JPH0367043B2 - - 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 exuded from the pressure-sensitive adhesive is used for treatment. What is done is being done. Such therapeutic adhesive tapes or sheets are made by adding a therapeutic drug with good solubility to a pressure-sensitive adhesive layer containing acrylic ester or (and) methacrylic ester as a polymerization component. There is. However, as a drug, nonsteroidal anti-inflammatory drugs such as indomethacin, diclofenac sodium, and amfenac sodium have a carboxyl group or an alkali metal salt thereof in the molecule, and are hydrophilic and ester-resistant. When insoluble or poorly soluble drugs are used, the drugs may be difficult to dissolve in pressure-sensitive adhesives or their compatibility may be unstable, making it difficult to formulate them into tapes, sheets, etc. There were flaws. Hydrophilic drugs that are insoluble or poorly soluble in esters are hydrophilic drugs that dissolve well in water, methanol, etc., but do not dissolve in esters such as ethyl acetate. Means something that does not substantially dissolve. Further, dissolution refers to the mixing of the drug with the pressure-sensitive adhesive to form a homogeneous phase state, and compatibility refers to the property that the drug and the pressure-sensitive adhesive dissolve into each other. In order to increase the solubility of the drug, the composition of the pressure-sensitive adhesive can be modified to increase its hydrophilicity by increasing the amount of polar components such as methacrylic acid, acrylonitrile, butoxyethyl (meth)acrylate, etc. However, in this case, the pressure-sensitive adhesive loses its tackiness, and has the disadvantage of causing other problems such as increased toxicity and skin irritation. The present invention solves the drawbacks of the conventional pressure-sensitive adhesive tapes or sheets as described above, and has a hydrophilic drug that has a carboxyl group or an alkali metal salt thereof in the molecule, such as indomethacin, diclofenac sodium, and amfenac sodium. A treatment that exhibits a stable compatibility state in pressure-sensitive adhesives and exhibits high medicinal efficacy over a long period of time, even when esters that are insoluble or poorly soluble are used. The purpose is to provide adhesive tapes or sheets for The gist of the present invention is that a pressure-sensitive adhesive layer containing an acrylic acid alkyl ester or a methacrylic acid alkyl ester as a polymerization component is provided on a base material, and the pressure-sensitive adhesive layer has a carboxyl group or an alkali metal group in the molecule. characterized in that a drug having a salt and being hydrophilic and poorly soluble or insoluble in the ester and a salt of a metal selected from magnesium, calcium, zinc or aluminum in acetic acid, nitric acid or hydrochloric acid are present. It consists in therapeutic adhesive tapes or sheets. 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. A pressure sensitive adhesive layer is formed on the base material. As the pressure-sensitive adhesive, a polymer or copolymer of acrylic acid alkyl ester, a methacrylic acid alkyl ester polymer or copolymer, or a copolymer system of acrylic acid alkyl ester and methacrylic acid alkyl ester is used. In addition, examples of ester residues in acrylic acid alkyl esters and methacrylic acid alkyl esters serving as polymerization components include methyl groups, ethyl groups, propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, n-pentyl groups, and isopentyl groups. , 2-methylbutyl group, n
-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 2-ethylbutyl group, n-octyl group, isooctyl group, 2-ethylhexyl group,
These include nonyl group, n-decyl group, lauryl group, etc. Particularly suitable acrylic acid alkyl esters include ethyl acrylate, n-butyl acrylate, isobutyl acrylate, isoamyl acrylate, 2-ethylhexyl acrylate, n-octyl acrylate, lauryl acrylate, etc., and methacrylic esters include methyl methacrylate. , butyl methacrylate, 2-ethylhexyl methacrylate, n-
These include octyl methacrylate and lauryl methacrylate. Other polymerizable monomers that can be copolymerized with acrylic acid alkyl esters and methacrylic acid alkyl esters include, for example, vinyl esters such as vinyl acetate; styrene, α-methylstyrene, acrylonitrile, vinyl chloride; ethylene, propylene, etc. α-olefin; diene monomers such as butadiene and isobrene, diacetone acrylamide, polypropylene glycol monoacrylate, polypropylene glycol methacrylate, and the like. The copolymerization content of such polymerizable monomers is preferably in the range of 0.1 mol% to 30 mol%,
If it is less than 0.1 mol %, the special significance of its addition is diminished, and if it is more than 30 mol %, the water resistance of the polymer decreases and its adhesion to the substrate decreases. Pressure-sensitive adhesives containing acrylic acid alkyl esters and methacrylic acid alkyl esters as polymerization components are suitable as described above because they are resistant to alteration and deterioration, have low toxicity and irritation to the skin, and have good adhesion to the skin. This is due to the fact that it has excellent properties and solubility of the drug. In the present invention, the compatibility between the pressure sensitive adhesive and the drug is determined by
Addition of metal salts of acetic acid, nitric acid, or hydrochloric acid, which will be described later, increases the solubility of the drug, resulting in further improvement. The pressure-sensitive adhesive layer contains a drug that has a carboxyl group or an alkali metal salt thereof in its molecule, is hydrophilic, and is sparingly soluble or insoluble in esters. Specifically, the degree of poor solubility or insolubility is determined by
The amount dissolved at 20℃ is 1g or less. As the alkali metal salt, sodium salt or potassium salt is suitable. In order to exhibit a medicinal effect, such a drug must be contained in a relatively large amount in the pressure-sensitive adhesive layer, ie, several times to several tens of times the amount of the usual drug. In addition, if the amount normally used is added to the pressure-sensitive adhesive layer as is, the medicinal effect will not be good; on the other hand, if it is added in a large amount, it will not dissolve well in the pressure-sensitive adhesive. . Typical examples of such drugs include non-steroidal anti-inflammatory drugs, such as indomethacin, acemethacin, sulindac, diclofenac, diclofenac sodium (or potassium), alclofenac, and alclofenac. Examples include sodium (or potassium) amfenac sodium (or potassium), fengfuen, tolmetin, mefenamic acid, flufenamic acid, sodium flufenate, aspirin or its derivatives, ibuprofen, naproquilone, ketoprofen, flaviprofen, fenoprofen, and the like. Even if it is attempted to mix the above-mentioned drug as it is with the pressure-sensitive adhesive, the solubility of the drug is not good. Furthermore, in order to obtain a medicinal effect, it is necessary to dissolve a large amount of the drug, and in order to dissolve a large amount of the drug, the pressure-sensitive adhesive must be made hydrophilic. When the hydrophilicity of a pressure-sensitive adhesive increases, its adhesive performance decreases, skin irritation increases, and the drug is not sufficiently dissolved, resulting in separation of the drug due to changes over time, accelerated aging, etc.
This tends to cause precipitation, crystallization, etc. Therefore, in the present invention, magnesium, calcium, acetic acid, nitric acid or hydrochloric acid,
A metal salt selected from zinc or aluminum is present in the pressure sensitive adhesive layer. It has become clear that when the metal salts of acetic acid, nitric acid, or hydrochloric acid are used, a large amount of the drug is dissolved in the pressure-sensitive adhesive without deterioration, and the dissolved state becomes stable over time. The reason for this effect is presumed to be due to the formation of weak ionic bonds between the carboxyl group or its alkali metal salt in the drug and the coexisting metal salts of acetic acid, nitric acid, or hydrochloric acid. be done. Examples of the metal salts of acetic acid, nitric acid, or hydrochloric acid include magnesium acetate, magnesium chloride, magnesium nitrate, calcium acetate, calcium chloride, calcium nitrate, zinc acetate, zinc chloride, aluminum chloride, and the like. The amount of these metal salts to be used is preferably 5 to 300% by weight, most preferably 10 to 100% by weight, based on the amount of the drug. When the pressure-sensitive adhesive is a copolymer of acrylic acid alkyl ester, methacrylic acid alkyl ester, diacetone acrylamide, polypropylene glycol monoacrylate, polypropylene glycol methacrylate, etc., the hydrophilicity of the pressure-sensitive adhesive is It will be expensive, so
Even if the amount of the metal salt of acetic acid, nitric acid, or hydrochloric acid is reduced, the solubility of the drug can be increased. According to the therapeutic adhesive tape or sheet of the present invention, a large amount of drug can be contained in the pressure-sensitive adhesive, so high drug efficacy can be obtained, the compatibility of the drug is stable, and separation and precipitation are unlikely to occur. and can maintain its medicinal efficacy over a long period of time. Example 1 2-ethylhexyl methacrylate
79.2g (0.4mol) Butyl acrylate 204.8g (1.6mol) 1,6-hexane glycol dimethacrylate
0.51 g (0.0002 mol) The above components were dissolved in ethyl acetate, and a 70% by weight solution was charged into a reaction vessel, and the reaction was carried out at 70° C. under a nitrogen stream for 20 hours with stirring. During this time, 1.3 g (0.008 mol) of azobisisobutyronitrile was added in 5 portions, and a method of gradually decreasing the concentration by adding ethyl acetate was used to prevent an increase in viscosity. The adhesive solution thus obtained had a non-volatile content of 24% by weight. For 50 g of the adhesive solution thus obtained, 2.5 g of indomethacin and magnesium acetate tetrahydrate were added.
1.0g was added. In this case, indomethacin was mixed as a 10% by weight solution in a 1:1 ratio of methyl ethyl ketone to methanol, and magnesium acetate tetrahydrate was mixed as a 5% by weight solution in methanol. The above mixed solution was applied onto silicone release paper using a knife adjusted so that the thickness after drying would be 40 μm, and dried. Polyethylene terephthalate was then treated with corona discharge on one side to improve its adhesion. A therapeutic adhesive sheet was obtained by overlapping and press-bonding the treated surface of a film (thickness: 20 μm). Next, this therapeutic adhesive sheet was tested for drug compatibility, adhesive strength, and drug release properties in the following manner. Drug-compatible agent: The degree of compatibility was determined by visual inspection as follows:
Divide into stages. A: No drug precipitation observed. B: The drug is deposited in sparse dots. C: The drug is deposited in dots at a fairly high density. D: The drug is completely deposited. Adhesive strength: In accordance with JIS-Z-1522, the tape was cut into a 15 mm wide tape, folded at 180°, and measured as peeling force. Drug release properties: Punch out a sample into a 60 mm diameter circle, peel off the release paper, immerse it in 50 ml of methanol, and incubate at 30°C for 30 minutes.
After standing for a period of time, the amount of the drug extracted into methanol was measured by a comparative quantitative method using liquid chromatography, and expressed as a percentage of the total content. The measurement results of the above-mentioned drug compatibility, adhesive strength, and drug release properties are shown in the column of Example 1 in Table 1. Examples 2 to 4 In Example 1, magnesium chloride hexahydrate was used instead of 1.0 g of magnesium acetate tetrahydrate.
1.0g (Example 2), calcium nitrate tetrahydrate
1.0g (Example 3), zinc acetate 0.8g (Example 4)
A therapeutic adhesive sheet was prepared in the same manner as in Example 1, except that the following was used, and then the same performance test as in Example 1 was conducted. The results are shown in Examples 2 to 4 in Table 1.
Shown in the column. Comparative Example 1 In this example, a therapeutic adhesive sheet was prepared without using magnesium acetate tetrahydrate, and then the same performance test as in Example 1 was conducted. The results are shown in the Comparative Example 1 column of Table 1. Example 5 Lauryl methacrylate 127g (0.5 mol) 2-ethylhexyl acrylate
55.2g (0.3mol) n-butyl acrylate 140.8g (1.1mol) Diacetone acrylamide 16.9g (0.1mol) Polyethylene glycol acrylate
0.093 g (0.0003 mol) The above components were dissolved in ethyl acetate, and a 70% by weight solution was charged into a reaction vessel, and the reaction was carried out at 65° C. under a nitrogen stream for 20 hours with stirring. During this time, 2.4 g (0.006 mol) of lauroyl peroxide was added in 5 portions, and the concentration was gradually reduced by adding ethyl acetate to prevent an increase in viscosity. The adhesive solution thus obtained had a non-volatile content of 26% by weight. To 50 g of the adhesive solution thus obtained, 1.3 g of diclofenac sodium and 0.8 g of magnesium chloride hexahydrate were added. In this case, both diclofenac sodium and magnesium chloride hexahydrate are
Mixed as a wt% methanol solution. A therapeutic adhesive sheet was obtained in the same manner as in Example 1 using the above mixed solution. Next, this therapeutic adhesive sheet was tested for drug compatibility, adhesive strength, and drug release properties in the following manner. Drug compatibility: The degree of compatibility is determined by visual inspection as follows:
Divide into stages. A: No drug precipitation observed. B: Drug crystals are sparsely precipitated. C: Drug crystals precipitate at a fairly high density. D: Drug crystals precipitate over the entire surface. Adhesive strength: Same as Example. Drug release properties: A water-methanol mixture (mixed volume ratio, water:methanol=95:5) was used as the extraction solvent, and the extraction conditions were 30° C. for 24 hours. Further, the amount of the extracted drug was measured by a comparative quantitative method using liquid chromatography, and expressed as a percentage of the total content. The measurement results of the drug compatibility, adhesive strength, and drug release properties are shown in the Example 5 column of Table 2. Examples 6-7 In Example 5, 0.8 g of calcium chloride dihydrate was used instead of 0.8 g of magnesium chloride hexahydrate.
A therapeutic adhesive sheet was prepared in the same manner as in Example 5, except that 0.5 g of zinc acetate (Example 6) and 0.5 g of zinc acetate (Example 7) were used, and then the same performance test as in Example 5 was conducted. The results are shown in the columns of Examples 6 to 8 in Table 2. Comparative Example 2 In Example 5, a therapeutic adhesive sheet was prepared without using magnesium chloride hexahydrate, and then the same performance test as in Example 5 was conducted. The results are shown in the Comparative Example 2 column of Table 2.

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Claims (1)

[Claims] 1. A pressure-sensitive adhesive layer containing an acrylic acid alkyl ester or a methacrylic acid alkyl ester as a polymerization component is provided on a base material, and the pressure-sensitive adhesive layer includes:
A drug that has a carboxyl group or an alkali metal salt thereof in its molecule and is hydrophilic and poorly soluble or insoluble in esters, and a metal selected from magnesium, calcium, zinc, or aluminum in acetic acid, nitric acid, or hydrochloric acid. Therapeutic adhesive tape or sheet 2, characterized in that a salt of sheet.