JP2000355535A - Transdermal absorption type pharmaceutical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a transdermal absorption type pharmaceutical preparation inhibiting causing adhesive transfer on the surface of the skin at the time of peeling thereof, capable of inhibiting swelling/deformation of the medicament- reserving layer-forming film due to a solvent for the medicament contained in the medicament-reserving layer, and moreover, having excellent transdermal absorbability of the medicament. SOLUTION: This transdermal absorption type pharmaceutical preparation is such one that a medicament excluding 2-tert-butylamino-1-(2-chloro-4- hydroxyphenyl)ethan-1-ol and its pharmacologically acceptable salt is enclosed in a medicament-reserving layer which is formed in the medicament-reserving layer-forming film itself, or formed by the medicament-reserving layer-forming film and an impermeable support medium provided on the medicament-reserving layer-forming film, and a fabric layer and an adhesive layer are sequentially laminated on one side of the medicament-reserving layer-forming film or the other side opposite to the support medium.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a medicament excluding 2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol and a pharmacologically acceptable salt thereof. The present invention relates to a percutaneous absorption-type preparation for percutaneous administration, and more particularly to a reservoir-type preparation, in which a fabric layer is provided between a drug storage layer-forming film and an adhesive layer to provide a good percutaneous administration when applied to the skin surface. The present invention relates to a practical transdermal preparation which gives absorbability.

[0002]

2. Description of the Related Art In recent years, research and development for transdermal administration of various drugs have been actively conducted in order to maintain the effect and reduce side effects. Is generally low and it is extremely difficult to absorb the required amount of drug from the skin with a practical application area.

[0003] In general, transdermal preparations are mainly of the monolysis type consisting of a support and a drug-containing pressure-sensitive adhesive layer, but due to the structure in which a drug is incorporated in the pressure-sensitive adhesive, Most of the drugs having low solubility in the adhesive were unable to dissolve in the preparation and existed in a crystalline state.
In the process of transferring the drug to the skin, the drug in the dissolved state can be transferred to the skin quickly, but the drug in the crystalline state must undergo a step of once dissolving in the adhesive,
Since this process is rate-determining, the drug release from the preparation was low, and a sufficient amount of the drug could not be absorbed into the skin. The simplest method for improving this, that is, enlarging the application area or increasing the thickness of the pressure-sensitive adhesive layer, is not always effective because it causes adverse effects such as an increase in discomfort during application and a longer diffusion distance of the drug. It was not a target.

[0004] When a drug is to be transdermally administered more efficiently, as a method for improving its absorbability, the solubility of the drug in the preparation is increased, that is, an adhesive is selected or is still insufficient. In such cases, it is common to add a solubilizer to increase drug release from the preparation, or to add a transdermal absorption enhancer to improve skin permeability.

[0005] However, the above-mentioned monolysis-type preparation has various restrictions in using the above-mentioned means, since the drug is mixed in the adhesive as described above. For example, there is a problem that the dissolving agent or the percutaneous absorption enhancer is not compatible with the pressure-sensitive adhesive, or they are volatilized in the heating step. Therefore, a sufficient amount is not necessarily mixed in the pressure-sensitive adhesive to obtain a desired effect. Not always. In addition, it is necessary to increase the cohesive strength of the pressure-sensitive adhesive in order to hold the liquid component containing the dissolving agent and / or the transdermal absorption enhancer in the pressure-sensitive adhesive, and the pressure-sensitive adhesive has a carboxyl group, a hydroxyl group, and an amino group. In this case, the pressure-sensitive adhesive can be cross-linked by a cross-linking agent, but when the liquid component has the functional group capable of reacting with the cross-linking agent, the reaction of the liquid component with the cross-linking agent occurs preferentially, and Since the crosslinking reaction of the agent is inhibited, the liquid component is not retained in the pressure-sensitive adhesive, and at the same time, the desired medicinal effect cannot be obtained.

[0006]

Therefore, the present inventors formed the drug storage layer-forming film itself or the drug storage layer-forming film and the impermeable support laminated on the drug storage layer-forming film. Attention was paid to a percutaneous absorption-type preparation in which a drug is encapsulated in the drug storage layer thus formed and a pressure-sensitive adhesive layer is further laminated on the drug storage-layer-forming film, that is, a percutaneous absorption-type preparation of a reservoir type preparation.

However, in the above-mentioned reservoir-type preparation containing a drug and a solubilizer in the drug storage layer, since the drug storage layer contains a large amount of liquid components, the adhesive force between the pressure-sensitive adhesive layer and the drug storage layer forming film is weak. During application or peeling, the drug storage layer-forming film may peel off leaving the pressure-sensitive adhesive layer. Also,
The adhesive often remains on the skin at the time of peeling (that is, adhesive residue), and when the drug storage layer forming film shows swelling properties with respect to the dissolving agent, there is a problem that the formulation itself is deformed. .

[0008] An object of the present invention is a preparation for suppressing the occurrence of adhesive residue on the skin surface when peeled off, and the drug storage layer-forming film is swollen by a drug solvent in the drug storage layer.
An object of the present invention is to provide a percutaneous absorption-type preparation capable of suppressing deformation and having excellent percutaneous absorption of a drug.

[0009]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, by providing a cloth layer between the drug storage layer forming film and the adhesive layer, the above-mentioned adhesive residue In addition, they have found that a transdermal preparation exhibiting good transdermal absorbability in a small area when administered to the skin without causing any deformation can be obtained, thereby completing the present invention.

The transdermal preparation of the present invention has the following characteristics. (1) The drug (drug) is formed on the drug storage layer-forming film itself or the drug storage layer formed by the drug storage layer-forming film and the impermeable support provided on the drug storage layer-forming film. However, 2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol and its pharmacologically acceptable salts are enclosed. A transdermal preparation comprising a fabric layer and an adhesive layer sequentially laminated on one side or the side opposite to the support. (2) The transdermal absorption preparation according to (1), wherein the drug storage layer further contains a solubilizer and / or a transdermal absorption enhancer. (3) the dissolving agent is an alcohol having 1 to 4 carbon atoms (2)
The percutaneous absorption type preparation according to the above. (4) The percutaneous absorption enhancer is at least one of esters of fatty acids having 12 to 18 carbon atoms, diesters of dicarboxylic acids having 6 to 10 carbon atoms, and glycerin esters of fatty acids having 8 to 10 carbon atoms. Percutaneous absorption preparation. (5) The drug storage layer forming film has a vinyl acetate content of 5 to 4
0% by weight of ethylene-vinyl acetate copolymer (1)
The percutaneous absorption type preparation according to the above. (6) The transdermal preparation according to (1), wherein the drug storage layer and / or the pressure-sensitive adhesive layer contains a pH adjuster.

In the preparation of the present invention, the fabric layer functions as a backing material of the drug storage layer forming film by providing a fabric layer between the drug storage layer forming film and the adhesive layer of the conventional reservoir type preparation. Further, it is possible to suppress the deformation of the preparation due to the swelling of the drug storage layer forming film. Furthermore, since the adhesiveness between the fabric layer and the pressure-sensitive adhesive layer is good, peeling of the drug storage layer side is suppressed, and the pressure-sensitive adhesive is less likely to remain on the skin.

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS As shown in FIGS. 1 and 2, the drug storage layer 3 may be formed by the drug storage layer forming film 4 itself (that is, in the form surrounded by the drug storage layer forming film). ),
Further, it may be formed by the drug storage layer forming film 4 and the impermeable support 2 provided on the drug storage layer forming film.

The film for forming the drug storage layer may be a heat-sealable polymer film, for example, a single layer of polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, or the like. Are exemplified.

In particular, an ethylene-vinyl acetate copolymer is preferred in that it has high permeability to polar solvents, and the vinyl acetate content of the ethylene-vinyl acetate copolymer is preferably 5 to 40% by weight. When the vinyl acetate content is less than 5% by weight, the membrane permeability of the dissolving agent becomes low, and the transfer of the drug to the pressure-sensitive adhesive layer (the layer indicated by reference numeral 6 in FIGS. 1 and 2) becomes insufficient. If it exceeds 40% by weight, the strength of the film itself becomes insufficient.

The thickness of the drug storage layer forming film is 10 to 100
μm is preferable, and 20 to 50 μm is more preferable.

The impermeable support laminated on the drug storage layer-forming membrane is impermeable to the storage composition (also referred to as a drug-containing liquid composition) in the drug storage layer, and is provided around the preparation. It is preferable that the resin can be heat-sealed with the above-mentioned drug storage layer forming film in the part, and for example, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer and the like can be used. In order to prevent the contents in the layer from passing through the support and being lost from the back surface, the drug-containing liquid composition in the drug storage layer such as a drug such as a metal foil such as polyester or aluminum or a transdermal absorption enhancer or a solvent is used. On the other hand, it is preferable to laminate an impermeable film.

The thickness of the impermeable support is usually 5 to 50
0 μm, preferably in the range of 5 to 200 μm. In addition, these supports have adhesiveness with the drug storage layer forming film,
In order to improve the anchoring property, it is preferable to perform a corona discharge treatment, a plasma treatment, an oxidation treatment or the like on the surface on which the drug storage layer forming film is provided.

The fabric layer (the layer indicated by reference numeral 5 in FIGS. 1 and 2) needs to be formed between the drug storage layer forming film and the pressure-sensitive adhesive layer. Is done. The fabric is not particularly limited as long as it is porous, can be well adhered to the pressure-sensitive adhesive layer, and can be heat-fused or pressure-bonded to the drug storage layer-forming film. Examples thereof include woven fabric and nonwoven fabric. You. Examples of the material constituting the fabric layer include polyester, polypropylene, rayon, nylon, and cellulose. Further, a porous film may be laminated on the fabric layer, and such a laminate is also included in the fabric layer according to the present invention. As the porous film, it is preferable to use a film which can be used as the drug storage layer-forming film or a film having an air permeability (Gurley method) of 9000 sec / 100 cc or less. The laminate is usually used such that the pressure-sensitive adhesive layer comes into contact with the cloth. The fabric layer adheres strongly to the pressure-sensitive adhesive layer due to its excellent anchor effect. For example, even if the plasticizing of the adhesive becomes remarkable by the dissolving agent,
It is possible to prevent the drug storage layer-forming film from being peeled off while leaving the pressure-sensitive adhesive layer during application or peeling, and to prevent adhesive residue on the skin surface during peeling. Further, since the fabric layer prevents the drug storage layer forming film from being swelled and deformed by a large amount of liquid components, even if the drug storage layer forming film is swellable with respect to the dissolving agent used, The deformation of the preparation of the present invention can be suppressed by the presence of the layer.

The drug storage layer contains a drug other than 2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol and a pharmacologically acceptable salt thereof. I have. The drug may be in the form of a pharmacologically acceptable salt of the drug or in the form of a prodrug.

The drug enclosed in the drug storage layer is not particularly limited, and includes, for example, corticosteroids, analgesics and anti-inflammatory agents, hypnotics and sedatives, tranquilizers, antihypertensives, antihypertensive diuretics, antibiotics, anesthetics Agents, antibacterial agents, antifungal agents, vitamins, coronary vasodilators, antihistamines, antitussives, sex hormones, antidepressants, cerebral circulation improving agents, antiemetic agents, antitumor agents, biopharmaceuticals and the like. Especially, it is preferable that the solubility with respect to the dissolving agent described later is 1% by weight or more.

The compounding amount of the drug in the composition enclosed in the drug storage layer can vary depending on the kind of the drug and the like.
Preferably it is 0.5 to 40% by weight. If it is less than 0.5% by weight, the therapeutic effect becomes insufficient, and if it exceeds 40% by weight, it is not preferable from the viewpoint of drug utilization.

It is preferable that the drug storage layer further contains a solubilizer and / or a transdermal absorption enhancer.

The mixing ratio of the solubilizer and the drug may vary depending on the purpose of the preparation, the drug to be encapsulated, and the like. Usually, the drug is preferably 0.1 to 100 parts by weight of the solubilizer.
It is 200 parts by weight, more preferably 1 to 100 parts by weight.

The mixing ratio between the transdermal absorption enhancer and the drug may vary depending on the purpose of the preparation, the drug to be encapsulated, and the like, but usually the drug is preferably 0.1 to 100 parts by weight of the transdermal absorption enhancer. 5 to 2000 parts by weight, more preferably 1 to
１０００1000 parts by weight.

When a solubilizer and a transdermal absorption enhancer are encapsulated in the drug storage layer, the mixing ratio of the two is such that the transdermal absorption enhancer is 3 to 200 parts by weight with respect to 100 parts by weight of the solubilizer. preferable. When the amount is less than 3 parts by weight, a sufficient amount of the transdermal absorption enhancer cannot be contained in the pressure-sensitive adhesive, so that the desired enhancing effect cannot be obtained. This is not preferred because the relative amount of the dissolving agent is reduced, so that the solubility of the drug is reduced.

A solubilizer is added to increase the solubility of the drug, and the dissolved drug penetrates the skin, preferably through the intervention of a transdermal absorption enhancer. Therefore, it is preferable that the dissolving agent dissolves the drug and is mixed with the transdermal absorption enhancer described below. As a dissolving agent, lower alcohols such as ethyl alcohol, polyhydric alcohols such as ethylene glycol and glycerin, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, N-methyl-2-pyrrolidone, dimethyllauramide, dodecylpyrrolidone, isosorbitol, liquid paraffin , Various liquid surfactants, mineral oil, lanolin, ethyl acetate, crotamiton, water and the like. Examples of suitable solubilizers include lower alcohols having 1 to 4 carbon atoms. As the alcohol having 1 to 4 carbon atoms, methyl alcohol,
Examples include ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, and tert-butyl alcohol.

Transdermal absorption enhancers include glycols such as ethylene glycol, oils and fats such as olive oil and squalene, polar solvents such as dimethyl sulfoxide and dimethylformamide, surfactants such as sodium lauryl sulfate and sorbitan fatty acid ester, and olein. Examples thereof include long chain fatty acids such as acids, which have 12 to 18 carbon atoms in terms of increasing the transdermal absorbability of the drug, and having good compatibility with the dissolving agent.
It is preferable to use at least one selected from the group consisting of fatty acid esters of the above formula, diesters of dicarboxylic acids having 6 to 10 carbon atoms and glycerin esters of fatty acids having 8 to 10 carbon atoms.

The fatty acid ester has 12 carbon atoms.
Alkyl esters of aliphatic monocarboxylic acids of, for example, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid and the like and alcohols having 1 to 10 carbon atoms, for example, methyl alcohol, ethyl alcohol, n
-Propyl alcohol, isopropyl alcohol, n-
Butyl alcohol, isobutyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol,
Esters with octyl alcohol, nonyl alcohol, isononyl alcohol and the like can be mentioned.

As the diester of the dicarboxylic acid, a dialkyl ester of an aliphatic dicarboxylic acid having 6 to 10 carbon atoms is preferable, and examples thereof include diesters of adipic acid, sebacic acid and an alcohol having 1 to 10 carbon atoms.

As the glycerin ester of a fatty acid, a glycerin ester of a fatty acid having 8 to 10 carbon atoms, for example, monoglyceride of caprylic acid, monoglyceride of capric acid,
And caprylic acid triglyceride.

Further, in order to improve the operability during the production of the composition enclosed in the drug storage layer, the viscosity is increased by adding glycerin, propylene glycol, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylcellulose and the like. Is possible.

When the drug is in the form of a salt, it is preferable to include a pH adjuster in the drug storage layer and / or the pressure-sensitive adhesive layer. Basic pH adjusters such as sodium hydroxide, triethanolamine, triisopropanolamine, diisopropanolamine, monoisopropanolamine, sodium caprylate, potassium hydroxide and the like or acidic pH adjusters such as citric acid, lactic acid, By blending gluconic acid, succinic acid, tartaric acid, lactic acid, maleic acid, etc., the salt of the drug in the form of a salt is released to make the drug in the form of a base or acid having higher transdermal absorbability. Is possible. It is preferable to add the amount of the pH adjuster necessary to neutralize the acid or base added to the drug in the form of base or acid.

When the amount is less than this, the percutaneous absorbability is slightly inferior because the amount of base or acid produced is small, but the drug stability in the preparation is excellent. May become basic or acidic and cause skin irritation when applied to the skin.

The amount of the composition enclosed in the drug storage layer into the drug storage layer is preferably 50 μL / cm ² or less, and when it exceeds 50 μL / cm ² , the composition can be completely retained in the drug storage layer. No composition or composition that has migrated from the drug storage layer to the pressure-sensitive adhesive layer is not sufficiently retained in the pressure-sensitive adhesive and separates (blooming) from the pressure-sensitive adhesive component, or the plasticization of the pressure-sensitive adhesive becomes remarkable. Glue residue may occur on the skin surface.

The pressure-sensitive adhesive layer and / or the drug storage layer may contain, if necessary, a solubilizer, ascorbic acid, tocopherol, dibutylhydroxytoluene, or the like, in addition to the pH adjuster and the transdermal absorption enhancer. Various known additives such as a stabilizer represented by an oxidizing agent, a plasticizer such as glycerin, propylene glycol and polyethylene glycol, and a filler such as titanium oxide, zinc oxide and hydrous silicon dioxide may be blended.

The pressure-sensitive adhesive layer may cover the entire surface of the fabric layer, or may cover only the edge of the fabric layer in a frame shape with an appropriate width.

The polymer used in the pressure-sensitive adhesive layer is a pressure-sensitive adhesive polymer having tackiness at room temperature, and is preferably one that can be compatible with the above-mentioned mixed solution of a solubilizer and a transdermal absorption enhancer. Preferred examples of the pressure-sensitive adhesive include an acrylic pressure-sensitive adhesive and a rubber-based pressure-sensitive adhesive.

Examples of the acrylic pressure-sensitive adhesive include a homopolymer of an alkyl acrylate or an alkyl methacrylate or a copolymer thereof. Here, the alkyl in the alkyl acrylate or alkyl methacrylate is a linear or branched alkyl having 1 to 18 carbon atoms, and specifically, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl , Isooctyl, 2-ethylhexyl, nonyl, isononyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and the like. Preferably, it is a linear or branched alkyl having 4 to 12 carbon atoms. Further, as the acrylic pressure-sensitive adhesive used in the present invention, a copolymer of the above-mentioned alkyl acrylate and / or alkyl methacrylate and one or more of the following monomers is also preferably used. be able to.

The monomer having a carboxyl group (for example, acrylic acid, itaconic acid, maleic acid,
Maleic anhydride), those having a sulfonic acid group (for example, styrene sulfonic acid, allyl sulfonic acid, sulfopropyl acrylate, acryloyloxynaphthalene sulfonic acid, acrylamidomethylpropane sulfonic acid), hydroxy lower alkyl acrylate (for example, acrylic acid) Hydroxymethyl, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate), acrylamide, acrylamide derivatives (for example, dimethylacrylamide, N-butylacrylamide, N-methylolacrylamide, N
-Methylolpropane acrylamide), aminoalkyl acrylate (eg, aminoethyl acrylate), alkylaminoalkyl acrylate (eg, dimethylaminoethyl acrylate, tert-butylaminoethyl acrylate), alkoxy acrylate Alkyl esters (eg, methoxyethyl acrylate, ethoxyethyl acrylate), tetrahydrofurfuryl acrylate, esters of acrylic acid and methoxydiethylene glycol, esters of acrylic acid and methoxypolyethylene glycol, acrylic acid and methoxypolypropylene glycol And lower alkyl esters of hydroxy methacrylate (for example, hydroxymethyl methacrylate, Hydroxyethyl acrylic acid, hydroxypropyl methacrylate, methacrylic acid hydroxybutyl) methacrylamide, methacrylamide derivatives (e.g., dimethyl methacrylamide, N- methacrylamide, N- methylolmethacrylamide, N-
Methylol propane methacrylamide), aminoalkyl methacrylate (eg, aminoethyl methacrylate), alkylaminoalkyl methacrylate (eg, dimethylaminoethyl methacrylate, tert-butylaminoethyl methacrylate), alkoxy methacrylate Alkyl esters (eg, methacrylic acid methoxyethyl ester, methacrylic acid ethoxyethyl ester), methacrylic acid tetrahydrofurfuryl ester, methacrylic acid and methoxydiethylene glycol, methacrylic acid and methoxypolyethylene glycol, methacrylic acid and methoxypolypropylene glycol With esters, methacrylonitrile, acrylonitrile, vinyl acetate, propionic acid Alkenyl, vinyl pyrrolidone, methyl vinyl pyrrolidone, vinyl pyridine, vinyl piperidone,
Vinyl pyrimidine, vinyl pyrazine, vinyl pyrazine, vinyl pyrrole, vinyl imidazole, vinyl caprolactam, vinyl oxazole, vinyl morpholine,
Styrene and the like.

In the case where a copolymer composed of the above monomers and an alkyl acrylate and / or alkyl methacrylate is used as the acrylic pressure-sensitive adhesive, an alkyl acrylate and / or alkyl methacrylate 30 to 30% is used. It is preferable to copolymerize at a rate of 99.5% by weight, preferably 50 to 90% by weight, and 0.5 to 70% by weight of the above monomer, preferably 10 to 50% by weight.

Further, by using the acrylic pressure-sensitive adhesive having a crosslinked structure, sufficient cohesive force can be obtained even when the dissolving agent or the transdermal absorption enhancer significantly plasticizes the pressure-sensitive adhesive layer. be able to. The cross-linking treatment can be performed when a monomer containing a carboxyl group or a hydroxyl group is used as a component of the acrylic pressure-sensitive adhesive. As the cross-linking agent, a metal alcoholate made of titanium or aluminum, a metal Chelate compounds, polyfunctional isocyanates (especially trifunctional isocyanates) and the like can be mentioned. These crosslinking agents are usually added in a range of 0.05 to 5 parts by weight based on 100 parts by weight of the acrylic polymer.

The rubber adhesive has a viscosity average molecular weight of 300,0.
Those containing from 00 to 2,500,000 high molecular weight rubber-based polymers are preferably used. The high-molecular-weight rubber-based polymer is an essential component for imparting a suitable cohesive force to the rubber-based pressure-sensitive adhesive, and is preferably contained in the rubber-based pressure-sensitive adhesive in an amount of 10% by weight or more, more preferably 20% by weight.
That is all. Examples of the high molecular weight rubber-based polymer include polyisobutylene, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, and the like.One or more of these may be used. It can be used as a mixture.

Further, in order to impart appropriate tackiness to the rubber-based pressure-sensitive adhesive, a rosin-based resin, a polyterpene resin,
A tackifier such as a coumarone-indene resin, a petroleum resin, a terpene-phenol resin, a xylene resin, or an alicyclic saturated hydrocarbon resin may be blended.

Preferred examples of the rubber-based pressure-sensitive adhesive include a high-molecular-weight polyisobutylene having a viscosity-average molecular weight of 300,000 to 2,500,000, and a viscosity-average molecular weight of 1
It is preferable to contain 0000 to 200,000 medium molecular weight polyisobutylene and / or low molecular weight polyisobutylene or polybutene having a viscosity average molecular weight of 500 to 4,000. Here, high molecular weight polyisobutylene was added to 1
0 to 80% by weight, preferably 20 to 70% by weight, and 0 to 90% by weight, preferably 10 to 90% by weight of a medium molecular weight polyisobutylene.
It is preferable to blend the low molecular weight polyisobutylene or polybutene in the range of 0 to 80% by weight, preferably 10 to 60% by weight. In the present invention, the viscosity average molecular weight is calculated from the Flory viscosity equation.

The thickness of the pressure-sensitive adhesive layer is 10 to 100 μm so as to obtain sufficient skin adhesion that can withstand long-time application.
It is preferable that

The pressure-sensitive adhesive layer may contain the above-mentioned transdermal absorption enhancer. The amount of the transdermal absorption enhancer is 100 parts by weight or less based on 100 parts by weight of the pressure-sensitive adhesive polymer. When the amount is more than 100 parts by weight, the adhesive component and the transdermal absorption enhancer may not be retained in the adhesive and may be separated (blooming) on the surface of the adhesive, resulting in poor skin adhesion.

In the transdermal preparation of the present invention, it is desirable that the exposed surface of the pressure-sensitive adhesive layer is covered and protected with a release liner (indicated by reference numeral 7 in FIGS. 1 and 2). The release liner is not particularly limited as long as it can be easily peeled off from the pressure-sensitive adhesive layer at the time of use. For example, a release treatment is performed by applying a silicone resin, a fluororesin, or the like to a surface in contact with the pressure-sensitive adhesive layer. For example, a film of polyester, polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, or the like, a paper of high quality paper, glassine paper, or the like, or a laminated film of high quality paper or glassine paper and a polyolefin is used. The thickness of the release liner is usually 10 to 200 μm, preferably 50 to 100 μm.
m.

FIGS. 1 and 2 show examples of cross-sectional views of the transdermal preparation of the present invention.

The method for producing the percutaneously absorbable preparation of the present invention is not particularly limited. For example, the following production method is exemplified. After applying the adhesive on the release liner and drying,
The fabric is laminated and thermally fused with the drug storage layer forming film. Thereafter, the impermeable support is heat-sealed at a suitable inner diameter and seal width except for the drug storage layer solution inlet, and cut off along the outer periphery of the heat-sealed portion. Next, after injecting the drug storage layer solution containing the drug from the injection port, the injection port is completely sealed by heat sealing to obtain the transdermal absorption type preparation of the present invention.

When the drug storage layer is formed on the drug storage layer forming film itself, the drug storage layer forming film is laminated on one side of an impermeable support in advance, and the formed film side and the adhesive The layer, the fabric, and the film formed by laminating the drug storage layer forming film in this order are heat-sealed except for the injection port. Next, after injecting the drug storage layer solution from the injection port in the same manner as described above, the injection port is completely sealed by heat sealing to obtain the transdermal preparation of the present invention.

[0051]

EXAMPLES Examples of the present invention will be shown below, and the present invention will be described more specifically. (A list of these compositions is shown in Tables 1 and 2.) In the following, parts and% mean parts by weight and% by weight, respectively.

(Preparation of Adhesive Solution A) An acrylic adhesive solution A was prepared by polymerizing 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid in ethyl acetate under an inert gas atmosphere.

(Preparation of Adhesive Solution B) High molecular weight polyisobutylene (viscosity average molecular weight 2,100,000, VIS
TANEX MML-140, manufactured by Exxon Chemical Co.) 50
Parts, medium molecular weight polyisobutylene (viscosity average molecular weight 60,
000, HIMOL 6H, 30 parts by Nippon Petrochemical Co., Ltd.) and an alicyclic petroleum resin (softening point 100 ° C., Alcon P)
(100, Arakawa Chemical Co., Ltd.) was dissolved in hexane to prepare a rubber-based pressure-sensitive adhesive solution B.

EXAMPLE 1 A polyisocyanate compound (Coronate HL, manufactured by Nippon Polyurethane Co., Ltd.) having a solid content of 0.15% based on the pressure-sensitive adhesive was added to the pressure-sensitive adhesive solution A, mixed, and released.
40 μm thick polyester film)
It was applied to a thickness of μm and dried. A polyester nonwoven fabric (having a basis weight of 8 g / m ² ) was laminated thereon, and a 50 μm-thick ethylene-vinyl acetate copolymer film (vinyl acetate content: 14%) was heat-sealed. The laminated support has an inner diameter of 20
mm and a seal width of 4 mm, the solution was heat-sealed leaving the drug storage layer solution inlet, and cut along the outer periphery of the heat-sealed portion. A drug storage layer solution 50 was prepared by adding ketoprofen to a mixture of ethyl alcohol-isopropyl myristate (mixing ratio 7: 3) to a concentration of 10%.
After injecting μL from the injection port, the injection port was completely sealed by heat sealing to obtain a transdermally absorbable preparation of the present invention.

Example 2 Example 1 was repeated except that the drug storage layer solution was changed to a mixture of ethyl alcohol-isopropyl myristate-caprylic acid monoglyceride (mixing ratio 7: 2: 1) with ketoprofen at a concentration of 10%. In the same manner as in the above, a transdermal preparation of the present invention was obtained.

Example 3 The present invention was carried out in the same manner as in Example 1 except that the drug storage layer solution was changed to a mixture of ethyl alcohol-diethyl sebacate (mixing ratio 7: 3) with a ketoprofen concentration of 10%. Was obtained.

Example 4 In Example 1, 40% of isopropyl myristate was added to the pressure-sensitive adhesive solution B, and the drug storage layer solution was added to a mixed solution of isopropyl alcohol-isopropyl myristate (mixing ratio 6: 4) with a metoprolol concentration of 10%. %, To obtain a transdermal preparation of the present invention in the same manner as in Example 1 except that the preparation was added so as to obtain a percutaneously absorbable preparation.

Example 5 In Example 4, the vinyl acetate content of the ethylene-vinyl acetate copolymer was set to 5%, and the drug storage layer solution was mixed with an ethyl alcohol-isopropyl myristate mixed solution (mixing ratio: 6:
A transdermal preparation of the present invention was obtained in the same manner as in Example 4, except that metoprolol was added to 4) so that the concentration was 10%.

Example 6 In Example 4, the vinyl acetate content of the ethylene-vinyl acetate copolymer was set to 33%, and metoprolol was added to the drug storage layer solution in a mixed solution of ethyl alcohol-isopropyl myristate (mixing ratio 6: 4). A transdermal preparation of the present invention was obtained in the same manner as in Example 4, except that the drug was added so as to have a concentration of 10%.

Example 7 In Example 4, the drug storage layer solution was added to an ethyl alcohol-isopropyl myristate mixed solution (mixing ratio 6: 4) so that metoprolol tartrate and triethanolamine became 10% and 7%, respectively. Example 4 except that
In the same manner as in the above, a transdermal preparation of the present invention was obtained.

Comparative Example 1 (Reservoir Type) A transdermal preparation of the present invention was prepared in the same manner as in Example 1 except that a polyester nonwoven fabric was not laminated between the pressure-sensitive adhesive layer and the drug storage layer-forming film. Obtained.

Comparative Example 2 (Monolysis Type) Ketoprofen and isopropyl myristate were added to the adhesive solution A so that the mixing amounts in the paste were 10% and 40%, respectively, and mixed, and the mixture was placed on a release liner. Coating and drying were performed so that the thickness after drying was 40 μm. A support (a polyester film having a thickness of 12 μm) was adhered to this to obtain a transdermally absorbable preparation.

Experimental Example In the transdermal preparations of Examples 1 to 7 and Comparative Examples 1 and 2, the amount of the drug permeated through the skin was measured using excised and dehaired rat abdominal skin. (Measurement method) Rat skin was attached to a glass permeation cell so that the part corresponding to the front side of the skin was in contact with the transdermal preparation, and the part corresponding to the back side of the skin was in contact with physiological saline. The permeated drug was quantified by high performance liquid chromatography. The results are shown in Tables 1, 2 and 3.

[0064]

[Table 1]

[0065]

[Table 2]

[0066]

[Table 3]

The preparation of Comparative Example 1 is different from that of the present invention in that
Deformation of the preparation such as wrinkles and undulations was remarkably large. Further, when peeling from the skin, the peeling occurred between the drug storage layer forming film and the adhesive layer, and the adhesive remained on the skin surface. Example 1
The percutaneous absorption-type preparations of Nos. 1 to 3 exhibited better skin permeability than that of Comparative Example 2.

[0068]

According to the transdermal preparation of the present invention, since the fabric layer is provided between the drug storage layer forming film and the pressure-sensitive adhesive layer, the drug storage layer forming film and the pressure-sensitive adhesive layer are strongly adhered. In addition, adhesive residue is suppressed when the drug storage layer forming film and the pressure-sensitive adhesive layer are peeled off and peeled off from the skin after use. Also, due to the presence of the fabric layer,
Even when the drug storage layer forming film shows swelling properties with respect to the dissolving agent, deformation of the preparation itself is suppressed. In addition, the preparation of the present invention is a transdermal preparation with excellent transdermal absorbability of the drug.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view schematically showing a transdermal preparation of the present invention.

FIG. 2 is a cross-sectional view schematically showing a transdermal preparation of the present invention.

[Explanation of symbols]

 REFERENCE SIGNS LIST 1 transdermal absorption preparation 2 support 3 drug storage layer 4 drug storage layer forming film 5 fabric 6 adhesive layer 7 release liner

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 47/12 A61K 47/12 47/14 47/14 47/18 47/18 47/32 47/32 A61P 1/08 A61P 1/08 3/02 101 3/02 101 5/24 5/24 5/38 5/38 9/10 9/10 9/12 9/12 11/14 11/14 13/02 13/02 23 / 00 23/00 25/04 25/04 25/18 25/18 25/20 25/20 25/24 25/24 25/28 25/28 31/00 31/00 31/04 31/04 31/10 31 / 10 35/00 35/00 37/08 37/08 43/00 43/00 (72) Inventor Mitsuhiko Hori 1-1-2 Shimohozumi, Ibaraki-shi, Osaka Nitto Denko Corporation F-term (reference) 4C076 AA78 AA81 BB31 CC01 CC04 CC11 CC15 CC16 CC17 CC22 CC27 CC30 CC31 CC32 DD37E DD45N DD46N DD47N EE03H EE08H EE48H FF12 FF34 4C206 AA01 AA02 DA25 FA21 MA05 MA52 MA83 ZA02 ZA04 ZA05 ZA08 ZA13 ZA13 ZA13 ZA13 ZA13 ZC22

Claims (6)

[Claims] 1. The method according to claim 1, wherein the film is formed on the drug storage layer forming film itself,
Alternatively, a drug (however, 2-tert-butylamino-1-) is added to the drug storage layer formed by the drug storage layer forming film and the impermeable support provided on the drug storage layer forming film.
(2-chloro-4-hydroxyphenyl) ethane-1-
All and a pharmacologically acceptable salt thereof) are enclosed, and a fabric layer and an adhesive layer are sequentially laminated on one side or the side opposite to the support of the drug storage layer forming membrane. Skin absorption type preparation. 2. The percutaneous absorption preparation according to claim 1, wherein a solubilizer and / or a percutaneous absorption enhancer is further enclosed in the drug storage layer. 3. The transdermally absorbable preparation according to claim 2, wherein the solubilizer is an alcohol having 1 to 4 carbon atoms. 4. The transdermal absorption enhancer is at least one of esters of fatty acids having 12 to 18 carbon atoms, diesters of dicarboxylic acids having 6 to 10 carbon atoms and glycerin esters of fatty acids having 8 to 10 carbon atoms. 2. The transdermally absorbable preparation according to 2. 5. The percutaneously absorbable preparation according to claim 1, wherein the drug storage layer forming film is an ethylene-vinyl acetate copolymer having a vinyl acetate content of 5 to 40% by weight. 6. The transdermal absorption preparation according to claim 1, wherein the drug storage layer and / or the pressure-sensitive adhesive layer contains a pH adjuster.