JPH0374204B2 - - Google Patents

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, as a patch that is applied 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, one side of the backing member is There are some laminated acrylic adhesive layers containing drugs (Japanese Patent Publication No. 52-31405, Japanese Patent Application Laid-Open No. 57-116011), but in this case, the drug is difficult to diffuse through the adhesive layer, Furthermore, since the drug is present in the adhesive layer in a crystalline state, it is difficult to absorb through the skin, so there is a drawback that it is difficult to absorb an effective amount of the drug through the skin.

In order to solve the above-mentioned drawbacks, 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 storage, especially water-soluble drugs, and filling with the drug solution requires forming an adhesive layer on the base material and then applying the drug solution. Since the drug is absorbed, it is difficult to manufacture, and it has the disadvantage that it is difficult to produce a drug in which the drug is uniformly dispersed.

(Object of the invention) In view of the above drawbacks, the present invention has good percutaneous absorption,
The purpose of this invention is to provide a therapeutic adhesive tape or sheet that does not cause drug precipitation and therefore has good storage stability.

(Structure of the Invention) The gist of the present invention is a therapeutic tape or sheet in which an acrylic pressure-sensitive adhesive layer containing a drug is provided on one surface of a base material, wherein the adhesive layer is made of an acrylic polymer homogeneous matrix and A therapeutic tape or sheet characterized by being of a heterogeneous type composed of aggregated fine particles of an acrylic polymer dispersed in the matrix and an acrylic polymer solution, and a poor solvent for the polymer. A drug is added and stirred to agglomerate and precipitate a portion of the acrylic polymer to form agglomerated fine particles, and a heterogeneous mixture of the polymer solution, the agglomerated fine particles, and the drug thus obtained is prepared. 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 acrylic pressure-sensitive adhesive used in the present invention is a pressure-sensitive adhesive made of a copolymer mainly composed of (meth)acrylic ester, and examples of the (meth)acrylic ester include methyl acrylate, ethyl acrylate, propyl acrylate,
Isopropyl acrylate, butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, decyl acrylate, isodecyl acrylate,
lauryl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate,
Examples include butyl methacrylate and 2-ethylhexyl methacrylate.

If the above 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. In order to obtain high release properties, monomers having these groups are introduced into the acrylic copolymer.

Examples of monomers having an amide group include acrylamide, dimethylacrylamide, diethyl acrylamide, butoxymethyl acrylamide, ethoxymethyl acrylamide, diacetone acrylamide, vinyl pyrodrine, etc. Monomers having a hydroxyl group As, 2
-Hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, and the like.

In addition, as monomers having carboxyl groups,
Monomers containing carboxyl groups such as acrylic acid, methacrylic acid, maleic acid, maleic anhydride, monoalkyl maleate esters such as butyl maleate, coumaric acid, and crotonic acid may be mentioned; If a large amount of carboxyl groups are present, the water-soluble drug will be easily changed, so after polymerization, add 80 mol% of alkali metal or alkaline earth metal-containing compounds such as sodium hydroxide, potassium hydroxide, magnesium acetate, barium acetate, sodium ethylate, etc. It is necessary to neutralize the above carboxyl groups.

In addition, if a large amount of a monomer having an amide group, hydroxyl group, ether group, or carboxyl group is copolymerized, water resistance and adhesion will decrease, and if the amount is small, compatibility with drugs will not improve. 0.1~
Preferably, 50 mol% of the copolymer is copolymerized. Further, the above copolymer may further contain vinyl esters such as vinyl acetate and vinyl butyrate, styrene, α-methylstyrene,
Acrylonitrile, vinyl chloride, 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 acrylic polymer solution obtained in this way, the precipitated agglomerated fine particles, and a heterogeneous mixture of the drug are applied to one surface of the substrate and dried. A therapeutic tape or sheet is produced by this process, and the therapeutic tape or sheet obtained in this way is
A drug-containing acrylic pressure-sensitive adhesive layer is provided on one side of the base material, and the adhesive layer is a homogeneous matrix of acrylic polymer produced by drying an acrylic polymer solution. It is a heterogeneous system consisting of agglomerated fine particles of acrylic polymer dispersed in the homogeneous matrix.

The method for obtaining the above-mentioned solvent solution includes manufacturing the pressure-sensitive adhesive by solution polymerization using a solvent such as ethyl acetate or toluene, or dissolving the pressure-sensitive adhesive prepared by emulsion polymerization or bulk polymerization in the above-mentioned solvent. There is a way to do it.

In addition, as the drug, drugs conventionally used in therapeutic tapes or sheets can be used as appropriate.
The preferred amount used is based on 100 parts by weight of the copolymer.
The range is from 0.1 to 200 parts by weight, but if a water-soluble drug such as sodium peparin, sodium salicylate, sodium diclofenac, or sodium gold thiomaleate is used, a therapeutic tape with high drug release properties and excellent therapeutic effects can be obtained. Alternatively, it is preferable because a sheet can be obtained. Like this,
High drug release properties can be obtained with alcohols such as methanol, ethanol, isopropanol, and water, which are used as poor solvents for acrylic polymers.
On the other hand, since it is a good solvent for the above-mentioned water-soluble drugs, in the mixture applied to the surface of the substrate, a large amount of the drug is mixed with a poor solvent in the polymer solution that does not aggregate or precipitate as fine particles. Therefore, after application and drying, the drug will be contained in a high concentration in the acrylic polymer homogeneous matrix formed by drying, and the drug will be contained in the homogeneous matrix at this high concentration. This is thought to be due to the fact that the drug has good release properties.

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 a part of the drug is contained or adsorbed inside or around the agglomerated fine particles, so not only does the drug have high release properties, but the drug also releases quickly. It also has long-lasting release properties, meaning that it continues to release water 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, causing some of the acrylic polymer to become insolubilized and precipitate as fine colloidal particles. However, the amount of poor solvent to be added varies somewhat depending on the poor solvent, the solvent, and the type of polymer, but it is usually 20 to 20% of 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 50% by weight. In addition, the particle size of the fine particles generated 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 0.5 to 100 microns. is within the range of
Further, the amount of precipitated fine particles is usually in the range of 5 to 95 parts by weight based on 100 parts by weight of the acrylic polymer initially contained in the polymer solution.

Also, adding a poor solvent and a drug to the polymer solution,
It is preferable to add an absorption aid to facilitate absorption of the drug into the skin during stirring. The absorption aid is preferably one that can dissolve the above-mentioned 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, ethylene glycol monoethyl ether, polyether synthetic oil, medium chain fatty acid triglyceride, and N-methylpyrrolidone, and the amount added must be within the range that completely dissolves the drug. Preferably, 1 to 100 parts by weight of the above copolymer
It is preferably 100 parts by weight, more preferably 2 to 25 parts by weight.

The base used in the present invention is preferably a flexible and drug-impermeable film, since it is used by being attached to the body, such as polyethylene, polypropylene, ethylene monovinyl acetate copolymer,
Films such as polyvinyl chloride, polyvinylidene chloride, vinyl acetate-vinyl chloride copolymer, polyamide, polyester, cellulose acetate, ethyl cellulose, cellophane, metal foils such as aluminum foil,
Examples include laminates of these materials. 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 therapeutic tape or sheet of the present invention has the structure as described above, and in particular, the drug-containing acrylic pressure-sensitive adhesive layer is composed of an acrylic polymer matrix and agglomerated fine particles of the acrylic polymer dispersed in the matrix. Since it is made of particles, it not only has good drug release properties, but also the presence of channels for drug diffusion, which are formed by the dispersion of aggregated fine particles, and the presence of flow paths inside and around the aggregated fine particles. Due to some of the drugs being contained or adsorbed,
The sustainability of drug release is also good, and excellent therapeutic effects can be expected. Furthermore, the therapeutic tape of the present invention has good retention of drugs in the adhesive layer, and has excellent storage stability without precipitation of drugs 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.

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

Example 1 100 parts of the copolymer was added to an ethyl acetate solution of a copolymer prepared 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. 1.5 parts of magnesium oxide and 10 parts of diclofenac sodium were added and mixed, and methanol, which is a poor solvent for the copolymer, was added to the methanol/methanol mixture in the mixed solution.
(Methanol + ethyl acetate) was added so that the weight ratio was 0.35, and the mixture was stirred with a stirrer for 1 hour.

By doing so, a part of the copolymer is aggregated and precipitated to form fine colloidal particles, which are then dispersed in the copolymer solution containing the drug and the aggregated fine particles. The body became a mixed liquid.

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 to prepare a therapeutic sheet containing diclofenac sodium.

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

When the drug dissolution rate with water was measured for the thus obtained therapeutic sheet, it was 61% in 2 hours and 83% in 24 hours, and the skin transfer rate was 13.4 after 2 hours of application.
%, it was 33.6% after 6 hours of application.

In addition, no denaturation or precipitation of the drug was observed in a test in which it was stored at 60°C for 2 months (hereinafter referred to as the "severe test").

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

Drug elution rate with water: Punch out a sample in a certain area, immerse it in water, and elute at 25° room temperature while 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.

Drug elution rate (%) = Amount of drug eluted/Amount of drug contained in sample x
100 Skin transfer rate: Remove hair from the rabbit's back 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 peeled off, extracted with a methanol solution, and the amount of drug remaining in the sample is determined using high performance liquid chromatography.

The skin transfer rate is calculated using the following formula.

Skin transfer rate (%) = Amount of drug contained in the sample - Amount of remaining drug / Amount of drug contained in the sample x 100 Severity test: Wrap the sample in aluminum foil, put it in a constant temperature room at 60℃, take it out after 2 months, and store it. I investigated the situation afterwards.

Example 2 In an ethyl acetate solution of a copolymer of 10 mol% 2-ethylhexyl acrylate, 53 mol% butyl acrylate, 32 mol% 2-ethylhexyl methacrylate, and 5 mol% diacetone acrylamide,
Magnesium oxide 1.5 per 100 parts of the above copolymer
10 parts of diclofenac sodium and 5 parts of propylene glycol, then methanol was added so that the ratio of methanol/(methanol + ethyl acetate) was 0.33, and the mixture was stirred for 1 hour using a stirrer. A dispersion mixture was prepared in which a portion of the copolymer coagulated and precipitated to form colloidal particles and dispersed in a drug-containing copolymer solution. Example 1 below
In the same manner as above, a pressure-sensitive adhesive sheet with a drug-containing layer thickness of 50 μm was obtained and a similar test was conducted, and the drug dissolution rate with water was 72% in 2 hours, 87% in 24 hours,
The skin transfer rate was 19.3% after 2 hours of application, and 19.3% after 6 hours of application.
38.4%, and no denaturation or precipitation of the drug was observed after the severe test.

Example 3 100 parts of the above copolymer was added to an ethyl acetate solution of a copolymer of 10 mol% 2-ethylhexyl acrylate, 53 mol% butyl acrylate, 32 mol% 2-ethylhexyl methacrylate, and 5 mol% diacetone acrylamide. Indomethacin was added to the mixture at a ratio of 4 parts, then methanol was added at a ratio of methanol/(methanol + ethyl acetate) to 0.40, and the mixture was stirred for 1 hour using a stirrer to copolymerize A dispersion mixture was prepared in which a portion of the coalescence was agglomerated and precipitated to form fine colloidal particles and dispersed in a 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 elution rate with water was 26% in 2 hours and 80% in 24 hours, and the skin transfer rate was 15.2% after 2 hours of application and 8 hours later.
32.7%, and no denaturation or precipitation of the drug was observed after the severe test.

Example 4 Into an ethyl acetate solution of the same copolymer used in Example 3, mendomethacin in an amount of 4 parts and diethyl sebacate in an amount of 10 parts per 100 parts of the copolymer were added. Then, methanol was added so that the methanol/(methanol + ethyl acetate) ratio was 0.37, and a colloidal particle dispersion mixture was prepared in the same manner as in Example 3. A therapeutic sheet was obtained by coating and drying on a polyethylene film. The water dissolution rate of this sheet was 37% in 2 hours and 88% in 24 hours, and the skin transfer rate was 22.7% after 2 hours of application and 88% after 8 hours of application.
36.1%, and no denaturation or precipitation of the drug was observed after the severe test.

Example 5 2-ethylhexyl methacrylate 10 mol%,
To an ethyl acetate solution of a copolymer of 70 mol% 2-ethylhexyl acrylate and 20 mol% vinylpyrrolidone, 1.5 parts of magnesium oxide and 10 parts of diclofenac sodium were added to 100 parts of the copolymer, and then 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, and a fine particle dispersion mixture was prepared in which the fine colloidal particles were dispersed in the copolymer solution containing the drug. This mixed solution was applied to an ethylene-vinyl acetate copolymer film and dried to form a therapeutic sheet having a 50 μm thick drug-containing adhesive layer and having fine particles dispersed in the copolymer matrix as in Example 1. I got it. The water dissolution rate of this therapeutic sheet is 62% in 2 hours and 84% in 24 hours, and the skin transfer rate is 12.8% after 2 hours of application and 31.7 after 6 hours of application.
%, and no denaturation or precipitation of the drug was observed after the severe test.

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 colloidal fine particles were not aggregated or precipitated.

The drug elution rate of this sheet with water is 5 in 2 hours.
%, 15% in 24 hours, skin transfer rate after 2 hours of application
It was 1.8%, and 2.7% after 6 hours.

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, 24
28% in time, skin transfer rate is 3.2% after 2 hours of application,
It was 7.3% in 6 hours.

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, 24
time: 57%, skin transfer rate: 9.8% after 2 hours of application.
The rate of application for 8 hours was 14.1%.

Comparative Example 4 A therapeutic sheet was obtained using the same materials and method as in Example 4, except that methanol was not added. The drug elution rate of this sheet with water was 23% in 2 hours, 24
73% in hours, skin transfer rate is 13% after 2 hours of application, 8
The rate was 21.7% for timed application.

Claims (1)

[Scope of Claims] 1. A therapeutic tape or sheet comprising an acrylic pressure-sensitive adhesive layer containing a drug on one side of a base material, wherein the adhesive layer comprises an acrylic polymer homogeneous matrix and a acrylic polymer homogeneous matrix in the matrix. 1. A therapeutic tape or sheet characterized in that it is a heterogeneous tape or sheet composed of aggregated fine particles of an acrylic polymer dispersed in. 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 heterogeneous mixture of a molecular solution, the above-mentioned aggregated fine particles, and a drug onto one surface of a substrate and drying the mixture.