JPH06145050A - Production of patch - Google Patents

Abstract

PURPOSE:To produce a patch uniformly mixable, having excellent water vapor transmission and low irritation to skin. CONSTITUTION:A tacky agent composition comprising 100 pts.wt. tacky agent, 1-75 pts.wt. one or more selected from a group consisting of ethyl cellulose powder, crystal cellulose powder cellulose acetate powder, cross-linking type polyvinylpyrrolidone powder which is composed of N-vinyl-2-vinylpyrrolidone and a polyfunctional monomer and has >=0.5 gel fraction and a cross-linking type polymer powder cross-linked with a cross-linking agent, having 1-200mum particle diameter, 1-75 pts.wt. polyhydric alcohol and 0.1-50 pts.wt. medicine is applied to one side of a substrate having water vapor transmission by a hot-melt coater to produce a patch.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a patch having good moisture permeability.

[0002]

BACKGROUND OF THE INVENTION A patch is a preparation for administering a drug to the circulatory system of the body through the skin, in which an adhesive layer composed of an adhesive and a drug is laminated on one surface of a support. It is excellent in the sustainability of blood concentration and the convenience of drug administration method. Adhesives used in this patch include acrylic-based adhesives, rubber-based adhesives, and silicone-based adhesives, which are widely used. Since these adhesives do not have moisture permeability, they tend to cause skin disorders such as rashes and inflammations when applied to the skin surface.

As a patch for solving such a problem, Japanese Patent Publication No. 54-44688 discloses a patch in which a hydrophilic polymer such as methyl cellulose and hydroxyethyl cellulose and a polyhydric alcohol such as glycerin and polyethylene glycol are added to the adhesive. Is proposed.

Although the above-mentioned patch is less likely to cause irritation or inflammation during peeling, the hydrophilic polymer absorbs sweat produced during sweating exercise, moisture is less likely to evaporate, moisture permeability is deteriorated, and unevenness occurs. Occurs. Further, during the production, the hydrophilic polymer absorbs the polyhydric alcohol and swells, so that the hydrophilic polymer cannot be uniformly blended.

[0005]

In view of the above-mentioned drawbacks, the present invention has an object of providing a method for producing a patch which can be uniformly blended, has good moisture permeability, and has low skin irritation. .

[0006]

The pressure-sensitive adhesive used in the present invention may be any conventionally known pressure-sensitive adhesive, for example, acrylic pressure-sensitive adhesive, rubber pressure-sensitive adhesive and silicone pressure-sensitive adhesive are preferably used. It

The acrylic adhesive has 1 to 1 carbon atoms.
8, preferably 4-18 aliphatic alcohols and (meth)
Examples thereof include homopolymers and copolymers of alkyl (meth) acrylates obtained from acrylic acid, and copolymers of alkyl (meth) acrylates with other functional monomers.

Examples of the alkyl (meth) acrylate include butyl (meth) acrylate and isobutyl (meth) acrylate.
Acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, 2-ethylhexyl (meth)
Examples thereof include acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, methyl acrylate and ethyl acrylate.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group,
Examples thereof include monomers having an amide group, monomers having an amino group, and monomers having a pyrrolide ring. Examples of the monomer having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and 2-hydroxypropyl (meth) acrylate. Examples of the monomer having a carboxyl group include α, β unsaturated carboxylic acids such as acrylic acid and methacrylic acid, monoalkyl maleates such as butyl maleate, maleic acid, fumaric acid and crotonic acid. Maleic anhydride is used as well as maleic acid. Examples of the amide group-containing monomer include N-alkyl (meth) acrylamides such as (meth) acrylamide, N, N′-dimethyl (meth) acrylamide, N, N′-diethyl (meth) acrylamide, butoxymethylacrylamide, ethoxy. Examples thereof include N-alkoxymethyl (meth) acrylamide such as methyl acrylamide, diacetone acrylamide and the like. Examples of the monomer having an amino group include dimethylaminoethyl acrylate. Examples of the monomer having a pyrrolidone ring include N-vinyl-2-pyrrolidone.

Further, a copolymerizable monomer having no functional group may be further copolymerized with the above copolymer, and examples of the copolymerizable monomer include vinyl acetate, styrene, and the like.
α-methylstyrene, vinyl chloride, acrylonitrile,
Examples thereof include ethylene, propylene and butadiene.
It is preferable that the adhesive contains 50% by weight or more of an alkyl (meth) acrylate as a (co) polymerization component.

If necessary, a polyfunctional monomer may be added to the acrylic pressure-sensitive adhesive. The addition of this polyfunctional monomer causes cross-linking between the produced polymers,
This increases the internal cohesive force of the adhesive. Therefore, the so-called adhesive residue phenomenon at the time of peeling is improved almost regardless of the property of the applied skin and the amount of perspiration. Moreover, the addition of this polyfunctional monomer does not have any adverse effect on drug release and low skin irritation. Examples of such polyfunctional monomers include, but are not limited to, di (meth) acrylate, tri (meth) acrylate, tetra (meth) acrylate, and the like. More specifically, hexamethylene glycol di (meth) acrylate, octamethylene glycol di (meth) acrylate, etc. obtained by combining poly (methylene glycols) such as hexamethylene glycol and octamethylene glycol with (meth) acrylic acid. Di (meth) acrylate,
Di (meth) acrylates obtained by combining polyalkylene glycols such as polyethylene glycol and polypropylene glycol with (meth) acrylic acid, tri (meth) acrylates such as trimethylolpropane tri (meth) acrylate and glycerin tri (meth) acrylate. ) Acrylate and tetra (meth) acrylates such as pentaerythritol tetra (meth) acrylate. Two or more kinds of these polyfunctional monomers may be added. The amount of the polyfunctional monomer added is preferably 0.5% by weight or less based on the total amount of the monomers used for producing the pressure-sensitive adhesive.

If necessary, a tackifier such as rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin or terpene-phenol resin may be added to the acrylic adhesive.

As the rubber-based adhesive, natural rubber, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-
Olefin-styrene block copolymer, polyisoprene, polybutene, polyisobutylene, 100 parts by weight of rubber elastic body such as ethylene-vinyl acetate copolymer, for example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, 20 to 200 parts by weight of a tackifier such as terpene-phenol resin and, if necessary,
Liquid paraffin, liquid polybutene, mineral oil, lanolin, liquid polyisoprene, liquid polyacrylate, and other softening agents, titanium oxide and other fillers, and butyl hydroxytoluene and other antioxidants may be added in appropriate amounts.

Examples of the silicone-based adhesive include those containing polydimethylsiloxane as a main component. If necessary, a plasticizer, a filler, an antiaging agent, etc. may be added to the pressure-sensitive adhesive.

The powder used in the present invention includes ethyl cellulose powder, crystalline cellulose powder, cellulose acetate powder,
One selected from the group consisting of crosslinked polyvinylpyrrolidone powder composed of N-vinyl-2-vinylpyrrolidone and a polyfunctional monomer with a gel fraction of 0.5 or more, and crosslinked hydrophilic polymer powder crosslinked with a crosslinking agent. It is the above powder.

The above-mentioned crystalline cellulose powder is (11th revised Japanese Pharmacopoeia manual, D-537) obtained by partially depolymerizing α-cellulose with a mineral acid, and is a pure cellulose mainly containing a crystalline region. Microcrystalline cellulose such as Avicel manufactured by Asahi Kasei.

The cross-linked polyvinylpyrrolidone is N-
It is obtained by copolymerizing vinyl-2-vinylpyrrolidone and a polyfunctional monomer, and has a gel fraction of 0.5 or more. As such, BASF Japan Ltd. (BA
Examples of the product include Kollidon CF manufactured by SF Co., Ltd., and polyplasdon manufactured by GF Japan (GAF).

Examples of the polyfunctional monomer include di (meth) acrylates such as hexamethylene glycol di (meth) acrylate, ethylene glycol di (meth) acrylate, and triethylene glycol di (meth) acrylate, trimethylolpropane tri (meth) acrylate. ) Tri (meth) acrylates such as acrylates, tetra (meth) acrylates, polyallyl compounds such as diethylene glycol bisallyl carbonate, triallyl glycerin, triallyl cyanurate, polymaleimide compounds such as ethylene bismaleimide, divinylbenzene, divinyl ketone, butadiene , Isoprene and the like.

The method for measuring the crosslinked polyvinylpyrrolidone gel fraction is as follows. 0.5 g (initial weight) of the crosslinked product is added to 300 ml of methanol and stirred at 25 ° C. for 16 hours. After stirring, filter with a filter paper having a retained particle size of 5 μm,
The residue is dried and the weight (dry residue weight) is measured,
The gel fraction is calculated by dry residue weight / initial weight.

The hydrophilic polymer powder cross-linked with the above-mentioned cross-linking agent includes cellulose and cellulose such as methyl cellulose, ethyl cellulose, propyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose. Examples thereof include powders of derivatives, starches such as wheat starch, corn starch and potato starch, powders of starch decomposition products such as hydroxypropyl starch and dextrin, and synthetic polymers such as polyvinyl alcohol.

As the cross-linking agent, formaldehyde,
Aldehydes such as glutaraldehyde and glyoxal, tolylene diisocyanate, hexamethylene diisocyanate, diisocyanates such as 4,4′-diphenylmethane diisocyanate, epichlorohydrin,
Epoxy compounds such as polyalkylene glycol diglycidyl ether and hexahydrophthalic acid diglycidyl ester, mono-methylol melamine, di-methylol melamine, tri-methylol melamine, tetra-methylol melamine, penta-methylol melamine, hexa-methylol melamine, Examples thereof include N-methylol compounds such as N-methylol palmitoamide.

As a method for crosslinking the hydrophilic polymer, a known method can be used, for example, methyl cellulose, ethyl cellulose, propyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, etc. In the case of powders of cellulose and cellulose derivatives and powders of starch decomposition products such as hydroxypropyl starch and dextrin, a method of dispersing them in a solvent such as diethyl ether or cyclohexane and adding a crosslinking agent and, if necessary, a catalyst can be mentioned. Then, a method of dispersing it in water at 20 to 30 ° C. and adding a crosslinking agent and a catalyst if necessary is used. For starch, methanol is used. Ethanol, it is dispersed in a solvent, such as n- hexane, a method of adding a catalyst and the like in accordance with crosslinking agent and necessary.

Examples of the catalyst include di-n-butyltin maleate ester salt, di-n-butyltin bisoctylthioglycol ester salt, dibutyltin compound such as di-n-butyltin dilaurate, hydrochloric acid, sulfuric acid and phosphoric acid. And acid catalysts such as pyridine, triethylamine and benzylamine, and amine catalysts such as dimethylethanolamine.

The method for measuring the gel fraction is as follows.
For powders of cellulose and cellulose derivatives such as methyl cellulose, ethyl cellulose, propyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose, and powders of starch decomposition products such as hydroxypropyl starch and dextrin. Then, 0.5 g (initial weight) of the crosslinked product is added to 300 ml of water and stirred at 25 ° C. for 16 hours. After stirring, the mixture is filtered through a filter paper having a retained particle size of 5 μm, the residue is dried and the weight (dry residue weight) is measured, and the gel fraction is determined by the dry residue weight / initial weight. For polyvinyl alcohol, the gel fraction is determined by the same method as above except that the stirring temperature is 80 ° C.

Regarding starch, 1 g of the crosslinked product and 10 g of sulfuric anhydride were added to 100 ml of dimethyl sulfoxide, and
Stir at 5 ° C. for 6 hours. After stirring, this solution is put in a cellulose dialysis tube having a molecular weight cut of 5,000, dialyzed with ion-exchanged water, and the content is dried to obtain sulfated starch. Next, 0.5 g (initial weight) of the obtained sulfated starch is added to 300 ml of water and stirred at 25 ° C. for 16 hours. After stirring, the mixture is filtered through a filter paper having a retained particle size of 5 μm, the residue is dried, and the weight (dry residue weight) is measured to obtain the dry residue weight / initial weight.

Examples of the crosslinkable hydrophilic polymer powder crosslinked with the above crosslinking agent include crosslinkable potato starch crosslinked with trimethylolmelamine, crosslinkable polyvinyl alcohol crosslinked with glyoxal, and the like.

The particle size of the powder used in the present invention is limited to 1 to 200 μm because if the particle size is too small, the moisture permeability deteriorates, and if it is too large, the dispersibility in the pressure-sensitive adhesive layer becomes poor.

The above-mentioned powder may be added alone.
More than one species may be added, the amount of addition is 1 to 75 parts by weight with respect to 100 parts by weight of the adhesive, because if the amount is too small, the drug release becomes poor, and if it is too large, the adhesiveness becomes poor. It is preferably 5 to 50 parts by weight, more preferably 10 to 40 parts by weight.

Examples of the polyhydric alcohol used in the present invention include glycerin, sorbitol, maltitol, (poly) ethylene glycol, (poly) propylene glycol, butylene glycol, hexylene glycol, ethylene-propylene glycol copolymer and the like. can give.

The above-mentioned polyhydric alcohols may be added alone or in combination of two or more kinds. If the amount of addition is too small, the moisture permeability deteriorates, and if it is too large, the adhesive residue after peeling off the patch is left. Occurs, so 1 is to 100 parts by weight of the adhesive.
To 75 parts by weight, preferably 3 to 50 parts by weight, and more preferably 5 to 30 parts by weight.

Drug (physiologically active substance) used in the present invention
It is sufficient that it can permeate the biological membrane transdermally, and typical drugs include isosorbide nitrate, indomethacin, ketoprofen and the like.

However, the drug (physiologically active substance) used in the tape preparation of the present invention is not limited to the above.
Examples of drugs include antipyretic anti-inflammatory analgesics, antiepileptics, antipsychotics, antidepressants / anxiolytics, antidepressants, hypnotics, sedatives, antispasmodics, muscle relaxants, autonomic nerve agents, cerebral circulation.・ Metabolism improver, cardiotonic agent, antianginal agent, hypertension / arrhythmia agent, vasodilator, antihypertensive agent, pressor, diuretic, respiratory stimulant, antitussive expectorant, bronchodilator, asthma / nasal allergy treatment Agents, respiratory agents, cold agents, antiemetics, antacids, anti-ulcer agents, laxatives, antidiarrheal agents, liver agents, pancreatic disease therapeutic agents, choleretic agents, female hormone agents, androgen agents, Hypothalamic and pituitary hormones, ovulation inducers, diabetes insipidus treatments, thyroid hormone agents, anabolic hormone agents, antithyroid agents, calcium metabolizers, steroidal anti-inflammatory agents, nonsteroidal anti-inflammatory agents, anti-inflammatory Enzyme, antihistamine, antirheumatic, gout remedy, Antihyperglycemic agents, vitamins, hematopoietic agents, hemostatic agents, hyperlipidemia treatment agents, antibiotics, antitumor agents, immunosuppressants, antidotes, emetics, anthelmintics, antiprotozoal agents, hemorrhoids therapeutic agents, genitourinary organs Examples include agents, local anesthetics, anticoagulants, etc.

Representative examples of each drug are shown below. Antipyretic and anti-inflammatory analgesics include, for example, indomethacin, salicylic acid,
Glycol salicylate, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibufenac, fenbufen, alclofenac, phenylbutazone, mefenamic acid, bendazac, piroxicam, flurbiprofen, pentazocine, Examples include buprenorphine hydrochloride and butorphanol tartrate.

Examples of the steroidal anti-inflammatory agent include hydrocortisone, prednisolone, fluocinolone acetonide, fludroxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, betamethasone acetate, diflucortron valerate and propionate. Examples include clobetasol and fluocinonide.

Examples of the vasodilator include diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, isosorbide dinitrate, nifedipine, nitroglycerin and the like.

Examples of the antihypertensive / arrhythmic agents include propanolol, atenolol, pindolol, quinidine sulfate, azimarin, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, disopyramide and the like.

Examples of the antihypertensive agent include clonidine hydrochloride, captopril, prazosin hydrochloride, penbutrol sulfate, guanabenz acetate, guanfacine hydrochloride, bunazosin hydrochloride, ellanapril maleate, arotinolol hydrochloride, and bunitrolol hydrochloride.

Examples of the antitussive and expectorant include procaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pirbuterol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimetoquinol hydrochloride and formoterol fumarate. can give.

Examples of the antitumor agent include 5-fluorouracil, 1- (2-tetrahydrofuryl) -5-fluorouracil, mitomycin C and the like. Examples of the local anesthetic include benzocaine, procaine, lidocaine and tetracaine.

Examples of the hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, progesterone and prostaglandin, and peptide hormones such as insulin. Examples of the therapeutic agent for asthma / nasal allergy include ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate and the like.

Examples of the antihistamine include cycloheptazine hydrochloride, diphenhydramine hydrochloride, phenbenzamine, mequitazine and the like. Examples of the anticoagulant include heparin and the like. Examples of antispasmodic agents include scopolamine, clofluperol, and the like.

Examples of the cerebral circulation / metabolic agent include vinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, brovincamine fumarate, dihydroergotoxine mesylate, ifenprodil tartrate, isoxuprine hydrochloride and the like.

Examples of the antidepressant / anxiolytic agents include maprotiline hydrochloride, etizolam, diazepam, bromazepam, amitriptyline hydrochloride, mianserin hydrochloride and the like. Examples of vitamin D preparations include alfacalcidol, ergocalciferol and the like.

Examples of hypoglycemic agents include glibenclamide, gliclazide and the like. Examples of the anti-ulcer agent include clevobride malate, famotidine,
Examples include glycopyrronium bromide.

Examples of the sleeping agent include phenobarbital and amobarbital. Examples of antibiotics include tetracycline and chloramphenicol.

The amount of these drugs added varies depending on the type of drug, the purpose of use of the transdermal preparation, etc. If the amount is too small, the desired drug effect cannot be expected, and if it is too large, no further drug effect can be expected. Since the compatibility with the base becomes poor, it is 0.1 to 50 parts by weight with respect to 100 parts by weight of the adhesive.
Further, an absorption promoter may be added to the pressure-sensitive adhesive layer in order to improve the absorbability of the drug into the living body.

The method for producing a patch of the present invention comprises an adhesive and one or more kinds selected from the group consisting of ethyl cellulose powder, crystalline cellulose powder, cellulose acetate powder, crosslinked polyvinylpyrrolidone powder and crosslinked hydrophilic polymer powder. A powder, a polyhydric alcohol, a drug, and an absorption promoter that is optionally added are melt-mixed to prepare a pressure-sensitive adhesive composition, and the pressure-sensitive adhesive composition is provided with a moisture-permeable support by a hot-melt coating machine. The above powder and polyhydric alcohol are preferably added to and mixed with the molten adhesive.
Alternatively, the pressure-sensitive adhesive layer may be formed on the protective release paper and then transferred to the support.

The melt-mixing temperature varies depending on the kind of the pressure-sensitive adhesive, but is generally 70 to 200 ° C., and it is preferable to carry out in a nitrogen atmosphere. Powders such as crystalline cellulose powder are preferably added and mixed at a melting temperature of the powder or lower and at 50 to 180 ° C. The mixing conditions are, for example, a rotation speed of 30 to 300 rpm and a rotation time of 1 to 300 in the melt mixer.
It is preferable that they are mixed by stirring for a minute.

The thickness of the pressure-sensitive adhesive layer varies depending on the purpose of use, but is preferably 10 to 400 μm.

As the moisture-permeable support, a non-woven fabric made of polyester, polyethylene, polyvinyl chloride, polyvinylidene chloride, polyethylene-vinyl acetate copolymer, polyurethane, cellulose, cellulose acetate, etc. as a raw material, Woven cloth or paper, polyurethane film, pore size 0.1
An example of the film is a perforated plastic film having a thickness of -60 μm. The thickness of the non-woven fabric, woven fabric or paper is preferably 5 to 2000 μm, and the polyurethane film has a pore size of 0.1 to 60 μm.
The thickness of m perforated plastic film is 5-10
0 μm is preferable.

The adhesive patch is usually provided with a release paper on its adhesive surface to protect the surface of the adhesive layer until use.
As the release paper, polyester film, polypropylene film, polyethylene-coated high-quality paper, polyethylene-coated glassine paper, and polyolefin-coated glassine paper treated with silicone are often used, but the release paper is not limited thereto. The thickness of the release paper is 1000 μm or less, preferably 20 to 200 μm.

The obtained patch is usually applied directly to the surface of the skin or mucous membrane for the purpose of transdermally or transmucosally administering the drug to the internal circulatory system. In addition, these patches may be applied to the skin or mucous membrane for the purpose of treating a diseased part of the skin or mucous membrane.

[0053]

The pressure-sensitive adhesive layer of the patch prepared by the present invention comprises 100 parts by weight of pressure-sensitive adhesive, ethyl cellulose powder having a particle size of 1 to 200 μm, crystalline cellulose powder, cellulose acetate powder, N
-Crosslinking polyvinylpyrrolidone powder having a gel fraction of 0.5 or more composed of vinyl-2-vinylpyrrolidone and a polyfunctional monomer, and crosslinkable hydrophilic polymer powder having a gel fraction of 0.5 or more crosslinked with a crosslinking agent. 1 to 75 parts by weight of at least one powder selected from the group consisting of
It consists of 75 parts by weight and 0.1 to 50 parts by weight of the drug, and since it is laminated on the support by the hot melt coating method,
Good moisture permeability. This is ethyl cellulose powder, crystalline cellulose powder, cellulose acetate powder, N-vinyl-2-
A cross-linking polyvinylpyrrolidone powder composed of vinylpyrrolidone and a polyfunctional monomer having a gel fraction of 0.5 or more and a cross-linking hydrophilic polymer powder having a gel fraction of 0.5 or more cross-linked with a cross-linking agent are contained in an adhesive layer. Since the polyhydric alcohol is uniformly dispersed and the polyhydric alcohol is added to the pressure-sensitive adhesive layer, a moisture transpiration path can be formed, and the moisture permeability of the patch is improved. Furthermore, ethyl cellulose powder, crystalline cellulose powder, cellulose acetate powder, cross-linked polyvinylpyrrolidone powder composed of N-vinyl-2-vinylpyrrolidone and a polyfunctional monomer with a gel fraction of 0.5 or more, and a gel component crosslinked with a crosslinking agent. The crosslinkable hydrophilic polymer powder having a ratio of 0.5 or more does not easily swell due to binding with water molecules, and therefore has no moisture trap and is excellent in moisture permeability.

Further, the gel fraction of ethyl cellulose powder, crystalline cellulose powder, cellulose acetate powder, N-vinyl-2-vinylpyrrolidone and polyfunctional monomer was 0.
The crosslinked polyvinylpyrrolidone powder of 5 or more and the crosslinkable hydrophilic polymer powder crosslinked with the crosslinking agent and having a gel fraction of 0.5 or more do not easily absorb the polyhydric alcohol, and thus can be uniformly blended during the production.

[0055]

EXAMPLES Next, examples of the present invention will be described. In the following, "parts" means "parts by weight". The evaluation methods and measurement methods for the coatability test, skin migration test, moisture permeability test, and patch test shown in the results are as follows.

1) Coating Property Test The coating property of the pressure-sensitive adhesive layer on the test piece of patch (area 12 cm ² ) was determined as follows. ◯: The adhesive layer is uniformly coated on the support. Δ: The pressure-sensitive adhesive layer is coated on the support, but it is non-uniform. X: The pressure-sensitive adhesive layer cannot be coated on the support. 2) Skin transfer test A test piece of the patch (on the depilated back of Wistar rats)
An area of 3.14 cm ² ) was attached, and after 12 hours, this was peeled and collected. The collected test pieces were subjected to extraction treatment with methanol, and the residual amount of the drug in the patch was measured by high performance liquid chromatography to obtain the difference between the amount of the drug before application and the amount after application of the patch. The amount transferred to the skin was represented by an average value obtained by repeating this operation 4 times and dividing the total sum of the measured values by 4 times of repetition.

3) Moisture Permeability Test It was conducted according to JIS Z0208. Put 12 g of anhydrous calcium chloride in the cup, seal the mouth of the cup with the test piece of the patch, put in constant temperature and humidity of temperature ± 1 ° C, humidity 90 ± 2% and leave for 24 hours, then measure the mass increase of calcium chloride. 1
It is expressed by the mass increase per m ² . 4) Adhesiveness test A patch test piece (area: 12 cm ² ) was applied to the forearm of a healthy person for 12 hours, and the adhesiveness of the adhesive patch, the adhesive residue, and the irritation caused by the adhesive patch were determined as follows. i) Adhesiveness ○: Residual patch area of patch is 95% or more △: Residual patch area of patch is more than 75% and less than 95% ×: Residual patch area of patch is 75% or less ii) Moisture 0: No stuffiness 1: Mild tinge barely discernible 2: Clear stuffiness

Crosslinking of Potato Starch 100 parts of 70-90 μm potato starch (manufactured by Hokuren Agricultural Cooperative Society) were dispersed in 100 parts of methanol, and hydrochloric acid was added to the dispersion to adjust the pH to 3. Further, 2 parts of trimethylolmelamine was added, the mixture was stirred at 25 ° C. for 10 hours to carry out a crosslinking reaction, and after the reaction, the solvent was distilled off to give 40
The residue remaining on the 0 mesh sieve was passed through an 80 mesh sieve to obtain a crosslinked potato starch having a particle size of 38 to 175 μm.

Crosslinking of polyvinyl alcohol Polyvinyl alcohol (C-17S, manufactured by Shin-Etsu Chemical Co., Ltd.) 1
00 parts was dispersed in 100 parts of water, and hydrochloric acid was added to the dispersion to adjust the pH to 3. Further, 2 parts of trimethylolmelamine was added, and the mixture was stirred at 25 ° C. for 24 hours to carry out a crosslinking reaction. After the reaction, the solvent was distilled off, and the remaining residue was passed through a 400-mesh sieve and passed through an 80-mesh sieve. Then, a cross-linked polyvinyl alcohol-1 having a particle size of 38 to 175 μm was obtained.

Polyvinyl alcohol (Shin-Etsu Chemical Co., Ltd., C
-17) 100 parts of water was dispersed in 100 parts of water, and hydrochloric acid was added to the dispersion to adjust the pH to 3. Further, 2 parts of trimethylolmelamine was added, and the mixture was stirred at 25 ° C. for 24 hours to carry out a crosslinking reaction. After the reaction, the solvent was distilled off, and the residue remaining on a 60 mesh sieve was taken out to obtain a particle size of 246.
Cross-linked polyvinyl alcohol-2 having a size of at least μm was obtained.

Synthesis of Adhesives A and B : Predetermined amount of styrene-isoprene-styrene block copolymer (Califlex TR1107 manufactured by Shell Chemical Co., Ltd.), alicyclic hydrogenated petroleum resin (Arakawa Chemical Co., Ltd.) Manufactured by Alcorn-P90), polybutene (manufactured by Nisseki Chemical Co., Ltd., HV-300) and liquid paraffin (manufactured by Nikko Pharmaceutical Co., Ltd.) by a melt mixer (manufactured by Tokushu Kika Kogyo Co., Ltd., TK Combimix 2T-100 type). ), While stirring and purging with nitrogen, the temperature is raised to 150 ° C. and the adhesive is melted.
Got

[0062]

[Table 1]

Synthesis of adhesive mass C 43.75 parts of lauryl acrylate, 31.25 parts of butyl methacrylate, 25 parts of N-vinyl-2-pyrrolidone and 12 parts of isopropyl alcohol were fed to a separable flask equipped with a stirrer and a cooling device. The temperature was raised to 110 ° C. while stirring and purging with nitrogen. Lauroyl peroxide 1.
A solution prepared by dissolving 3 parts in a mixed solvent of 50 parts of cyclohexane and 50 parts of ethyl acetate was divided into 20 parts, and 1 part thereof was added to a separable flask to start polymerization. The remaining 19 was added at 1-hour intervals from the 5th hour after the start of the reaction, and the reaction was continued for another 19 hours after the completion of the addition. After completion of the reaction, the solvent was distilled off under reduced pressure,
An adhesive mass C having a solid content of 99.8% or more was obtained. Examples 1 to 6 and Comparative Examples 1 to 9 Adhesives A, B or adhesive lump C were supplied to a melt mixer (manufactured by Tokushu Kika Kogyo Co., Ltd., TK Combimix 2T-100 type), stirred and stirred. The temperature was raised to 150 ° C. while substituting with nitrogen, and a predetermined amount of crystalline cellulose powder shown in Table 2 was added to the melted adhesive A, B or C (Avicel, Asahi Kasei, particle size 30 μm).
m), cross-linked polyvinyl pyrrolidone powder (manufactured by BASF, Kollidon CL), cross-linked polyvinyl alcohol powder-1 (particle size 38 to 175 μm), cross-linked polyvinyl alcohol powder-2 (particle size 246 μm or more), cross-linked potato starch. Powder (particle size 38 to 175 μm), potato starch powder (Hokuren Agricultural Cooperative, particle size 70
˜90 μm) and polyhydric alcohol are added, and the mixture is stirred and mixed, further cooled to 110 ° C. with stirring, and the drug and crotamidon shown in Table 2 are mixed with the adhesive A, the adhesive B or the adhesive C, A mixture was obtained. This mixture was spread on a polyethylene-coated high-quality paper with a thickness of 200 μm by a hot-melt coater (Yuri Roll Machine Co., Ltd., GPD300E), and a 30 μm-thick polyurethane film support was laminated to obtain a patch. It was

[0064]

[Table 2]

With respect to the obtained patch, a coatability test,
A skin migration test, a moisture permeability test and an adhesive property test were conducted, and the results are shown in Table 3.

[0066]

[Table 3]

[0067]

The method for producing a patch of the present invention comprises an adhesive,
Ethyl cellulos powder having a particle diameter of 1 to 200 μm, crystalline cellulose powder, cellulose acetate powder, cross-linking polyvinylpyrrolidone powder having N-vinyl-2-vinylpyrrolidone and a polyfunctional monomer with a gel fraction of 0.5 or more, and a cross-linking agent. A pressure-sensitive adhesive composition composed of one or more powders selected from the group consisting of cross-linked hydrophilic polymer powder having a gel fraction of 0.5 or more, a polyhydric alcohol, and a drug is passed through a hot melt coating machine. Since it is applied to one side of the wet support,
The adhesive layer can be applied uniformly, and the obtained patch has good moisture permeability and low irritation to the skin.

Claims (1)

[Claims] 1. Adhesive 100 parts by weight, particle size 1 to 200 μm
m ethyl cellulose powder, crystalline cellulose powder, cellulose acetate powder, crosslinked polyvinylpyrrolidone powder having a gel fraction of 0.5 or more composed of N-vinyl-2-vinylpyrrolidone and a polyfunctional monomer, and a crosslinked type crosslinked with a crosslinking agent. Hot-melt coating an adhesive composition comprising 1 to 75 parts by weight of one or more powders selected from the group consisting of hydrophilic polymer powders, 1 to 75 parts by weight of polyhydric alcohol and 0.1 to 50 parts by weight of a drug. A method for producing a patch, which comprises applying to a surface of a support having moisture permeability with a machine.