JPS60228413A - Tape or sheet for therapeutic use and its preparation - Google Patents

Abstract

PURPOSE:To prepare a therapeutic tape having high releasability of the drug component and the durability of the drug action, by adding a poor solvent and a drug to a solution of an acrylic polymer, stiring the mixture to coagulate and pulverize a part of the acrylic polymer to fine particles, and applying the resultant mixture to one surface of a substrate. CONSTITUTION:A solution of an acrylic polymer is added with its poor solvent (e.g. methanol, ethanol, etc.) and with a drug (preferably a water-soluble drug such as heparin sodium, sodium salicylate, etc.), and is stirred to convert a part of the acrylic polymer to coagulated fine particles. The resultant mixture of the polymer solution, coagulated fine particlesand drug is applied to one surface of a substrate and dried to obtain the objective tape or sheet for therapeutic use. The adhesive layer of the tape is composed of the homogeneous matrix of the acrylic polymer and the coagulated fine particles dispersed therein. It has high transcutaneous absorptivity, high resistance to the separation of the drug, and good preservability. It can be prepared by a simple process.

Description

DETAILED DESCRIPTION OF THE INVENTION (Technical Field) The present invention relates to a medical tape or sheet containing a medical drug in a pressure-sensitive adhesive layer, and a method for manufacturing the same.

(Prior art) Conventionally, patches that are attached to the body to treat diseased parts of the body's outer skin or to continuously administer drugs to the circulatory system via the skin have been used to An acrylic adhesive layer containing one drug is laminated on the
2-31405, JP-A-57-116011), but in this case, the drug diffuses through the adhesive layer, and since the drug exists in the adhesive layer in a crystalline state, it may cause damage to the skin. The drawback is that it is difficult to absorb an effective amount of the drug through the skin.

In order to eliminate the father's entry point, a method was proposed in which a particulate pressure-sensitive adhesive layer was formed on one side of the base material and a drug solution was filled in the gaps between the adhesive layers (Japanese Patent Application Laid-Open No. 57-42619). However, in this case, there is a drawback that the drug tends to precipitate during holding, especially water-soluble drugs, and the drug solution is filled after forming an adhesive layer on the base material and then applying the drug solution. Since it is absorbed, it is difficult to manufacture because it is dusty, and it has the disadvantage that it is difficult to manufacture a product in which the drug is uniformly dispersed.

(Object of the Invention) In view of the above-mentioned drawbacks, the present invention has been made for the purpose of providing a therapeutic adhesive tape or adhesive sheet that has good transdermal absorption, does not cause drug precipitation, and has good storage stability. It is something that

(Structure of the Invention vi,) Summary of the Invention d A therapeutic tape or mechanism sheet comprising an acrylic pressure-sensitive adhesive layer containing a drug on one side of a base material, wherein the adhesive layer is made of an acrylic polymer. A therapeutic tape or sheet consisting of a homogeneous matrix and agglomerated fine particles of an acrylic polymer dispersed in the matrix, and an acrylic polymer solution containing: 1 a poor solvent for the polymer; A part of the acrylic polymer is collected and precipitated into aggregated fine particles by stirring, and a mixture of the polymer solution, the above aggregated fine particles, and the drug is mixed. The present invention relates to a method for producing a therapeutic tape or sheet, which is characterized in that it is coated on one side of a base material and dried.

The pressure-sensitive adhesive used in the present invention is composed of a copolymer mainly composed of an acrylic pressure-sensitive adhesive and a branched (meth)acrylic ester. Examples of the (meth)acrylic ester include methyl acrylate, Ethyl acrylate, propyl acrylate, isopropyl acrylate, butyl acrylate, inbutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, decyl acrylate, isodecyl acrylate, ucryl acrylate, methacrylic acid Examples include methyl, ethyl methacrylate, propyl methacrylate, butyl methacrylate, and 2-ethylhexyl methacrylate.

If the above-mentioned copolymer has an amide group, hydroxyl group, ether group, or neutralized carboxyl group, the compatibility and release properties with water-soluble drugs will be improved, so that the copolymer will have good compatibility with the drug and adhesive. In order to obtain compatibility and high release properties, monomers having these groups are introduced into the acrylic copolymer.

Examples of monomers having an amide group include ttf acrylamide, dimethyl acrylamide, diethylamide, butoxymethyl acrylamide, ethoxymethyl acrylamide, dimethyl acrylamide, vinylpyrrolidone, etc. Monomers having a hydroxyl group Examples include 2-hydroxyethyl acrylate), 2-hydroxyethyl methacrylate, hydroxypropyl acrylate, and hydroxyethyl methacrylate.

In addition, monomers having a carboxyl group include monoalkyl maleic esters such as acrylic acid, methacrylic acid, maleic acid, maleic anhydride, and gtylated maleate;
Examples include monomers containing carboxyl groups such as fumaric acid and crotonic acid, but if a large amount of free carboxyl groups are present in the copolymer, water-soluble drugs are likely to change, so sodium hydroxide and potassium hydroxide are used after polymerization. 8 with alkali metal or alkaline earth metal-containing compounds such as magnesium acetate, barium acetate, sodium ethylate, etc.
It is necessary to neutralize 0 or more moles of carboxyl groups.

In addition, copolymerization of monomers having amide groups, hydroxyl groups, ether groups, or carboxyl groups in large amounts will reduce water resistance and adhesion, and if the amount is small, compatibility with drugs will not improve. During coalescence (preferably 11 to 50 moles are copolymerized).

The above copolymer may further contain vinyl acetate, vinyl ester of butyrate, styrene, α-methylstyrene, acrylonitrile, fJI vinyl, α-olefins such as ethylene and propylene, diene monomers such as butadiene and isoprene, etc. may be copolymerized.

In the present invention, a part of the acrylic polymer is added to the poor solvent by adding a poor solvent for the polymer and a drug to the acrylic polymer solution, which is a solvent solution of the pressure-sensitive adhesive, and stirring the mixture. As a result, the mixture is agglomerated and precipitated to form agglomerated fine particles, and the mixture of the acrylic polymer solution obtained in this way, the precipitated agglomerated fine particles, and the drug is applied to one surface of the substrate and dried. Therapeutic tapes and sheets are manufactured by the above method, and the therapeutic tapes and sheets obtained in this manner have a drug-containing acrylic pressure-sensitive adhesive layer provided on one side of the base material. The adhesive layer is composed of a homogeneous matrix of acrylic polymers produced by drying an acrylic polymer solution and aggregated fine particles of acrylic polymers dispersed in the homogeneous matrix. be.

Method for obtaining the above solvent solution KG-j: A pressure sensitive adhesive is produced by solution polymerization using a solvent such as ethyl acetate or toluene, or an adhesive prepared by emulsion polymerization or bulk polymerization is dissolved in the above solvent. There is a way.

In addition, as the drug, any drug conventionally used in therapeutic tapes or sheets can be used as appropriate, and the paper used preferably ranges from 0.1 to 200 parts by weight per 100 parts by weight of the copolymer. For example, by using water-soluble drugs such as be/(linnatrichum, sodium salicylate, dichloro7enafucnatrichum, goldthiomaleate sodium, etc.), it is possible to obtain therapeutic tapes or sheets with high drug release properties and excellent therapeutic effects. Although high drug release properties can be obtained, alcohols such as methanol, ethanol, isopronol, etc., and water, which are used as poor solvents for acrylic polymers, on the other hand, are good for the water-soluble drugs mentioned above. Since it is a solvent, a large amount of the drug will be mixed with the poor solvent in the polymer solution that did not aggregate or precipitate as fine particles in the mixture applied to the surface of the substrate, and therefore, the coating, After drying, the acrylic polymer homogeneous matrix formed by drying contains the drug at a high concentration, and the drug contained in the homogeneous matrix at a high concentration of kernels has good release properties. It is thought that.

Furthermore, in the present invention, the agglomerated fine particles of acrylic polymer are dispersed in the drug-containing adhesive layer as described above. A flow path is formed, and some of the drug is also adsorbed inside and around the agglomerated fine particles, so not only does the drug have a high release property, but the drug is also released in a short period of time. It also has a long-lasting release that allows the release to continue over a long period of time.

As mentioned above, agglomerated fine particles are produced by adding a poor solvent to an acrylic polymer solution and stirring it, so that part of the acrylic polymer becomes insolubilized and precipitates as fine colloidal particles. However, the amount of poor solvent added varies somewhat depending on the poor solvent, the solvent, and the type of polymer, but it is usually based on the total amount of the solvent in the polymer solution and the added poor solvent. It is preferable to select it within a range of 20 to 50% by weight. Furthermore, the particle size of fine particles produced by addition of a poor solvent and stirring varies depending on the addition ratio of the poor solvent, the method of stirring, the molecular weight of the polymer, etc., but is usually in the range of cL5 to 100 microns. The amount of fine particles precipitated is usually in the range of 5 to 95 parts by weight per 100 parts by weight of the acrylic polymer initially contained in the polymer solution.

Further, it is preferable to add a poor solvent and a drug to the polymer solution and, when stirring, add an absorption aid to facilitate absorption of the drug into the skin.

The absorption aid is preferably one that can dissolve the above drug, has good safety, and is a liquid substance, such as isopropyl myristate, diethyl sebacate, squalene, squalane, liquid paraffin, propylene glycol, polypropylene glycol. , ethylene glycol, polyethylene glycol, glycerin, water, octyloxystearate, lanolin alcohol, cecyl alcohol, stearyl alcohol, dimethyl sulfoxide,
Examples include alcohols and carboxylic acids such as dimethylformamide and ethylene glycol monoethyl ether, synthetic oils such as polyether, medium chain fatty acid triglycerides, and N-methylpyrrolidone, and the amount added is within the range that completely dissolves the drug. is preferable, and the above copolymer 10
It is preferably 1 to 10031tJi 1 part, more preferably 2 to 25 parts by weight per 0 parts by weight.

The base used in the present invention is preferably a flexible, drug-impermeable film, since it is used by pasting it on the body, such as polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride. Films such as polyvinylidene chloride, vinyl acetate-vinyl chloride copolymer, polyamide, polyester, cellulose acetate, ethyl cellulose, and hexalonone, metal foils such as aluminum foil, and laminates of vinyl etc. can be used. The film is preferably surface-treated by corona discharge treatment or the like in order to improve the adhesive strength with the pressure-sensitive adhesive layer.

(The following is a blank space) The therapeutic tape or mechanism sheet of the present invention has the structure as described above, and in particular, the acrylic pressure-sensitive adhesive layer containing one drug is comprised of an acrylic polymer matrix and an acrylic adhesive dispersed in the matrix. Since it is made of aggregated fine particles of polymer, it not only has good drug release properties, but also has a flow path for drug diffusion formed by dispersion of aggregated fine particles, and Since a part of the drug is contained or adsorbed inside or around the drug, the drug release can be sustained for a long time, and an excellent therapeutic effect can be expected. Furthermore, the therapeutic tape of the present invention is
It also has good retention properties for drugs that are difficult to maintain in the adhesive layer.
It has excellent storage stability, with no drug precipitation even after long-term storage.

Further, according to the manufacturing method of the present invention, a therapeutic tape or sheet having the above-mentioned excellent performance can be manufactured and provided by simple operations without requiring complicated steps.

The present invention will be explained below based on Examples. Note that in the following, parts mean parts by weight.

Example 1 A coelectrolyte obtained by copolymerizing 10 mol% of 2-ethylhexyl acrylate, 53 mol% of butyl acrylate, 32 mol% of 2-ethylhexyl methacrylate, and 5 mol% of diacetone acrylamide was added to an ethyl acetate solution. 15 parts of magnesium oxide and 10 parts of diclofenac sodium are added and mixed to 100 parts of the polymer, and methanol, which is a poor solvent for the copolymer, is added until the weight ratio of methanol/(methanol + ethyl acetate) in the mixture is α3
5 Km was added to the mixture, and the mixture was stirred for 1 hour using a stirrer.

By doing so, a part of the above copolymer aggregates and precipitates to form fine colloidal particles, which are combined with the solution copolymer dispersed in the drug-containing copolymer solution and the aggregated fine particles. A dispersion mixture was obtained.

This mixed solution was applied to an ethylene-vinyl acetate copolymer film and dried to form a drug-containing adhesive layer with a thickness of 50 μm, thereby producing a therapeutic sheet containing diclofenac sodium.

The resin component forming the adhesive layer exists in a homogeneous matrix portion of the copolymer produced when the solvent of the solution copolymer evaporates, and is dispersed in the matrix, and is bonded and held by the matrix. It was composed of agglomerated fine particle dispersion.

The therapeutic drug obtained in this way was measured for drug dissolution rate with water and found to be 61% in 2 hours and 83% in 24 hours.
The skin transfer rate Fi was 13.4% after 2 hours of application and 33.6% after 6 hours of application.

Further, when a test of storing the product at 60° C. for several months (hereinafter referred to as the "severe test"), no denaturation or precipitation of the drug was observed.

The details of each of the above test methods are as follows.

Drug elution rate with water: A sample is punched out in a certain area and immersed in water, and eluted at 25° room temperature under stirring.

After a predetermined period of time, the eluate is sampled and quantified using a spectrophotometer.

The drug dissolution rate is calculated using the following formula.

Skin transfer rate: Remove hair from the back of Kusaya with a hair removal agent.

Four hours after hair removal, a sample containing a known amount of drug is pasted on the back. After a predetermined period of time, the sample is pricked, extracted with a methanol solution, and the amount of drug remaining in the sample is determined by high performance liquid chromatography.

The skin transfer rate is calculated using the following formula.

Amount of drug contained in the sample x 100 Severity test: The sample was wrapped in 9mm aluminum foil, placed in a constant temperature room at 60°C, and taken out after 2 months to examine its condition after storage.

Example 2 2-ethylhexyl acrylate 10 mol%, phthyl acrylate 53 mol%, 2-ethylhexyl methacrylate 32 mol%, diacetone acrylamide 5 mol%
15 parts of magnesium oxide, 10 parts of diclofenac sodium and 5 parts of propylene glycol are blended with 100 parts of the above copolymer into the ethyl acetate solution of the copolymerization,
Next, methanol was added so that the ratio of methanol/(methanol + ethyl acetate) was 0.33 K, and the mixture was stirred for 1 hour with a stirrer, so that a part of the copolymer coagulated and precipitated, forming colloidal particles. Thus, a dispersion mixture containing KO dispersed in a drug-containing copolymer solution was prepared. A pressure-sensitive adhesive sheet with a drug-containing layer thickness of 50 μm was obtained in the same manner as in Example 1, and the same test was conducted.
72% in hours, 87% in 24 hours, skin transfer rate Vi 19.3% when applied for 2 hours, and 38.4% after applied for 6 hours.
Further, no denaturation or precipitation of the drug was observed after the severe test.

Example 3 10 mol% of 2-ethylhexyl acrylate, 53 mol% of phthyl acrylate, 32 mol% of 2-ethylhexyl methacrylate, and 5 mol% of diacetone acrylamide
The above copolymer 1 was added to an ethyl acetate solution of mol% copolymer.
Add indomethacin at a ratio of 4 parts to 0.00 parts, then add methanol so that the methanol/(ethyl methanol decacetate) ratio is 0.40 K, and stir simultaneously with a stirrer. A dispersion mixture was prepared in which a part of the copolymer was agglomerated and precipitated to form fine colloidal particles and dispersed in the drug-containing copolymer solution. Next, the mixed solution was applied to a polyethylene film and dried to obtain a therapeutic sheet with a drug-containing adhesive layer having a thickness of 50 μm and in which aggregated fine particles were dispersed in the adhesive layer in the same manner as in Example 1.

When the sheet was tested, the drug dissolution rate with water was 26% in 2 hours, 80% in 24 hours, and the skin transfer rate was F.
i 15.2% after 2 hours of application, same <32.7% after opening at 8 o'clock
Moreover, no denaturation or precipitation of the drug was observed after the severe test.

Example 4 To a solution of the same copolymer used in Example 3 in ethyl acetate was added mendomethacin in an amount of 4 parts per 100 parts of the copolymer and diethyl sebacate in an amount of 10 parts. Then, methanol was added so that the methanol/(methanol + ethyl acetate) ratio was α37, and in the same manner as in Example 3, a colloid F-like particle dispersion mixture was prepared. The mixed solution was applied to a polyethylene film and dried to obtain a therapeutic sheet.

The drug elution rate of this sheet according to this paper was 37% in 2 hours, 24
8896 in hours, skin transfer rate is 7% in 2 parts after 2 hours of application.
The concentration was 1% in 3 parts when applied for 8 hours, and no denaturation or precipitation of the drug was observed after the severe test.

Example 5 2-ethylhexyl methacrylate 10 mol%, 2-
To an ethyl acetate solution of a copolymer of 70 mol% (ethylhexyl acrylate) and 20 mol% of vinylpyrrolidone, 15 parts of magnesium oxide and 10 parts of dichloro-7-enatricium were added to 100 parts of the copolymer. Next, methanol was added so that the ratio of methanol/(methanol+ethyl acetate) was 0.35, and the mixture was stirred with a stirrer for 1 hour. In this way, a part of the copolymer coagulated and precipitated to form fine colloidal particles, which were dispersed in the copolymer solution containing the drug to prepare a fine particle dispersion mixture.

This mixed solution was applied to an ethylene-vinyl acetate copolymer film and dried to form a drug-containing adhesive layer with a thickness of 50 μm.
A therapeutic sheet in which fine particles were dispersed in a copolymer matrix was obtained in the same manner as in Example 1. The drug elution rate of this therapeutic sheet with water was 62% at 12 hours and 84% at 24 hours, and the skin transfer rate was 128% when applied for 2 hours and 317% after 6 hours. No denaturation of the drug or precipitation of Fi was observed.

Comparative Example 1 A therapeutic sheet was obtained using the same materials and method as in Example 1, except that methanol was not added, and cosidic fine particles were not agglomerated or precipitated.

The drug elution rate of this sheet with water was 5% in 2 hours, 24
Time: 15%, skin transfer rate: 1896.6 after 2 hours of application
The time was 2m796.

Comparative Example 2 A therapeutic sheet was obtained using the same materials and method as in Example 2, except that methanol was not added. The water dissolution rate of this sheet was 18% in 2 hours and 28% in 24 hours.
Skin transfer rate ij 3.296.6 hours after application for 2 hours 7.
It was 396.

Comparative Example 3 A therapeutic sheet was obtained using the same materials and method as in Example 3, except that methanol was not added. The water dissolution rate of this sheet was 19% in 2 hours and 57% in 24 hours, and the skin transfer rate was 9.896 for 2 hours.14 for 8 hours.
．． It was 196.

Comparative Example 4 A therapeutic sheet was obtained using the same materials and method as in Example 4, except that no methanol was added. The water dissolution rate of this sheet was 23% in 2 hours and 7396 in 24 hours.
The skin transfer rate #'lt was 13% after 2 hours of application and 217% after 8 hours of application.

patent applicant Sekisui Chemical Co., Ltd. Representative: Mototoshi Fujinuma

Claims (1)

[Scope of Claims] L A therapeutic tape or mechanism sheet comprising an acrylic pressure-sensitive adhesive layer containing a drug on one surface of a base material, wherein the adhesive layer comprises an acrylic polymer homogeneous matrix and the matrix. 1. A therapeutic tape and sheet that is composed of aggregated fine particles of an acrylic polymer dispersed therein. 2. A poor solvent for the polymer and a drug are added to the acrylic polymer solution, and the mixture is stirred to agglomerate and precipitate a portion of the acrylic polymer to form agglomerated fine particles. A method for producing a therapeutic tape or sheet, which comprises applying a mixture of a molecular solution, the above-mentioned aggregated fine particles, and a drug onto one surface of a base material and drying the mixture.