the adhesive layer on the supporting body by pressure. To produce an acrylic tape patch which has acrylic adhesive base agent, dissolve or disperse a base, medicinal property and absorption promoter in a solvent; and apply the resulting coating solution to the surface of the supporting body; and dry to form adhesive base agent. A solvent used herein preferably be able to dissolve all the components such as base, medicinal property and the like; for example, aromatic hydrocarbons such as toluene, benzene, and xylene and the like; esters such as ethyl acetate and the like; and halogenated hydrocarbons such as carbon tetrachloride, chloroform, and methylene chloride and the like. 
     As aluminum hydroxide, without limiting type of crystal such as the number of crystal water or presence or absence thereof, anhydrous aluminum hydroxide, plate-like crystal aluminum hydroxide, aluminum hydroxide gel and the like can be used. 
     As titanium oxide, without limiting type of crystal, a rutile type or an anatase type and the like can be used. 
     ADVANTAGEOUS EFFECT OF THE INVENTION 
     An adhesive patch of the present invention can provide an adhesive patch for external use which can significantly reduce incidence of rash and has reduced skin irritation by a drug by containing low-molecular-weight polyisobutylene and at least one component selected from the group consisting of aluminum hydroxide and titanium oxide, in an adhesive base agent. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a graph showing test results of containing aluminum hydroxide in an adhesive patch of the present invention. 
         FIG. 2  is a graph showing test results of containing titanium oxide in an adhesive patch of the present invention. 
         FIG. 3  is a graph showing test results of containing low-molecular-weight polyisobutylene in an adhesive patch of the present invention. 
     
    
    
     The present invention is further illustrated by the following examples but not limited to these examples. 
     EXAMPLE 1 
     Preparation of an Adhesive Patch 
     Each components (% by mass) indicated as Examples 1-8 shown in Table 1 were homogenously mixed, and the mixture was laminated over a supporting body to cover an adhesive base agent which was spread over a polyester film by coater to the thickness of 100 μm then cut to a given shape. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 1 
               
             
            
               
                   
                   
               
               
                   
                 Comp. Example 
                 Example 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Component 
                 1 
                 2 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Indomethacin 
                 Plaster of 
                 Indomethacin- 
                 4 
                 4 
                 4 
                 4 
                 4 
                 4 
                 4 
                 4 
               
               
                 L-menthol 
                 Japan 
                 containing 
                 4 
                 4 
                 4 
                 4 
                 4 
                 4 
                 4 
                 4 
               
               
                 Disodium edetate 
                 phamacopoeia 
                 adhesive 
                 — 
                 1 
                 — 
                 1 
                 — 
                 1 
                 1 
                 1 
               
               
                 Aluminum hydroxide 
                   
                 patch A 
                 — 
                 — 
                 2 
                 2 
                 2 
                 2 
                 2 
                 2 
               
               
                 S-I-S block copolymer 
                   
                   
                 19 
                 19 
                 20 
                 21 
                 19 
                 19 
                 20 
                 20 
               
               
                 High-MW polyisobutylene 
                   
                   
                 3 
                 3 
                 3 
                 2 
                 3 
                 3 
                 2 
                 2 
               
               
                 Low-MW polyisobutylene 
                   
                   
                 10 
                 10 
                 11 
                 6 
                 10 
                 10 
                 8 
                 11 
               
               
                 Alicyclic saturated HC resin 
                   
                   
                 13 
                 13 
                 13 
                 14 
                 13 
                 13 
                 14 
                 13 
               
               
                 Titanium oxide 
                   
                   
                 3 
                 3 
                 — 
                 — 
                 3 
                 3 
                 — 
                 — 
               
               
                 Liquid paraffin 
                   
                   
                 44 
                 43 
                 43 
                 46 
                 42 
                 41 
                 45 
                 43 
               
               
                 Skin irritation index (SI value) 
                 5.2 
                 27.6 
                 17.2 
                 15.5 
                 15.0 
                 15.0 
                 8.6 
                 6.9 
                 10.0 
                 5.0 
               
               
                   
               
               
                 (Note) 
               
               
                 S-I-S; Styrene-Isoprene-Styrene 
               
               
                 HC; Hydrocarbon 
               
            
           
         
       
     
     According to the above method (examples 1-8), an adhesive patch was produced, and skin irritancy of the adhesive patch was assessed by 48-hour patch test on 30 healthy male adult subjects. 
     A plaster of Japan Pharmacopoeia was used as Comparative Example 1, and a conventional indomethacin-containing adhesive patch (a content of indomethacin of 3.75% by mass) was used as Comparative Examples 2 respectively. 
     Each adhesive patch (size: circular form, 1.5 cm in diameter) was applied to a subject on the back for 48 hours, and after removing the patch skin irritation index (SI value) was obtained. The skin irritation index was obtained by the Sugai equation (see “Skin Research” vol. 27, No. 4, August 1985). The results are shown in Table 1,  FIG. 1 ,  FIG. 2  and  FIG. 3 . The vertical axis of each of the drawings shows the skin irritation index (SI value). 
       FIG. 1  shows test results on Examples 1 and 2 which did not contain aluminum hydroxide and Examples 5 and 6 which contained aluminum hydroxide. From these results, it was found that the skin irritation index (SI value) was reduced to half or less by containing aluminum hydroxide. It was also found that an adhesive patch containing only titanium oxide (Example 1 and 2) could reduce skin irritation index (SI value) to about 15-17 compared to comparative example 2 of 27.6 which contained indomethacin.  FIG. 2  shows test results on Example 3 which did not contain titanium oxide and Example 5 which contained titanium oxide. From these results, it was found that the skin irritation index (SI value) was reduced from 15.0 to 8.6 by containing titanium oxide. It was also found that the skin irritation index (SI value) was reduced from 27.6 to 15.0 by containing aluminum hydroxide. As above, it was found that an adhesive patch of Example reduced skin irritation and incidence of rash by containing aluminum hydroxide and/or titanium oxide in an adhesive base agent. Also, as shown in  FIG. 3 , an adhesive patch of Example similarly reduced skin irritation index (SI value) by increasing content of low-molecular-weight polyisobutylene in an adhesive base agent. Further, it was found that the skin irritation index (SI value) was reduced by containing an edetate (see Example 3 and Example 8). Therefore, according to the present invention, an adhesive patch with sufficiently reduced skin rash can be provided. 
     INDUSTRIAL APPLICABILITY 
     The present invention provides an adhesive patch for external use which causes reduced incidence of rash and reduced skin irritation by a drug itself, and the present invention has industrial applicability in pharmaceutical industry or industry relating to health promotion.