JPH0818975B2 - Patch for disease treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Industrial Field of Application The present invention relates to a patch for treating a disease for transdermally administering a drug into a living body.

(B) Conventional Technology In recent years, a transdermal absorption method of administering a drug through the skin surface as a means of administering a drug into the living body has been actively developed from the viewpoint of manifestation of continuous pharmacological effects and reduction of side effects. Among them, patches prepared in the form of adhesive tapes are drawing attention because of their ease of handling and strictness of dosage.

The basic structure of such a patch is composed of a support made of a plastic film or a non-woven fabric, and a drug-containing layer provided on one side of the support. It is the one that tries to exert sex, sustainability and other effects.

For example, in Japanese Patent Publication No. 54-16566, in order to control the release of the contained drug, the drug-containing layer has a laminated structure consisting of a drug storage layer, a drug release control film, and an adhesive layer, and a patch or drug. A patch is disclosed in which microcapsules containing a drug and controlling drug release are dispersed in an adhesive layer.

In addition, Japanese Patent Publication No. 60-55044 also specifies the drug diffusion coefficient and solubility in both layers with a laminated structure of a drug storage layer and an adhesive layer in order to control the release of the drug. A pharmaceutical preparation comprising a base layer containing isosorbitol nitrate on the surface of a polyester film, wherein the isosorbitol nitrate can be transferred to the base layer adhesive surface of the film. It has been proposed that the above is coated (Japanese Patent Laid-Open No. 61-112015).

Then, in this case, a plurality of adhesives are superposed on the film base material, and at this time, the amount of the drug in the base material layer is increased toward the inside so that the drug is sequentially supplied to the outer base layer. Has been devised.

(C) Problems to be Solved by the Invention Although the feature of the patch is to maintain the pharmacological effect for a long period of time, the patch described in JP-B-54-16566 discloses a drug release control film. Since the process of the drug passing through the walls of microcapsules and microcapsules is the rate-determining step, it becomes impossible to control if there is a slight defect, and due to its strict controllability, all the drugs in the drug storage layer are controlled. It may not be released effectively.

Further, in the patch described in JP-B-60-55044, the drug may be smoothly transferred from the storage layer to the adhesive layer, and then the transferred drug may be favorably released from the adhesive layer to the skin surface. The adhesive layer that plays an important role in releasing the drug onto the skin surface has not been studied at all, and it is difficult to say that the drug release onto the skin surface will occur reliably.

Furthermore, the pharmaceutical preparation described in JP-A-61-12015,
Similar to the patch described in JP-B-60-55044, the drug is sequentially transferred from the base layer having a high drug concentration inside to the base layer on the outside. The drug migrates smoothly from the layer to the outer base layer,
After that, the transferred drug may be released from the base layer to the skin surface well, but no consideration has been given to the base layer that plays an important role in the release of the drug to the skin surface. It is hard to say that the drug will be released into the skin reliably.

On the other hand, in recent years, the number of patients who complain of symptoms of angina and hypertension has been increasing year by year, and a drug product that exhibits an excellent sustained pharmacological effect to prevent and improve these symptoms has been earnestly desired. Despite this, the reality is that sufficient products have not yet been developed and provided.

(D) Means for Solving the Problems In view of the above problems, the present inventors provide a patch showing a sustained pharmacological effect and having a good drug transfer property into the living body through the skin surface. As a result of repeated studies, it was found that the acrylic trans-adhesive containing a carboxyl group has a slightly inferior solubility of the drug, but on the other hand, it exerts an extremely excellent effect on the drug release property and the bioavailability. The invention has been completed.

That is, the patch for treating diseases of the present invention is a patch in which a drug-containing polymer substance layer and a carboxyl group-containing acrylic pressure-sensitive adhesive layer are sequentially laminated on one side of a support, and the pressure-sensitive adhesive layer is substantially It does not contain a drug or contains a drug at a lower concentration than the drug-containing effective polymer substance layer.

 Hereinafter, the present invention will be described in detail.

The support used in the patch for treating diseases of the present invention, a support that has been conventionally used, for example, polyethylene, polypropylene, polyester, polyvinyl acetate,
Single-layer film or single-layer sheet made of materials such as polyurethane, polyvinyl alcohol, polyvinylidene chloride, or polyamide, foamed film or sheet made of rubber and / or synthetic resin, non-woven fabric, woven fabric, metal foil or laminated film formed of these A laminated sheet or the like can be used, and these supports can also be used after being perforated according to the purpose.

The drug-containing polymer substance layer provided on one surface of the support has good solubility of a transdermally absorbable drug, and
It is a layer that contains and holds the drug and exerts an action of imparting a sustained drug release property to the patch for disease treatment of the present invention.

That is, when the drug concentration in the pressure-sensitive adhesive layer decreases due to release and migration of the drug from the below-mentioned carboxyl group-containing acrylic pressure-sensitive adhesive layer to the skin surface, the drug content is increased by the concentration difference so as to compensate for the decreased amount of drug. The drug is transferred from the polymer layer into the pressure-sensitive adhesive layer and replenished to exert a sustained release of the drug.

As the material for forming such a polymer material layer, any of a synthetic polymer material, a semi-synthetic polymer material and a natural polymer material can be used. Considering the affinity, anchorage and adhesiveness with the agent layer, it is preferable to use a tacky polymer substance, and especially an acrylic polymer substance is used from the viewpoint of affinity with the carboxyl group-containing acrylic pressure-sensitive adhesive layer. Is desirable.

Among the above acrylic polymer materials, the glass transition temperature (Tg) thereof is preferably −70 to 10 ° C., more preferably Tg of −55 to −25 ° C.

When Tg is in the above range, the shape retention of the base material and the diffusive mobility of the drug in the acrylic polymer are excellent, and therefore the drug release is good.

Incidentally, it is optional to adjust the Tg by adding a liquid softening component having good compatibility such as liquid paraffin, or a generally known compounding material such as various softening materials to the acrylic polymer material.

Examples of the acrylic polymer include homopolymers of (meth) acrylic acid alkyl ester having an alkyl group having 4 or more carbon atoms, or copolymerization of (meth) acrylic acid alkyl ester as a main monomer. The copolymer obtained can be mentioned.

As the (meth) acrylic acid alkyl ester,
For example, n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate,
Examples thereof include undecyl acrylate, dodecyl acrylate, tridecyl acrylate and tridecyl methacrylate.

As the other monomer copolymerizable with the (meth) acrylic acid alkyl ester, for example, (meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride, a carboxyl group-containing monomer such as fumaric acid, Sulfoxyl group-containing monomers such as styrene sulfonic acid, allyl sulfonic acid, sulfopropyl acrylate, (meth) acryloyloxynaphthalene sulfonic acid, acrylamidomethylpropane sulfonic acid, acryloyloxybenzene sulfonic acid, (meth) acrylic acid hydroxyethyl ester, Hydroxy group-containing monomer such as (meth) acrylic acid hydroxypropyl ester, (meth) acrylamide, dimethyl (meth) acrylamide, N-butylacrylamide, tetramethylbutylacrylamide, N-
Amido group-containing acrylic monomers such as methylol (meth) acrylamide, (meth) acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic acid diethylaminoethyl ester, (meth) acrylic acid tert. An alkylaminoalkyl group-containing acrylic monomer such as butylaminoethyl ester, (meth) acrylic acid methoxyethyl ester,
(Meth) acrylic acid ethoxyethyl ester, (meth)
(Meth) acrylic acid alkoxyalkyl esters such as acrylic acid butoxyethyl ester, (meth) acrylic acid tetrahydrofurfuryl ester, (meth) acrylic acid methoxyethylene glycol ester, (meth) acrylic acid methoxydiethylene glycol ester, (meth)
Acrylic acid methoxy polyethylene glycol ester,
Alkoxy group-containing (or ether bond in the side chain) -containing monomer such as (meth) acrylic acid methoxy polypropylene glycol ester, vinyl-based monomer such as N- (meth) acryloyl amino acid, urethane of acrylic acid, urea, isocyanate ester Functional monomers such as acrylic monomers such as, and (meth) acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, vinylpyridine, vinylpyrazine, vinylpiperazine, vinylpiperidone, vinylpyrimidine, vinylvirol, vinylimidazole, Examples thereof include vinyl monomers such as vinylcaprolactam, vinyloxazole, vinyl aerosol, vinylmorpholine, styrene, α-methylstyrene, and bis (N, N′-dimethylaminoethyl) maleate.

These monomers have a function of imparting cohesive force by copolymerization with the main component monomer or improving drug solubility, and unless the solubility of the drug is extremely lowered, The polymerization ratio can be arbitrarily selected and used.

In the present invention, the above-mentioned (meth) acrylic acid alkyl ester and a copolymerizable monomer include various isomers having a linear or branched alkyl moiety, and various isomers and derivatives having different substituent positions. Includes.

Further, other polymer substances used in the present invention include, for example, silicone rubber, polyisoprene rubber, polyisobutylene rubber, polybutadiene, styrene-butadiene (or isoprene) -styrene block copolymer, acrylic rubber, gum arabic and the like. Examples thereof include rubber-based substances such as natural rubber, synthetic resins such as polyurethane, polyester, polyamide, and ethylene-vinyl acetate copolymer, and examples of tackifying components thereof include rosin and modified rosin, petroleum-based resin, and polyterpene. Examples thereof include resins, polystyrene resins, polybutene, and liquid polyisobutylene, and examples of plasticizers include machine oils, trans oils, rosin oils, and various liquid paraffins.

Further, other polymer substances include starch, modified starch, soluble starch, dextrin, sodium alginate, casein, gelatin and the like.

The polymer substance contains a drug, and the drug is not particularly limited as long as it is transdermally absorbable, and specific examples thereof include the following.

A) Ca ²⁺ antagonists: dihydropyridine Ca ²⁺ antagonists such as nifedipine, nizoldipine, nimodipine, nildipine, nicardipine, isolidipine, etc. b) Corticosteroids: eg hydrocortisone, prednisolone, beclomethasone propionate,
Flumethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, etc. c) Analgesic and anti-inflammatory agents: For example, acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, diclofenac. Sodium, alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicylic acid, methyl salicylate, 1-menthol, camphor, sulindac, tolmetin sodium, naproxen, fenbufen, etc. d) Sleep sedatives: eg pheno Barbital, amobarbital, cyclobarbital, triazolam, nitrazepam, lorazepam, haloperidol. , E) tranquilizers: for example fluphenazine, Teoritajin, diazepam, full diazepam, flunitrazepam,
Haloperidol, chlorpromazine, etc. f) Antihypertensive agents: For example, clonidine, clonidine hydrochloride, pindolol, propranolol, propranolol hydrochloride, bufuranol, indenolol, nivadipine, lofezixin, nipradilol, bucumolol, etc.) Antihypertensive diuretics: for example, hydrothiazide, bendrof. Luna thiazide, cyclobent azide, etc.) Antibiotics: eg penicillin, tetracycline, oxytetracycline, fradiomycin sulfate,
Erythromycin, chloramphenicol, etc. i) Anesthetics: eg lidocaine, dibucaine hydrochloride, benzocaine, ethyl aminobenzoate, etc.) Antibacterial substances: eg benzalkonium hydrochloride, nitrofurazone, nice titanium, acetosulfamine, clotrimazole Le) antifungal substances: eg pentamycin, amphotericin B, pyrrole nitrine, clotrimazole, etc. w) vitamin agents: eg vitamin A, ergocalciferol, cholecalciferol, octothiacin, riboflavin butyrate, etc. Antiepileptic agents: eg nitrazepam, mepropamate, clonazepam, etc. c) Coronary vasodilators: eg nitroglycerin, nitroglycol, isosorbide dinitrate, erythritol tetranitrate, N) erythritol tetranitrate, propatil nitrate, etc. yo) Antihistamines: eg diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole etc. ta) Antitussives: eg dextromethorphan hydrobromide, terbutazone sulfate, ephedrine, ephedrine hydrochloride, sulfate Salbutamol, isoprotenol hydrochloride, isoprotenol sulfate, etc.) Sex hormones: eg, progesterone, estradiol, etc.) Antidepressants: eg, doxepin, etc.) Cerebral circulation improving agents: eg, bidergine, ergot alkaloids, isofenprodil, etc. E) Antiemetics, antitumor agents: eg metoclopramide, crevopride, domperidone, scopolamine, scopolamine hydrobromide, 5-fluorouracil, mercaptopuri Etc., Na) biological pharmaceutical: e.g. polypeptides (TRH, LHRH derivative), such as prostaglandins, La) Others: for example fentanyl, digoxin, desmopressin, dihydroergotamine methanesulfonate and dihydroergotamine tartrate, and the like.

Among these transdermally absorbable drugs, especially dihydropyridine Ca ²⁺ antagonists are transdermally effective in the pharmacologically effective amount of C ²⁺ antagonists in relation to the carboxyl group-containing acrylic adhesive described below. It is most preferable because it is rapidly and continuously absorbed into the living body, and its effect remarkably appears.

That is, Ca ²⁺ antagonists that bring about effective therapeutic effects on conditions such as angina and hypertension are still more difficult than their chemical and physical properties in their transdermal absorbability,
No effective transdermal formulation has been developed.

The patch for treating diseases of the present invention, in association with the carboxyl group-containing acrylic pressure-sensitive adhesive layer, rapidly provides a pharmacologically effective amount of a drug, particularly for a drug with difficult percutaneous absorption such as a Ca ²⁺ antagonist. In addition, it is possible to continuously and percutaneously absorb the skin.

The compounding ratio of the drug (A) and the polymeric substance (B) is preferably such that (A) is contained in the range of 3 to 50% by weight based on the total amount of (A + B), and the content of (A) is 3%. If the amount is less than 50% by weight, the dose of the drug in the body may be small and the therapeutic effect may be poor. On the other hand, if the amount exceeds 50% by weight, the therapeutic effect may be limited and it is uneconomical.

The carboxyl group-containing acrylic patch layer constituting the patch for treating diseases of the present invention is a layer laminated on the drug-containing polymer substance layer, and its exposed surface is stuck to the skin surface to which it is applied, and adhered thereto. The drug is absorbed into the living body through the exposed surface.

The pressure-sensitive adhesive layer comprises a monomer having a carboxyl group such as (meth) acrylic acid, maleic acid, maleic anhydride, itaconic acid, and fumaric acid, and a monomer such as a (meth) acrylic acid alkyl ester that imparts adhesiveness. A copolymer with the body,
A rosin, a tackifier such as a petroleum resin, an oily substance, a plasticizer such as a polyhydric alcohol, or a rubber such as polyisoprene, polyisobutylene or polybutadiene is added to a polymer composed of a monomer having a carboxyl group. It can be obtained by appropriately mixing the components.

Of these, from the viewpoint of drug stability and release (meta)
A copolymer of an acrylic acid alkyl ester and (meth) acrylic acid is preferable, and when a monomer having an alkyl group of the (meth) acrylic acid alkyl ester with a carbon number of 4 to 14 is used, Good results are obtained in tackiness and adhesion.

In the case of this copolymer, the weight ratio of the copolymer of (meth) acrylic acid alkyl ester (C) and (meth) acrylic acid (D) is 99 to 70: 1 to 30, particularly 99 to 80: 1 ~
It is preferable to set it in the range of 20.

In the above-mentioned copolymer of (C) and (D), if the ratio of (D) is less than 1, it is not preferable because adhesive residue may occur when applied to the skin due to lack of cohesive force. It is not preferable because it has poor skin adhesiveness and accordingly lacks percutaneous absorbability.

By the way, the above-mentioned thing is mentioned as a thing whose carbon number of the alkyl group is 4-14 in the said (meth) acrylic acid alkyl ester.

The carboxyl group-containing acrylic pressure-sensitive adhesive is not good in terms of drug solubility, but when the drug is contained in the pressure-sensitive adhesive, the drug release is extremely good. When the adhesive layer on the skin surface side is formed using the patch of the present invention, the drug is effectively released to the skin surface and the drug is transdermally absorbed into the living body.

The carboxyl group-containing acrylic pressure-sensitive adhesive layer contains substantially no transdermal drug, or contains a drug at a lower concentration than the drug-containing polymer substance layer. Of these, those containing a drug are preferable.

In this case, the content of the drug is contained in the carboxyl group-containing acrylic pressure-sensitive adhesive layer in the range of 10% by weight or less, whereby the immediate effect of the disease-treating member of the present invention can be further realized. .

In the patch for treating a disease of the present invention, the drug concentration in the carboxyl group-containing acrylic pressure-sensitive adhesive layer is lower than the drug concentration in the drug-containing polymeric substance layer to control the drug release.

In the patch for treating a disease of the present invention, the transdermal absorbability is considerably improved even when only the carboxyl group-containing acrylic pressure-sensitive adhesive layer on the skin adhesive layer side is applied, but a further superior transdermal absorbability is realized and sufficient. In order to surely achieve the transdermal absorbability of various drugs, various transdermal absorption enhancers may be added to the pressure-sensitive adhesive layer.

The above-mentioned percutaneous absorption enhancer can be simply defined as one that accelerates the release of the drug to the body surface. However, in the drug-containing polymer substance layer or the carboxyl group-containing adhesive layer, the solubility of the drug or the Those that have the function of improving diffusivity, water retention of keratin, keratin softening, keratin penetration (looseness), those that function as penetration aids and pore-opening agents, and change the skin interface state Those having the function of improving transdermal absorbability such as functions, those having the above-mentioned functions in combination, or those having the function of promoting drug efficacy to further enhance the pharmacological effect of the drug, etc. Is included.

Examples of this type of transdermal absorption promoting agent include lower alcohols such as methanol and ethanol, glycols (mainly improving drug solubility) such as diethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol, olive oil, squalene and lanolin. Oils and fats (mainly improving drug diffusion), urea derivatives such as urea and allantoin (mainly improving water retention of the stratum corneum),
Dimethyldecylphosphoxide, methyloctylsulfoxide, dimethylsulfoxide, dimethylformamide,
Polar solvents such as dimethylacetamide, dimethyllaurylamide, dodecylpyrrolidone and isosorbitol (mainly to improve keratin permeability), salicylic acid (mainly to improve keratin softening property), amino acids (mainly to improve keratin permeability), nicotinic acid benzyl ester ( Mainly pore-opening agents), sodium lauryl sulfate (mainly changes the skin interface state) and the like.

Others include diisopropyl adipate, phthalates, plasticizers such as diethyl sebacate, ethoxylated stearyl alcohol, N-methylpyrrolidone, glycerin esters, 1-dodecyl-azacycloheptan-2-one, isopropyl myristate, ethyl laurate, etc. Can be mentioned.

 Two or more of these may be added, if desired.

The amount of the transdermal absorption promoting aid added is 0.1 with respect to the total weight of the drug, the pressure-sensitive adhesive layer, and the transdermal absorption promoting aid optionally added in consideration of the balance between skin adhesiveness and cohesive force. It is desirable to set it in the range of up to 30% by weight, and if the addition amount is less than 0.1% by weight, its effect is poor, and 30% by weight
If it exceeds, the skin adhesiveness and cohesive force may be deteriorated, which is not preferable.

(E) Action In the patch for treating a disease of the present invention, the reason why transdermal absorption of a drug is rapidly performed is not clear, but the concentration of the drug in the carboxyl group-containing acrylic pressure-sensitive adhesive layer on the skin adhesive surface side is made thin. By doing so, it is understood that the skin adhesiveness of the pressure-sensitive adhesive layer is improved and the skin interface is changed by the action of the carboxyl group, whereby the drug is continuously absorbed in the living body.

Further, when the drug concentration in the pressure-sensitive adhesive layer decreases due to the release and migration of the drug from the carboxyl group-containing acrylic pressure-sensitive adhesive layer to the skin surface, the drug-containing polymer is added due to the difference in concentration so as to compensate for the reduced amount of drug. The drug moves from the substance layer into the pressure-sensitive adhesive layer and is replenished to maintain the drug concentration within a predetermined range, and thus has the action of allowing continuous transdermal absorption of the drug in the living body.

(F) Examples Next, the present invention will be described in detail based on examples, but the present invention is not limited thereto.

In the following, parts or% means parts by weight or% by weight.

Example 1 (Drug-containing polymer substance layer) 65 parts of acrylic acid isononyl ester, 35 parts of vinyl acetate and 100 parts of ethyl acetate were charged into a four-necked flask under a nitrogen gas atmosphere, and azobisisobutyrate was used as a polymerization initiator. Add 0.2 parts of ronitrile (AIBN) and keep the bath temperature at 60 ~ 6
After maintaining the temperature at 3 ° C and stirring and gradually dropping 133.3 parts of ethyl acetate to carry out the polymerization reaction for 8 hours while controlling the reaction, the inner bath temperature was further raised to 70 to 75 ° C and aged for 2 hours. By doing so, a copolymer solution was obtained.

The polymerization rate of this copolymer is 92.8%, and the solid content concentration is 30%.
% Copolymer solution had a viscosity of 110 poise at a temperature of 30 ° C.

The content of nifedipine in the obtained copolymer solution was 80
The mixture was added and mixed at 0 μg / cm ² and applied on the polyethylene side of the polyethylene / aluminum vapor deposition film (support) so that the thickness after drying was 40 μm, and dried at a temperature of 100 ° C. for 5 minutes to prepare the drug ( A nifedipine) -containing polymeric material layer was laminated.

(Carboxyl group-containing acrylic pressure-sensitive adhesive layer) Using 90 parts of n-butyl acrylate and 10 parts of acrylic acid, copolymerization was performed in the same manner as above to obtain a polymerization rate of 99.6% and a solid content concentration.
A 30% copolymer solution having a viscosity of 160 poise at a temperature of 30 ° C. gave a carboxyl group-containing acrylic pressure-sensitive adhesive solution.

The content of nifedipine in the obtained copolymer solution was 50
Add and mix so that it becomes μg / cm ^2, and apply it on the separator so that the thickness after drying becomes 10 μm.
After drying for a minute, a carboxyl group-containing acrylic pressure-sensitive adhesive layer containing a drug (nifedipine) was obtained.

The carboxyl group-containing acrylic pressure-sensitive adhesive layer containing nifedipine thus obtained was transferred and laminated on the drug-containing polymer substance layer side to obtain a patch for treating diseases of the present invention.

Comparative Example 1a The above nifedipine-containing polymeric substance, the thickness after drying on the polyethylene side in the same support as above 40μ
What was apply | coated and dried so that it might become m was used.

Comparative Example 1b The carboxyl group-containing acrylic pressure-sensitive adhesive containing the above nifedipine was used, and the one obtained by the same method as in Comparative Example 1a was used. The pressure-sensitive adhesive layer had a thickness of 40 μm.

Example 2 (Polymer substance containing drug) As in Example 1, 2-ethylexyl acrylate was used.
Copolymerization of 45 parts, 30 parts of 2-ethoxyethyl acrylate and 25 parts of vinyl acetate, a copolymer solution having a polymerization rate of 93% and a solid content of 30% had a viscosity of 95 poise at a temperature of 30 ° C.

The content of nisoldipine in the obtained copolymer solution was 10
Add and mix so that it becomes 00 μg / cm ^2, and apply to the aluminum side of polyethylene / aluminum vapor deposition film (support) so that the thickness after drying will be 40 μm, and the temperature will be 120 ° C.
And dried for 4 minutes to obtain a drug (nisoldipine) -containing polymer substance layer.

(Carboxyl group-containing acrylic pressure-sensitive adhesive layer) Using 98 parts of isooctyl acrylate and 2 parts of methacrylic acid in the same manner as above, and copolymerizing in the same manner as above, the polymerization rate
A carboxyl group-containing acrylic adhesive having a viscosity of a copolymer solution of 99.2% and a solid content concentration of 30% was 70 poise was obtained.

In the obtained copolymer solution, nisoldipine (drug) and dimethylsulfoxide were contained at 100 μg / cm ² and 50 μg / cm ² , respectively.
The mixture was added and mixed so as to have a cm ^2, and applied on a separator so as to have a thickness of 20 μm after drying, and dried at a temperature of 100 ° C. for 5 minutes to obtain a carboxyl group-containing acrylic pressure-sensitive adhesive layer containing nisoldipine.

The carboxyl group-containing acrylic pressure-sensitive adhesive layer containing nizoldipine thus obtained was transferred and laminated on the drug-containing polymer substance layer side to obtain a patch for disease treatment of the present invention.

Comparative Example 2a The drug (nizoldipine) -containing polymer substance obtained in Example 2 was applied to the aluminum side of the same support as in Example 2 so that the thickness after drying was 40 μm, and dried. .

Comparative Example 2b Comparative Example except that the acrylic adhesive containing a carboxyl group containing the drug (Nisoldipine) obtained in Example 2 was used.
What was formed similarly to 2a was used.

Example 3 (Drug-containing polymeric substance layer) Copolymerization of 75 parts of 2-esterhexyl acrylate and 25 parts of 1-vinyl-2-pyrrolidone to obtain a viscosity of a copolymer solution having a polymerization rate of 99.7% and a solid content of 30% A polymer solution of 120 poise was obtained at a temperature of 30 ° C.

A drug (isolodipine) was added to and mixed with the obtained polymer solution so that the content was 1200 μg / cm ^2, and the thickness after drying was 50 μm on the aluminum side of the polyethylene terephthalate / aluminum vapor deposition film (support). And then dried at a temperature of 120 ° C. for 5 minutes to obtain a drug (isolodipine) -containing polymer substance layer.

(Carboxyl group-containing acrylic pressure-sensitive adhesive layer) 95 parts of isononyl acrylate and 5 parts of acrylic acid are copolymerized to obtain a copolymer solution having a polymerization rate of 99.6% and a solid content concentration of 30% and a viscosity of 160 poise at a temperature of 30 ° C. A carboxyl group-containing acrylic pressure-sensitive adhesive solution was obtained.

A drug (isolodipine) was added to and mixed with the obtained copolymer solution so that the content was 50 μg / cm ^2, and the mixture was applied on a separator so that the thickness after drying was 10 μm, and the temperature was adjusted to 10 μm.
It was dried at 0 ° C. for 3 minutes to obtain a carboxyl group-containing acrylic pressure-sensitive adhesive layer containing isodidipine.

The carboxyl group-containing acrylic pressure-sensitive adhesive layer containing isodidipine thus obtained was transferred and laminated on the drug (isolodipine) -containing polymer substance layer side to obtain a patch for treating diseases of the present invention.

Comparative Example 3a The drug (isolodipine) -containing polymer substance obtained in Example 3 was applied to the aluminum side of the same support as in Example 3 so that the thickness after drying was 50 μm, and dried. .

Comparative Example 3b Comparative Example except that the acrylic adhesive containing a carboxyl group containing the drug (Nisoldipine) obtained in Example 2 was used.
What was formed similarly to 2a was used. In this case, the thickness of the adhesive layer was 40 μm.

Table 1 shows the skin adhesiveness of each of the above-mentioned Examples and Comparative Examples and the time-dependent changes in blood concentration thereof after application to rabbits.

Note 1) Each sample (5 vertical, 5 horizontal) is affixed to the inside of the upper arm for 24 hours, and there is no terminal peeling, and the hair is almost pulled out. The degree of adhesion is ○, and the terminal peeling occurs or the hair is pulled out. The adhesiveness of was defined as x.

Note 2) Rabbit (body weight 2 kg) is shaved on the back, 100 cm ² of each sample is attached, and after attachment 2, 4, 8, 12, 24
After a lapse of time, blood was collected from the ear vein and the blood concentration was measured by gas chromatography.

From Table 1, in each Example, the skin adhesiveness is good because the content of the drug in the carboxyl group-containing acrylic pressure-sensitive adhesive layer adhering to the skin surface side is small, and the drug is rapidly released to the skin surface. It is recognized that the drug can be continuously administered to the body in vivo.

(G) Effect of the Invention The patch for treating a disease of the present invention has the above-mentioned constitution, and the drug is rapidly percutaneously absorbed to exhibit an excellent pharmacological effect. When the drug concentration in the pressure-sensitive adhesive layer decreases due to the release and migration of the drug from the drug layer to the skin surface, the drug is transferred from the drug-containing polymer substance layer to the pressure-sensitive adhesive layer due to the difference in concentration so as to compensate for the decreased amount of drug. It transfers to the inside and is replenished to exert an excellent pharmacological effect.

The patch for treating diseases of the present invention is a dihydropyridine-based patch.
A drug having poor transdermal absorbability such as a Ca ²⁺ antagonist is rapidly and continuously transdermally absorbed into the living body, and an excellent therapeutic effect is exhibited over a long period of time.

Claims (6)

[Claims] 1. A patch comprising a drug-containing polymer substance layer and a carboxyl group-containing acrylic pressure-sensitive adhesive layer, which are sequentially laminated on one side of a support, wherein the pressure-sensitive adhesive layer contains substantially no drug. Alternatively, a patch for treating a disease, which contains a drug at a lower concentration than the drug-containing polymer layer. 2. The patch according to claim 1, wherein the carboxyl group-containing acrylic pressure-sensitive adhesive layer is a copolymer of (meth) acrylic acid alkyl ester and (meth) acrylic acid. 3. The patch for treating a disease according to claim 2, wherein the (meth) acrylic acid alkyl ester has an alkyl group having 4 to 14 carbon atoms. 4. The patch according to any one of claims 1 to 3, wherein the drug is a dihydropyridine Ca ²⁺ antagonist. 5. A patch for treating a disease according to any one of claims 1 to 4, wherein the drug is contained in the drug-containing polymer substance layer in a range of 3 to 50% by weight. Agent. 6. The patch according to any one of claims 1 to 5, wherein the drug is contained in the carboxyl group-containing alkyl pressure-sensitive adhesive layer in an amount of 10% by weight or less.