JPH0726231A - Adhesive composition and percutaneous absorption preparation using the same - Google Patents

Abstract

(57) [Summary] [Object] To provide a pressure-sensitive adhesive composition having a good balance between the adhesive force and the cohesive force and having less skin irritation, and a transdermal preparation using the same. [Structure] A pressure-sensitive adhesive composed of a copolymer containing an amide compound as a constituent and a polymer containing a maleic anhydride as a constituent, or a pressure-sensitive adhesive composed of a copolymer containing an amine compound as a constituent and an anhydride. An adhesive composition comprising a polymer having maleic acid as a constituent, and a transdermal preparation comprising an adhesive layer comprising the adhesive composition and a drug laminated on one side of a support.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an adhesive composition having excellent adhesiveness and less irritation, and a percutaneous absorption preparation using the same.

[0002]

2. Description of the Related Art Conventionally, in the treatment of diseases, oral administration and injection administration of drugs are generally used. However, normally, in the case of oral administration of a drug, it is difficult to keep the absorption amount constant because the absorbability of the drug depends on the pH in the stomach or intestines and the presence or absence of food residues. Depending on the type, the blood concentration rises sharply,
Side effects such as orthostatic anemia and headache may occur. Further, in the case of a drug having a short half-life, the effective blood concentration may have a short duration, so that it may not be possible to maintain a sufficient drug effect.

In order to solve the above-mentioned problems, an adhesive layer containing a drug is laminated on a support, and a preparation is attached to the skin,
A method of transdermally administering a drug to the body is known. For example, JP-B-54-16566 proposes a transdermal absorption preparation in which a storage layer in which a drug is encapsulated is dispersed in an adhesive layer. However, in the case of this transdermal preparation, there is a drawback that the diffusion of the drug into the adhesive layer adjacent to the storage layer is rate-determining and the drug release property is low.
Further, the encapsulation has a drawback that the manufacturing process becomes complicated and the cost becomes high.

In addition to the above-mentioned properties, the transdermal preparations are required to be surely adhered to the skin for about 24 to 48 hours after being applied to the skin to absorb the required amount of drug.
It is necessary that it adheres and does not separate even when sweating or taking a bath. It is also necessary to be able to peel off with a peeling force that does not hurt when peeling, and if the adhesive strength is stronger than necessary, peeling of the hair and exfoliation of the keratin will occur during peeling, and mechanical skin irritation due to skin tension will occur. . As a result, erythema occurs,
In severe cases, scab formation and edema formation are involved, and this may continue for several days even after peeling. Therefore, it is necessary to minimize such inconvenience. It is also required that the adhesive does not remain on the skin surface after peeling the transdermal preparation from the skin.

Japanese Unexamined Patent Publication (Kokai) No. 58-134020 discloses an acrylate ester 8 having an ester moiety having 4 to 10 carbon atoms.
5 to 99 wt% and (meth) acrylic acid 1 to 15 wt%
A percutaneous absorption preparation has been proposed in which a drug is contained in an adhesive composition consisting of. However, in the case of this percutaneous absorption preparation,
Although it has the above-mentioned characteristics and mechanical skin irritation due to pulling of the skin is small, it has a drawback that skin irritation may occur due to the influence of the (meth) acrylic acid component when applied for a long time.

In Japanese Patent Laid-Open No. 61-100520, 2
-Ethylhexyl acrylate 45 mol%, vinylpyrrolidone 20-55 mol% and the carbon number of the ester portion is 3
Consists of 35 mol% or less of acrylic acid ester of
Further, the polyfunctional monomer is added to 0.005 of the total monomer weight.
Adhesives containing ~ 0.5 wt% have been proposed. However, although the transdermal preparation using this adhesive has the above-mentioned properties, when a softening agent, a plasticizer or the like is added to improve the drug release property, the cohesive force is insufficient and the adhesive residue remains. There was a drawback that it would occur. Therefore, in order to obtain an excellent patch, it is necessary to solve the problem of adhesive residue.

By the way, in transdermal absorption preparations, a method of crosslinking the pressure-sensitive adhesive has been used in order to secure an appropriate cohesive force of the pressure-sensitive adhesive layer and eliminate adhesive residue. For example, a method of slightly cross-linking the pressure-sensitive adhesive itself with a cross-linking agent, or a method of forming a pressure-sensitive adhesive layer and then crosslinking by a metal ion cross-linking, urethane cross-linking, epoxy cross-linking, melamine cross-linking or a radical reaction by peroxide or electron beam irradiation. It has been known. However, when the above-mentioned cross-linking method is applied, there is a drawback that the cohesive force is improved, but the adhesiveness is lowered due to curing of the pressure-sensitive adhesive, and the sticking property is deteriorated.

As a technique for improving the cohesive force without using such a crosslinking method, JP-A-63-135328 discloses a water-soluble polymer substance and a first methoxyethylene-maleic anhydride copolymer. A percutaneous absorption preparation containing a primary alcohol monoester has been proposed. However, in the case of this percutaneous absorption preparation, although the shape retention of the pressure-sensitive adhesive layer can be enhanced, the adhesive strength to the skin is poor, and stickiness at the time of application due to insufficient cohesive strength of the adhesive and adhesive residue on the skin There was a drawback.

[0009]

SUMMARY OF THE INVENTION In view of the above, the present invention provides an adhesive composition having a good balance between adhesive strength and cohesive strength and less skin irritation, and a transdermal preparation using the same. The purpose is to

[0010]

The gist of the present invention is that a pressure-sensitive adhesive composition is composed of a pressure-sensitive adhesive comprising a copolymer having an amide compound as a constituent and a polymer having maleic anhydride as a constituent. Exist in.

The above amide compounds include primary amides, secondary amides and tertiary amides. The above-mentioned primary amide means that the two substituents of the nitrogen atom bonded to the carbonyl carbon are both hydrogen atoms. The secondary amide means that only one substituent of the nitrogen atom bonded to the carbonyl carbon is a hydrogen atom. The above-mentioned tertiary amide means that the two substituents of the nitrogen atom bonded to the carbonyl carbon are both other than hydrogen atom. The tertiary amide includes, in addition to the chain amide, a cyclic amide in which a nitrogen atom is bonded to a carbonyl carbon via an alkylene group having 2 to 7 carbon atoms.

Examples of the primary amide include acrylamide, crotonamide, and 3,4-buteneamide.

Examples of the secondary amide include N-
Methyl (meth) acrylamide, N-ethyl (meth) acrylamide, N-butyl (meth) acrylamide, N
-Methylol (meth) acrylamide, N-vinyl acetamide, N-vinyl propionamide, N-vinyl butanamide, N-vinyl pentanamide, etc. are mentioned.

Examples of the chain-like tertiary amide include, for example,
N, N-dimethyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, N, N-dinormalpropyl (meth) acrylamide, N, N-diisopropyl (meth) acrylamide, N, N-dibutyl (meth)
Examples thereof include acrylamide and the like, and examples of the cyclic tertiary amide include N-vinylpropiolactam, N-vinyl-2-pyrrolidone, N-vinyl-2-piperidinone and the like, and particularly N-vinyl-2. -Pyrrolidone is preferably used.

The above primary amide, secondary amide or tertiary amide may be used alone or in combination.

If the content of the above primary amide, secondary amide or tertiary amide is reduced, the effect of enhancing the cohesive force due to the addition of the polymer having maleic anhydride as a constituent is less likely to be exhibited, and if it is increased. Since the adhesive strength decreases, it is preferably 1 to 60% by weight in the adhesive, more preferably 5 to 3
It is 0% by weight.

The above-mentioned pressure-sensitive adhesive is a copolymer having the above-mentioned amide compound as a constitutional component, and for example, a copolymer with (meth) acrylic acid alkyl ester; a copolymer with ethylene and vinyl acetate; polybutene, poly With respect to rubber-based polymers such as isoprene and styrene-isoprene-styrene block copolymers, for example, adducts such as N-vinyl-2-pyrrolidone and the like can be mentioned. Particularly, copolymers with (meth) acrylic acid alkyl ester are preferable. It is preferably used.

Examples of the above-mentioned (meth) acrylic acid alkyl ester include methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate,
Butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl (meth) acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate, (meth)
Isodecyl acrylate, lauryl (meth) acrylate,
Examples thereof include tridecyl (meth) acrylate and stearyl (meth) acrylate, and these may be used alone or in combination.

In the copolymer with the (meth) acrylic acid alkyl ester, a polyfunctional monomer may be copolymerized in the range of 0.005 to 0.5% by weight for the purpose of enhancing the cohesive force of the pressure-sensitive adhesive. Good.

Examples of the polyfunctional monomer include, for example,
1,6-hexane glycol dimethacrylate, tetraethylene glycol diacrylate, trimethylolpropane triacrylate, divinylbenzene, divinyltoluene, diallyl phthalate and the like can be mentioned.

To prepare a copolymer with the above-mentioned (meth) acrylic acid alkyl ester, usually, solution polymerization of the required monomer is carried out in the presence of a polymerization initiator. However, the polymerization form is not limited to this. The polymerization reaction conditions are appropriately selected mainly depending on the type of monomer. When carrying out solution polymerization, for example, ethyl acetate or other general polymerization solvent is added to a predetermined amount of the required monomer, and azobis type, peroxide type, etc. are added in a reaction vessel equipped with a stirrer and a cooling reflux device. 70 to 90 ° C. in a nitrogen atmosphere in the presence of a polymerization initiator,
The reaction may be performed for 8 to 40 hours. The above-mentioned monomer and solvent may be added all at once, or may be added in divided amounts as appropriate. It is desirable to add the polymerization initiator appropriately in divided portions according to the progress of the reaction.

Examples of the azobis-based polymerization initiator include 2,2'-azobis-iso-butyronitrile,
1,1′-azobis (cyclohexane-1-carbonitrile), 2,2′-azobis- (2,4-dimethylvaleronitrile) and the like can be mentioned. Examples of the peroxide-based polymerization initiator include peroxides. Examples thereof include lauroyl oxide, benzoyl peroxide, di (ter-butyl) peroxide and the like.

If desired, a tackifier, a plasticizer or the like may be added to the pressure-sensitive adhesive. Examples of the pressure-sensitive adhesive include rosin-based resins such as hydrogenated rosin ester,
Examples thereof include terpene-based resins, petroleum-based resins, coumarone-indene resins, terpene-phenol resins, and rosin-based resins are preferably used.

Examples of the plasticizer include cetyl octanoate, hexyl laurate, isopropyl myristate, isopropyl palmitate, butyl stearate,
Fatty acid esters of monohydric alcohols such as octyl stearate, octyl hydroxystearate, ethyl oleate, decyl oleate, myristyl lactate; dibasic acid esters such as dioctyl adipate, diethyl sebacate, dioctyl sebacate, dioctyl succinate; Propylene glycol dicaprate, glyceryl trioctanoate, tri (octanoic acid / decanoic acid) glyceryl, fatty acid esters such as polyhydric alcohols such as medium chain fatty acid triglycerides, fatty acids corresponding to these fatty acid esters; polyvalent such as glycerin and diglycerin Alcohol; C4 or more alkylene glycol; Allyl alkyl alcohol; Low molecular weight polyvinyl methyl ether; Triacetin; Liquid polysaccharide; C12 or more alkyl trimethyl ammonium chloride Liquid cationic surfactants such as; nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, fatty acid diethanolamides, sorbitan alkyl esters, sorbitan polyoxyethylene alkyl esters; amphoteric interfaces such as dimethyl betaine Activators: liquid amino acids and the like can be mentioned, and isopropyl myristate, isopropyl palmitate, diethyl sebacate, fatty acid esters such as medium-chain fatty acid triglyceride, polyethylene glycol and triacetin are preferably used.

The above-mentioned plasticizer is added as necessary, but if it increases, the cohesive force and the adhesive force of the pressure-sensitive adhesive will decrease. Therefore, it is preferably 50% by weight or less, more preferably 40% by weight or less in the pressure-sensitive adhesive layer. Is.

The polymer having maleic anhydride as a constituent used in the present invention is not particularly limited as long as it contains maleic anhydride, and other constituents are not particularly limited, and examples thereof include methoxyethylene and ethoxyethylene. Copolymer with vinyl ether; Copolymer with alkyl (meth) acrylate such as methyl (meth) acrylate and ethyl (meth) acrylate; Copolymer with styrene; Polyolefin with polyethylene, polypropylene, etc. Copolymers; maleic anhydride adducts of rubber-based polymers such as polybutadiene, polyisoprene, styrene-isoprene-styrene block copolymers, and the like, and particularly copolymers with ethoxyethylene, copolymers with styrene, and A maleic anhydride adduct of polyisoprene is preferably used.

The copolymer of methoxyethylene and maleic anhydride is, for example, GANTREZ AN.
(Manufactured by G.A.F.) is commercially available, and grades thereof include AN-119 (intrinsic viscosity 0.1 to 0.5),
AN-139 (intrinsic viscosity 1.0 to 1.4), AN-14
9 (intrinsic viscosity 1.5 to 2.0), AN-169 (intrinsic viscosity 2.6 to 3.5), AN-179 (intrinsic viscosity 3.5 to
4.5) and the like, AN-119 (intrinsic viscosity 0.1
.About.0.5) and AN-169 (intrinsic viscosity 2.6 to 3.
5) is preferably used.

The content of the polymer containing maleic anhydride as a constituent component varies depending on the components of the polymer containing maleic anhydride as a constituent component and the composition ratio thereof, and cannot be generally stated, but in general, When the amount is small, the effect of improving the cohesive force of the pressure-sensitive adhesive is small, and when the amount is large, the cohesive force of the pressure-sensitive adhesive is improved, but the pressure-sensitive adhesive force is decreased. Therefore, 0.01 to 20% by weight is preferable in the pressure-sensitive adhesive layer, and more preferably 0. It is 1 to 5% by weight.

The present invention 3 comprises a pressure-sensitive adhesive composition comprising a pressure-sensitive adhesive comprising a copolymer having an amine compound as a constituent and a polymer having maleic anhydride as a constituent.

The above-mentioned amine compounds include primary amines, secondary amines and tertiary amines. Examples of the above primary amines include allylamine and p-aminostyrene. Examples of the secondary amine include ethyleneimine and N-methylallylamine. Examples of the tertiary amine include 2-vinylpyridine, 4-vinylpyridine, dimethylaminoethyl (meth) acrylate, and the like.

The above primary amine, secondary amine or tertiary amine may be used alone or in combination.

If the content of the above primary amine, secondary amine or tertiary amine decreases, the effect of enhancing the cohesive force due to the addition of the polymer having maleic anhydride as a constituent component is less likely to be exhibited, and thus the content is high. If so, the adhesive strength is reduced, so 1 to 60% by weight in the adhesive is preferable, and more preferably 5 to
It is 30% by weight.

The copolymer containing the above amine compound as a constituent is, for example, a copolymer with (meth) acrylic acid alkyl ester; a copolymer with ethylene and vinyl acetate; polybutene, polyisoprene, styrene-isoprene- Examples thereof include adducts of rubber polymers such as styrene block copolymers, and particularly, copolymers with alkyl (meth) acrylates are preferably used.

The fourth aspect of the present invention comprises a percutaneous absorption preparation in which a pressure-sensitive adhesive layer comprising the pressure-sensitive adhesive composition of the present invention and a drug is laminated on one side of a support.

The support is preferably one which is impermeable or hardly permeable to the drug and is flexible, and examples thereof include cellulose acetate, ethyl cellulose, polyethylene, polypropylene, polyvinyl chloride, and vinyl acetate-vinyl chloride copolymer. Coal, ethylene-methyl acrylate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-carbon monoxide copolymer, polyvinylidene chloride, polyurethane, nylon, Examples thereof include resin films such as polyethylene terephthalate and polybutylene terephthalate; aluminum sheets and the like, which may be a laminated sheet of these and may be laminated with a woven fabric or a nonwoven fabric. Further, for the purpose of enhancing the adhesiveness to the pressure-sensitive adhesive layer, surface treatment such as corona treatment or plasma discharge treatment may be performed, or anchor coating treatment may be performed with an anchor agent.

The drug contained in the pressure-sensitive adhesive composition is not particularly limited as long as it can permeate the biological membrane transdermally, and examples thereof include general anesthetics, sleep / analgesics, antiepileptics, antipyretic analgesia. Anti-inflammatory agents, steroidal anti-inflammatory agents, stimulants / stimulants, sedatives, neuropsychiatric agents, local anesthetics, skeletal muscle relaxants, autonomic nerve agents, antispasmodic agents, antiparkinson agents, antihistamines, cardiotonic agents, arrhythmic agents, Diuretic, antihypertensive,
Vasoconstrictor, vasodilator, arteriosclerosis agent, respiratory stimulant,
Antitussive expectorant, peptic ulcer treatment agent, choleretic agent, hormonal agent,
Urogenital and anal agents, parasitic skin disease agents, emollients, vitamins, mineral agents, hemostatic agents, blood coagulation inhibitors, liver disease agents, addictive agents, gout remedies, diabetes agents , Antineoplastic agents, radiopharmaceuticals, Kampo medicines, antibiotics, chemotherapeutic agents, antiparasitic / antiprotozoal agents, narcotics and the like.

Examples of the antipyretic analgesic and anti-inflammatory agent include acetaminophen, phenacetin, mefenamic acid, diclofenac sodium, flufenamic acid, aspirin, sodium salicylate, aminopyrine, alclofenac, ibuprofen, naproxen, flurpiprofen, ketoprofen, Examples of the steroidal anti-inflammatory agent include amphenac sodium, mepyrizole, indomethacin, pentazocine, piroxicam, and the like, for example, hydrocortisone, triamcinolone,
Examples include dexamethasone, betamethasone, and prednisolone.

Examples of the vasodilators include diltiazem hydrochloride, pentaerythritol tetranitrate, isosorbide nitrate, trazipyr, nicorandil, nitroglycerin, prenylamine lactate, molsidomine, amyl nitrite, and the like.
Examples thereof include tolazoline hydrochloride. Examples of the agent for arrhythmia include procainamide hydrochloride, lidocaine hydrochloride,
Examples thereof include propranolol hydrochloride, alprenolol hydrochloride, atenolol, nadolol, metoprolol tartrate, azmarin, disopyramide, mexiletine hydrochloride and the like.
Examples of the antihypertensive agent include ecarazine hydrochloride, indapamide, clonidine hydrochloride, bunitrolol hydrochloride, labetalol hydrochloride, captopril, guanabenz acetate, mebutamate, betanidine sulfate and the like. As the antitussive expectorant, for example, carbetapentane citrate,
Cloperastine, oxerazine tannate, clobutynol hydrochloride, clofedanol hydrochloride, noscapine hydrochloride, ephedrine hydrochloride, isoproterenol hydrochloride, chlorprenaline hydrochloride, methoxyphenamine hydrochloride, procaterol hydrochloride, tulobuterol hydrochloride, clenbuterol hydrochloride, ketotifen fumarate, etc. Can be mentioned.

Examples of the antineoplastic agents include cyclophosphamide, fluorouracil, degafur, mitomycin C, procarbazine hydrochloride, doxyfluridine, ranimustine and the like. Examples of the local anesthetic include ethyl aminobenzoate, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, oxybuprocaine hydrochloride, propitocaine hydrochloride and the like. Examples of the hormone agents include propylthiouracil, thiamazole, metenolone acetate, estradiol, estriol, progesterone and the like. Examples of the antihistamine include diphenonehydramine hydrochloride, chlorpheniramine maleate, promethazine, cyproheptadine hydrochloride, diphenylpyraline hydrochloride and the like. Examples of the blood coagulation inhibitor include warfarin potassium, ticlopidine hydrochloride and the like.

Examples of the antispasmodic agents include methylatropine bromide, scopolamine and the like. Examples of the general anesthetic include thiopental sodium and pentobarbital sodium. Examples of the sleep / analgesic include bromvalerylurea, amobarbital, phenobarbital and the like. Examples of the anti-epileptic agent include phenytoin sodium. Examples of the stimulant / stimulant include methamphetamine hydrochloride and the like. Examples of the anti-pain agents include difendol hydrochloride, betahistine mesylate and the like.

Examples of the psychiatric agents include chlorpromazine hydrochloride, thioridazine, meprobamate, imipramine hydrochloride, chlordiazepoxide, diazepam and the like. Examples of the skeletal muscle relaxant include suxamethonium hydrochloride, eperisone hydrochloride and the like.
Examples of the agent for self-sustaining nerve include neostigmine bromide, bethanechol chloride and the like. Examples of the anti-Parkinson's agent include amantadine hydrochloride and the like. Examples of the diuretic include hydroflumethiazide, isosorbide, furosemide and the like.

Examples of the vasoconstrictor include phenylephrine hydrochloride and the like. Examples of the respiratory stimulants include lobeline hydrochloride, dimorphoramine, naloxone hydrochloride and the like. Examples of the therapeutic agent for peptic ulcer include glycopyrronium bromide, proglumide, cetraxate hydrochloride, cimetidine, spizofron and the like. Examples of the choleretic agent include ursodesoxycholic acid and osalmid. Examples of the urogenital and anal agents include hexamine, sparteine, dinoprost, and ritodrine hydrochloride. Examples of the above-mentioned agents for parasitic skin diseases include salicylic acid, ciclopirox olamine, croconazole hydrochloride and the like.

Examples of the emollient include urea and the like. Examples of the vitamin agent include calcitriol, thiamine hydrochloride, sodium riboflavin phosphate, pyridoxine hydrochloride, nicotinic acid amide, panthenol, and ascorbic acid. Examples of the inorganic preparations include calcium chloride, potassium iodide, sodium iodide and the like. Examples of the hemostatic agent include ethanesylate and the like. Examples of the above-mentioned agents for liver diseases include thiopronin and the like. Examples of the drug for addiction include cinnamide and the like. Examples of the gout treatment agent include:
Colchicine, probenecid, sulfinpyrazone and the like can be mentioned.

Examples of the antidiabetic agents include tolbutamide, chlorpropamide, sodium glymidine, glybsol, buformin hydrochloride, insulin and the like. Examples of the above antibiotics include benzylpenicillin potassium, propicillin potassium, cloxacillin sodium, ampicillin sodium, bacampyricin hydrochloride, carbenicillin sodium, cephaloridine, cefoxitin sodium, erythromycin, chloramphenicol, tetracycline, kanamycin sulfate. , Cycloserine and the like. Examples of the chemotherapeutic agent include isoniazid, pyrazinamide, ethionamide and the like. Examples of the narcotics include morphine hydrochloride, codeine phosphate, cocaine hydrochloride, pethidine hydrochloride and the like.

The content of the above-mentioned drug is appropriately determined according to the kind of the drug and the purpose of use of the preparation, but when the content is low, the drug efficacy is lowered, and when it is high, the tackiness is lowered, so that the content in the pressure-sensitive adhesive layer is 0. 01 to 50% by weight is preferable. There is no particular problem even if the drug is present in the pressure-sensitive adhesive layer in a supersaturated state or in a state in which crystals are precipitated. Further, the drug may be encapsulated with an absorption enhancer, or a drug storage layer may be provided.

The thickness of the pressure-sensitive adhesive layer of the present invention is not particularly limited, but if it becomes thin, a large amount of a drug must be added, and the adhesive force will decrease. The existing drug is less likely to diffuse to the surface of the pressure-sensitive adhesive layer and the drug release rate is reduced, so 10 to 200 μm is preferable.

For producing the percutaneous absorption preparation of the present invention, a conventionally known method for producing an adhesive tape can be used, and examples thereof include a solvent coating method, a hot melt coating method, an emulsion coating method and the like. When performing solution coating, for example, a predetermined amount of a polymer having a pressure-sensitive adhesive, a drug and maleic anhydride as a constituent, is dissolved or dispersed in a solution such as ethyl acetate, and the resulting liquid is applied onto a support. A method of drying, a method of coating on a release paper, drying and then transferring to a support, and the like are preferably used.

[0048]

In the percutaneous absorption preparation of the present invention, the mechanism of action on the skin by using a copolymer having a specific component and a polymer having maleic anhydride as a component in the adhesive composition is as follows. Can be thought of as.

By using a copolymer having specific constituents and a polymer having maleic anhydride as a constituent,
The amount of drug released per unit area and unit time and the amount transferred into the skin are improved. This is because the polymer having maleic anhydride as a constituent serves to improve the cohesive force of the pressure-sensitive adhesive and then to maintain an appropriate pressure-sensitive adhesive force,
It is thought to be because it affects the skin and reduces the barrier function of the stratum corneum. Further, although the polymer containing maleic anhydride as a constituent component lowers the fluidity of the pressure-sensitive adhesive, it does not reduce the diffusion rate of the drug in the pressure-sensitive adhesive layer. As a result, the partition coefficient of the drug between the adhesive layer and the skin is changed, or the diffusion rate of the drug in the skin is increased, the release amount of the drug is improved, and the required amount of the drug easily removes the skin. It permeates and is absorbed by the circulatory system in the body.

Due to the above-mentioned mechanism of action, the effective dose per area becomes large, and the same effect can be obtained with the transdermal preparation having an area smaller than that of the conventional product, so that erythema can be caused even in a person sensitive to skin irritation. It does not occur or the erythema area is reduced. Moreover, since the area of the preparation is small, the sticking operation is easy and there is no discomfort due to sticking.

[0051]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. In the following, "parts" means "parts by weight".

Example 1 302 parts of 2-ethylhexyl acrylate, N-vinyl-
98 parts of 2-pyrrolidone and 400 parts of ethyl acetate were supplied to a separable flask equipped with a stirrer and a reflux cooling device,
The temperature was raised to 80 ° C. while stirring and substituting with nitrogen. A solution prepared by dissolving 2 parts of lauroyl peroxide in 100 parts of cyclohexane was divided into 10 parts, and 1 was added to a separable flask,
Polymerization started. Remaining 9 from the second hour after starting the reaction to 1
Addition was carried out at time intervals, and after the addition was completed, the reaction was continued for 2 hours. In order to adjust the viscosity, 50 parts of ethyl acetate was added 5 times every 2 hours after the reaction was started. After completion of the reaction, the mixture was cooled, and then ethyl acetate was added to obtain an adhesive solution having a solid content concentration of 35% by weight and a viscosity of 1.5 × 10 ⁴ cps. In the obtained solution, indomethacin as a drug, isopropyl myristate as a plasticizer, and a methoxyethylene-maleic anhydride copolymer (GANTREZ AN-11
9, G.I. A. Manufactured by Company F) in the total solid content (the total weight of the acrylic copolymer, the plasticizer, the drug, and the polymer containing maleic anhydride as a constituent) at concentrations of 3% by weight, 30% by weight, and 2% by weight, respectively. Then, the whole liquid was uniformly stirred with a dissolver to obtain a mixed liquid. The obtained mixed solution was applied onto a silicon-treated PET film having a thickness of 35 μm so that the thickness of the adhesive layer after drying was 80 μm, dried, and then polyethylene terephthalate of a PET / EVA laminated film having a thickness of 35 μm. The above-mentioned adhesive layer was laminated on the layer to obtain a percutaneous absorption preparation. When this percutaneous absorption preparation was applied to the lumbar region of five adult males having pain in the lower back, the symptoms were improved after 2 to 4 hours.

Evaluation The following transdermal preparations were evaluated and the results are shown in Table 1. Each transdermal preparation was attached to the upper arm of 5 irritating adult males, and 24
It peeled after a time. One hour after peeling, the state of the skin was visually observed and evaluated according to the following evaluation criteria, and the average value of the sum of the scores of 5 persons was used as an index. (Evaluation criteria) 0: No erythema 1: Very slight erythema barely discernible 2: Clear erythema 3: Medium erythema 4: Strong erythema of deep crimson Adhesive residue on each upper arm of 5 adult males Attach the absorption preparation, 24
It peeled after a time. The state of the adhesive residue on the skin immediately after peeling was visually observed and evaluated according to the following evaluation criteria. In addition,
The adhesive residue is a state in which an adhesive is attached to the skin. (Evaluation Criteria) ○: No adhesive residue on all members, Δ: Adhesive residue on 1 to 4 people,
×: glue residue on all

Examples 2 and 3 A transdermal preparation was obtained in the same manner as in Example 1 except that the adhesive, the polymer having maleic anhydride as a constituent and the additives were blended as shown in Table 1. , Evaluated. The results are shown in Table 1.
Shown in. When this percutaneous absorption preparation was applied to the lumbar region of five adult males having pain in the lower back, the symptoms were improved after 2 to 4 hours.

Example 4 A pressure-sensitive adhesive, a polymer having maleic anhydride as a constituent, and additives were blended as shown in Table 1 to prepare a pressure-sensitive adhesive solution having a solid content concentration of 37% by weight and a viscosity of 1.7 × 10 ⁴ cps. A transdermal preparation was obtained and evaluated in the same manner as in Example 1 except that the above was obtained. The results are shown in Table 1.

Comparative Example 1 A transdermal preparation was obtained in the same manner as in Example 1 except that the pressure-sensitive adhesive, the polymer having maleic anhydride as a constituent and the additives were blended as shown in Table 1 to obtain a transdermal preparation. Did. The results are shown in Table 1.
Shown in.

Comparative Example 2 An adhesive solution having a solid content concentration of 32% by weight and a viscosity of 1.0 × 10 ⁴ cps was prepared by blending the adhesive, a polymer having maleic anhydride as a constituent and additives as shown in Table 1. A transdermal preparation was obtained and evaluated in the same manner as in Example 1 except that the above was obtained. The results are shown in Table 1.

In Tables 1 to 4, EHA is 2-ethylhexyl acrylate, NVBA is N-vinyl-butanamide, AAM is acrylamide, and VP is N-vinyl-2.
-Pyrrolidone, VA vinyl acetate, NAA N, N
-Dimethylacrylamide, NVPP is N-vinyl-
2-piperidinone, ALA allylamine, VPY
Represents 4-vinylpyridine, and AA represents acrylic acid. A to D represent a polymer having maleic anhydride as a constituent component (hereinafter, also referred to as “maleic anhydride-containing polymer”), and A represents GANTREZ AN-119 (GAF.
Methoxyethylene-maleic anhydride copolymer) manufactured by
B is GANTREZAN-169 (a methoxyethylene-maleic anhydride copolymer manufactured by G.A.F.), and C is polyisoprene-maleic anhydride (15 of maleic anhydride).
% Adduct) and D represents a styrene-maleic anhydride copolymer, respectively. E is isopropyl myristate,
F represents polyethylene glycol and G represents polypropylene glycol. H is indomethacin, I
Represents ketoprofen, J represents vitamin E, and K represents nifedipine.

[0059]

[Table 1]

Example 5 Transdermal absorption was performed in the same manner as in Example 1 except that the adhesive, the polymer having maleic anhydride as a constituent and the additives were blended as shown in Table 2 and no drug was used. A formulation was obtained.

Evaluation The following evaluation was carried out using the obtained transdermal preparation, and the results are shown in Tables 2-4. Holding power Based on JIS Z 0237-1980, the holding power of each preparation was measured, and the cohesive force of the pressure-sensitive adhesive was evaluated. In this method, those having sufficient cohesion for application to the skin are
The holding power is about 20 minutes or more. A tape test piece (area: 10 cm ² ) was attached to the dehaired back of an irritating Japanese white rabbit and peeled off after 24 hours, and the erythema state of the skin was visually observed immediately after peeling and 1 hour after peeling. I observed. In this test, neither edema nor crust formation was observed. The number of repetitions was 4 times for each preparation. The degree of erythema was evaluated according to the following 5 criteria of 0-4. 0: No erythema 1: Very slight erythema barely discernible 2: Clear erythema 3: Medium erythema 4: Strong erythema of deep crimson color The total sum of scores at each time divided by 4 times the average value of each tape preparation Was used as the skin irritation index.

[0062] In the same procedure as adhesive residue the irritation test, the tape preparation was stuck for 24 hours to the skin of rabbits was observed whether the remaining glue after peeling was visually. The number of repetitions was 4 times for each preparation. The evaluation criteria are as follows. 0: No adhesive residue 1: Adhesive residue was observed in a very small part 2: Adhesive residue was clearly observed The average value (value obtained by dividing the sum of evaluation points by the number of repetitions 4) was used as the adhesive residue index of each preparation.

Examples 6, 7, 9 to 11, 15 The same operation as in Example 5 was repeated except that the adhesive, the polymer having maleic anhydride as a constituent and the additives were blended as shown in Table 2. A percutaneous absorption preparation was obtained and evaluated. The results are shown in Table 2.
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Examples 8 and 13 Adhesives, polymers having maleic anhydride as a constituent and additives were blended as shown in Table 2, and an adhesive having a solid content concentration of 32% by weight and a viscosity of 1.1 × 10 ⁴ cps. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that a solution was obtained. The results are shown in Table 2.

Example 12 A pressure-sensitive adhesive, a polymer having maleic anhydride as a constituent and additives were formulated as shown in Table 2, and a pressure-sensitive adhesive solution having a solid content concentration of 37% by weight and a viscosity of 1.7 × 10 ⁴ cps was prepared. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that the above was obtained. The results are shown in Table 2.

Example 14 A pressure-sensitive adhesive, a polymer having maleic anhydride as a constituent and additives were blended as shown in Table 2, and a pressure-sensitive adhesive solution having a solid content concentration of 35% by weight and a viscosity of 1.4 × 10 ⁴ cps was prepared. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that the above was obtained. The results are shown in Table 2.

Example 16 A transdermal preparation was obtained in the same manner as in Example 5 except that the adhesive, the polymer having maleic anhydride as a constituent and the additives were blended as shown in Table 3 to obtain a transdermal preparation. Did. The results are shown in Table 3.
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Example 17 A pressure-sensitive adhesive, a polymer having maleic anhydride as a constituent, and additives were blended as shown in Table 3, and a pressure-sensitive adhesive solution having a solid content concentration of 32% by weight and a viscosity of 1.1 × 10 ⁴ cps was prepared. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that the above was obtained. The results are shown in Table 3.

Comparative Examples 3 to 5, 8 to 10 Transdermal operation was carried out in the same manner as in Example 5 except that the composition shown in Table 3 was used for the adhesive, the polymer having maleic anhydride as a constituent and the additives. An absorption preparation was obtained and evaluated. The results are shown in Table 3.
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Comparative Example 6 An adhesive solution having a solid content concentration of 32% by weight and a viscosity of 1.1 × 10 ⁴ cps was prepared by blending the adhesive, a polymer having maleic anhydride as a constituent and additives as shown in Table 3. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that the above was obtained. The results are shown in Table 3.

Comparative Example 7 An adhesive solution having a solid content concentration of 32% by weight and a viscosity of 1.0 × 10 ⁴ cps was prepared by blending the adhesive, a polymer having maleic anhydride as a constituent and additives as shown in Table 3. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that the above was obtained. The results are shown in Table 3.

Comparative Example 11 An adhesive solution having a solid content concentration of 37% by weight and a viscosity of 1.7 × 10 ⁴ cps was prepared by blending the adhesive, a polymer having maleic anhydride as a constituent and additives as shown in Table 3. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that the above was obtained. The results are shown in Table 3.

Comparative Examples 12 and 17 Adhesives, polymers having maleic anhydride as a constituent and additives were blended as shown in Table 4, and a solid content concentration of 32% by weight and a viscosity of 1.1 × 10 ⁴ cps. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that a solution was obtained. The results are shown in Table 4.

Comparative Example 13 An adhesive solution having a solid content concentration of 35% by weight and a viscosity of 1.4 × 10 ⁴ cps was prepared by blending the adhesive, a polymer having maleic anhydride as a constituent and additives as shown in Table 4. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that the above was obtained. The results are shown in Table 4.

Comparative Examples 14 and 18 Adhesives, polymers having maleic anhydride as a constituent and additives were blended as shown in Table 4, and the solid content concentration was 32% by weight and the viscosity was 1.0 × 10 ⁴ cps. A transdermal absorption preparation was obtained and evaluated in the same manner as in Example 5 except that a solution was obtained. The results are shown in Table 4.

Comparative Examples 15 and 16 A transdermal preparation was obtained in the same manner as in Example 5, except that the adhesive, the polymer having maleic anhydride as a constituent and the additives were blended as shown in Table 4. , Evaluated. The results are shown in Table 4.
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From the examples of Tables 1 to 3, it can be seen that the preparations of the present invention have good cohesive strength while maintaining low irritation, and the adhesive residue due to insufficient cohesive strength, which is a big problem of the prior art. It was clear that was solved.

[0078]

[Table 2]

[0079]

[Table 3]

[0080]

[Table 4]

[0081]

EFFECTS OF THE INVENTION Since the adhesive composition and the transdermal preparation of the present invention have the above-mentioned constitutions, a sufficient amount of the drug is required to enhance the drug release and to exhibit the desired drug effect. It can be absorbed through the skin, and has good adhesiveness with a good balance of adhesive strength and cohesive strength.Therefore, there is no adhesive residue when peeled off, and damage to the stratum corneum on the skin surface Skin irritation due to mechanical irritation can be reduced.

Claims (4)

[Claims] 1. A pressure-sensitive adhesive composition comprising a pressure-sensitive adhesive composed of a copolymer containing an amide compound as a constituent and a polymer containing maleic anhydride as a constituent. 2. The pressure-sensitive adhesive composition according to claim 1, wherein the amide compound is N-vinyl-2-pyrrolidone. 3. A pressure-sensitive adhesive composition comprising a pressure-sensitive adhesive comprising a copolymer containing an amine compound as a constituent and a polymer containing maleic anhydride as a constituent. 4. A percutaneous absorption preparation comprising a support and a pressure-sensitive adhesive layer comprising the pressure-sensitive adhesive composition according to claim 1, 2 or 3 laminated on one surface of the support.