JPS6260102B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to therapeutic adhesive tapes or sheets.

A therapeutic adhesive tape or sheet with a thin layer of pressure-sensitive adhesive mixed with a therapeutic drug is applied to the skin as a base material, and the drug that exudes from the pressure-sensitive adhesive layer acts locally. This treatment is attracting attention as a new treatment method to replace the conventional occlusive dressing therapy (ODT therapy).

As such therapeutic adhesive tapes or sheets, a pressure-sensitive adhesive layer containing an acrylic ester or (and) a methacrylic ester as a polymerization component and a drug having good compatibility therewith is used. However, if such drugs, such as indomethacin (sodium salt),
- If it is a metal salt of a carboxylic acid derivative having active hydrogen, it is acidic and unstable, so there is a risk that the drug will deteriorate economically, the pressure-sensitive adhesive layer may change color, and the drug's efficacy may decrease. . The present invention was made with the aim of eliminating such drawbacks, and its gist is that a pressure-sensitive adhesive layer containing an acrylic ester or (and) a methacrylic ester as a polymerization component is provided on a base material, The pressure-sensitive adhesive layer contains (a) a drug consisting of a metal salt of a carboxylic acid derivative having α-active hydrogen, and (b) an oxide of an alkali metal or alkaline earth metal, or an alkali metal or alkali of a weak acid. A therapeutic adhesive tape or sheet characterized by containing an earth metal salt.

Next, the therapeutic adhesive tape or sheet of the present invention will be explained in more detail.

The base material used in the present invention is preferably made of a flexible material such as polyethylene, polypropylene, ethylene-vinyl acetate copolymer, soft polyvinyl chloride, cellophane, or the like.
The thickness of the base material is preferably in the range of 0.02 to 0.15 mm.

The base material is subjected to corona discharge treatment, plasma treatment, primer coating, etc., if necessary, in order to increase the adhesion with the pressure-sensitive adhesive layer.

On the base material, acrylic ester or (and)
A pressure-sensitive adhesive layer containing methacrylic acid ester as a polymerization component is provided.

The reason why pressure-sensitive adhesives contain acrylic esters and (and) methacrylic esters as polymerization components is because they do not have chemically active groups and do not interact chemically with drugs, so they do not impair their medicinal efficacy. This is because the drug exudes well and does not cause strong irritation to the skin.

Examples of ester residues in acrylic esters or (and) methacrylic esters serving as polymerization components include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, n-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 2-ethylbutyl group, n-octyl group, isooctyl group, 2-ethylhexyl group, nonyl group, n-decyl group, lauryl group etc.

Particularly suitable acrylic esters include ethyl acrylate, n-butyl acrylate, isobutyl acrylate, isoamyl acrylate, 2-ethylhexyl acrylate, n-
Octyl acrylate, lauryl acrylate, etc., and methacrylic acid esters include methyl methacrylate, butyl methacrylate, 2
-ethylhexyl methacrylate, n-octyl methacrylate, lauryl methacrylate, etc.

When acrylic ester or (and) methacrylic ester is used as a polymerization component, in addition to polymers of acrylic ester, polymers of methacrylic ester, copolymers of acrylic ester and methacrylic ester, acrylic It includes copolymers of esters or (and) methacrylic esters and other polymerizable monomers that can be copolymerized with these.

Other polymerizable monomers that can be copolymerized with acrylic esters and (and) methacrylic esters include, for example, vinyl esters such as vinyl acetate; styrene, α-methylstyrene, acrylonitrile, vinyl chloride; ethylene, propylene, etc. α-olefins; copolymers with diene monomers such as butadiene and isoprene;

The copolymerization content of such polymerizable monomers is preferably in the range of 0.1 mol% to 30 mol%,
When the amount is less than 0.1 mol%, drug compatibility is not achieved, and when it is more than 30 mol%, the water resistance of the polymer decreases and the adhesion to the substrate decreases. Amide groups, hydroxyl groups, ether groups, and neutralized carboxyl groups can be introduced into the polymer constituting the pressure-sensitive adhesive, thereby improving the compatibility between the pressure-sensitive adhesive and the drug. Also, the exudation of the drug from the pressure-sensitive adhesive layer can be improved.

In order to introduce an amide group, for example, (meth)acrylamide; alkyl (meth)acrylamide such as dimethyl (meth)acrylamide and diethyl (meth)acrylamide; alkyl ether such as butoxymethyl (meth)acrylamide and ethoxymethyl (meth)acrylamide; One or more amide monomers such as methylol (meth)acrylamide; diacetone acrylamide; and vinylpyrrolidone are copolymerized.

In order to introduce a hydroxyl group, for example, hydroxyalkyl (meth)acrylates such as 2-hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate; polyalkylene glycols such as polyethylene glycol (meth)acrylate and polypropylene glycol (meth)acrylate. One or more types of polyalkylene glycol (meth)acrylates such as (meth)acrylates are copolymerized.

In order to introduce an ether group, for example, polyalkylene glycol (meth)acrylate such as polyethylene glycol (meth)acrylate, polypropylene glycol (meth)acrylate, etc.
Copolymerize more than one species.

In order to introduce a neutralized carboxyl group, for example, one or more types of (meth)acrylic acid, maleic anhydride, itaconic acid, fumaric acid, crotonic acid, maleic acid alkyl ester, etc. are copolymerized, and 80 mol% or more of the carboxyl groups are neutralized with an alkali metal such as sodium, potassium, or lithium, or an alkaline earth metal such as magnesium or barium.

In the production of pressure-sensitive adhesives, solution polymerization, emulsion polymerization, suspension polymerization, etc. can be carried out using ordinary radical polymerization catalysts such as azobis-based compounds and peroxide-based compounds, but this is a post-process. Considering the mixing and dissolving process of the drug, solution polymerization is optimal.

For example, each component constituting the copolymer and a solvent such as ethyl acetate are added to a reaction vessel to form a solution with a concentration of approximately 60% by weight, the atmosphere inside the reaction vessel is replaced with nitrogen gas, and the temperature is raised while stirring. Then, at a temperature of 60 to 80°C, a solution of the radical generating catalyst dissolved in the same solvent was added dropwise or injected in portions, and the viscosity was suppressed by adding only the solvent according to the increase in viscosity. Polymerization is completed in 20 hours.

The drug used is a metal salt of a carboxylic acid derivative having α-active hydrogen.
Examples of such drugs include indomethacin (sodium salt) and diclofenac (sodium salt).
etc. exist.

The amount of the drug contained in the pressure-sensitive adhesive layer varies depending on the thickness of the pressure-sensitive adhesive layer, the type of drug, etc., but is preferably in the range of 1 μg to 5 mg per 1 cm ² of the pressure-sensitive adhesive layer.

However, such drugs are acidic and unstable, and may deteriorate over time in the pressure-sensitive adhesive layer, making it impossible to obtain long-term stability in drug efficacy. Therefore, in the present invention, an alkali metal or alkaline earth metal oxide, or a weak acid salt of an alkali metal or alkaline earth metal is contained in the pressure-sensitive adhesive layer together with the drug. It has good stability over time.

Examples of oxides of alkali metals and alkaline earth metals include sodium oxide, potassium oxide, magnesium oxide, calcium oxide, and barium oxide. Examples of the alkali metal or alkaline earth metal salts of weak acids include sodium acetate, potassium acetate, calcium acetate, sodium phosphate, calcium phosphate, magnesium phosphate, and magnesium pyrophosphate.

The appropriate amount of these metal oxides or metal salts of weak acids to be used is 1 to 300 parts by weight per 100 parts by weight of the drug; if the amount is less than 1 part by weight, it is difficult to obtain stability of the drug over time. Also, if the amount is more than 300 parts by weight, the adhesiveness of the pressure-sensitive adhesive tends to be reduced.

In the present invention, an anionic surfactant or an anionic nonionic surfactant can be further added to the pressure-sensitive adhesive layer. Addition of such a surfactant is necessary if the pressure-sensitive adhesive contains acrylic ester or (and) methacrylic ester as a polymerization component, but does not have amide groups, hydroxyl groups, ether groups, or neutralized carboxyl groups. This is effective in maintaining good compatibility between the drug and the pressure-sensitive adhesive and good exudation of the drug. Examples of anionic surfactants include alkyl sulfates, alkyl sulfonates, alkyl carboxylates, fatty acid salts, alkyl phosphates such as sodium lauryl sulfate, sodium laurylbenzenesulfonate, and sodium lauryl;
Alkali of α-β unsaturated carboxylic acid copolymers such as sodium salt of α-olefin copolymer, sodium salt of maleic anhydride-styrene copolymer half-ester, sodium salt of maleic anhydride-isobutylene copolymer, etc. Examples include metal salts. or,
Examples of the anionic nonionic surfactant include alkylbenzene sulfonate salts of polyalkylene glycol such as polyethylene glycol sodium lauryl benzene sulfonate and polypropylene glycol sodium lauryl benzene sulfonate. The amount of such surfactant used is preferably 10 parts by weight or less per 100 parts by weight of the polymerized acrylic ester or (and) methacrylic ester constituting the pressure-sensitive adhesive layer. If the amount exceeds 10 parts by weight, the water resistance of the pressure-sensitive adhesive may decrease, and the adhesiveness of the pressure-sensitive adhesive to the substrate may decrease.

The pressure-sensitive adhesive layer is formed by dissolving or dispersing each component in a pressure-sensitive adhesive solution, applying it to the base material, drying it, and forming it to a thickness of, for example, 0.02 to 0.2 mm.
Next, the releasable sheet is pressed with a roll or the like, or a solution of each component is dissolved or dispersed in a pressure-sensitive adhesive solution is first applied onto the surface of the releasable sheet, dried, and the base material is applied with a roll. By pressing onto the adhesive surface, a therapeutic adhesive tape or sheet with a protected pressure-sensitive adhesive layer is obtained.

According to the therapeutic adhesive tape or sheet of the present invention, a drug consisting of a metal salt of a carboxylic acid derivative having α-active hydrogen is used in the pressure-sensitive adhesive layer,
Despite being susceptible to denaturation over time, it has excellent stability over time due to the presence of alkali metal or alkaline earth metal oxides, or weakly acidic alkali metal or alkaline earth metal salts. This will not cause discoloration of the pressure-sensitive adhesive layer or decrease in medicinal efficacy.

Example 1 2.0 mol of 2-ethylhexyl methacrylate,
3.0 mol of each component of butyl acrylate was placed in a reaction vessel, 3 x 10 ^-2 mol of azobisisobutyronitrile was added as a catalyst, and an ethyl acetate-cyclohexane mixture was added as a solvent, and solution polymerization was carried out at 70°C until the solid content was 20 A copolymer solution of % by weight was obtained. Next, 3 parts by weight of magnesium oxide, 1 part by weight of sodium lauryl sulfate, and 6 parts by weight of indomethacin (sodium salt) were mixed per 100 parts by weight of the copolymer, and the mixture was placed on a 0.05 mm thick polyethylene sheet that had been subjected to corona discharge treatment. The pressure-sensitive adhesive layer was applied to a thickness of 0.05 mm and dried.

Test pieces were punched out from the therapeutic adhesive sheet obtained in this way, and the sample immediately after production and the sample that had been subjected to a severe test at 60°C for 10 days were immersed in methanol for 24 hours, and the amount of extracted drug was measured. The rate was 94.8% immediately after production and 85.4% after the severe test. In both cases, no discoloration of the pressure-sensitive adhesive layer or precipitation of the drug on the surface was observed.

Example 2 1.5 mol of 2-ethylhexyl methacrylate,
Put 3.0 mol of butyl acrylate and 0.5 mol of diacetone acrylamide into a reaction vessel, add 3 x 10 ^-2 mol of azobisisobutyronitrile as a catalyst and ethyl acetate-cyclohexane mixture as a solvent, and carry out solution polymerization at 70°C. did. 3 parts by weight of sodium acetate and diclofenac (sodium salt) per 100 parts by weight of the copolymer in the obtained copolymer solution.
Thickness of 6 parts by weight and corona discharge treatment
The pressure-sensitive adhesive layer was coated on a 0.05 mm polyethylene sheet to a thickness of 0.05 mm and dried.

Test pieces were punched out from the thus obtained therapeutic adhesive sheet, and the test pieces immediately after manufacture and those subjected to a severe test at 60°C for 10 days were mixed in a water-methanol mixture (water:methanol = 3:1, weight ratio) for 24 hours. When the extraction rate of the drug was determined by immersion for a time, it was 91.1% immediately after manufacture, and 91.8% after the severe test.

Moreover, no discoloration of the pressure-sensitive adhesive layer or precipitation of the drug on the surface was observed in either case.

Example 3 0.8 mol of 2-ethylhexyl methacrylate,
3.0 moles of butyl acrylate and 0.2 moles of acrylic acid were placed in a reaction vessel, azobisisobutyronitrile was added as a catalyst, and an ethyl acetate-cyclohexane mixture was added as a solvent, and solution polymerization was carried out at 70°C.
A copolymer solution with a solid content of 20% by weight was obtained. Add the carboxyl groups of the copolymer in the obtained copolymer solution to the sodium salt (depending on the degree of neutralization of the carboxyl groups).
100%), 3 parts by weight of sodium acetate and 6 parts by weight of diclofenac (sodium salt) per 100 parts by weight of this copolymer, and a pressure-sensitive adhesive layer was placed on a 0.05 mm thick polyethylene sheet that had been subjected to corona discharge treatment. The coating was applied to a thickness of 0.05 mm and dried.

Test pieces were punched out from the thus obtained therapeutic adhesive sheet, and the samples immediately after production and those subjected to a severe test at 60°C for 10 days were immersed in methanol for 24 hours to determine the extraction rate of the drug. The test result was 100%, and the test result after the severe test was 100%. In both cases, no discoloration of the pressure-sensitive adhesive layer or precipitation of the drug on the surface was observed.

Example 4 1.7 mol of 2-ethylhexyl acrylate, 3.0 mol of butyl acrylate, and 0.3 mol of dimethylaminoacrylamide were placed in a reaction vessel.
Solution polymerization was carried out in the same manner as in Example 1. Calcium oxide 1.5 parts by weight, sodium lauryl sulfate per 100 parts by weight of copolymer in the obtained copolymer solution
0.5 parts by weight, diclofenac (sodium salt)
6 parts by weight was blended, coated on an ethylene-vinyl acetate copolymer film, and dried to obtain a therapeutic adhesive sheet with a pressure-sensitive adhesive layer having a thickness of 0.05 mm.

Test pieces were punched out from the therapeutic adhesive sheet obtained in this way, and the test pieces immediately after production and those subjected to a severe test at 60°C for 10 days were immersed in a water-methanol mixture (water:methanol = 3:1, weight ratio) for 24 hours. When the extraction rate of the drug was determined by immersion for a time, it was 98.0% immediately after manufacture, and 97.2% after the severe test. Moreover, no discoloration of the pressure-sensitive adhesive layer or precipitation of the drug on the surface was observed in either case.

Comparative Example 1 A therapeutic adhesive sheet was obtained in the same manner as in Example 1 except that 3 parts by weight of magnesium oxide was not used.

Regarding the therapeutic adhesive sheet thus obtained,
When the extraction rate of the drug was determined in the same manner as in Example 1, it was 61.5% immediately after production, and 60.3% after the severe test. Moreover, fading of the pressure-sensitive adhesive layer was observed after the severe test.

Claims (1)

[Scope of Claims] 1. A pressure-sensitive adhesive layer containing an acrylic ester or (and) a methacrylic ester as a polymerization component is provided on a base material, and the pressure-sensitive adhesive layer includes (a)
Contains a drug consisting of a metal salt of a carboxylic acid derivative having α-active hydrogen, and (b) an oxide of an alkali metal or alkaline earth metal, or a salt of an alkali metal or alkaline earth metal of a weak acid. A therapeutic adhesive plate or sheet characterized by: 2. The pressure-sensitive adhesive contains acrylic ester or (and) methacrylic ester as a polymerization component, and the polymer contains amide groups, hydroxyl groups, ether groups,
and a neutralized carboxyl group is introduced,
A therapeutic adhesive tape or sheet according to claim 1. 3. The therapeutic adhesive tape or sheet according to claim 1, wherein the pressure-sensitive adhesive layer contains either an anionic surfactant or an anionic nonionic surfactant.