JPH0853354A - Aqueous plaster for dermatosis - Google Patents

Abstract

PURPOSE:To obtain an aqueous plaster for dermatitoses, excellent in a moisture- holding effect, little in skin irritability, excellent in adhesivity to skin, and high in various treating effects. CONSTITUTION:This aqueous plaster for dermatioses contains a base agent ingredient comprising a water-soluble polymer, a humectant, a solubilizing agent, a dissolution agent and/or an absorption-stimulating agent, and an adrenocorticotrophic hormone selected from diflucotolone valerate, difluprednate, prednisolone valerate, hydrocortisone butyrate, diflorasone acetate, dexamethasone propionate, betamethasone dipropionate, amcinonide, dexamethasone valerate, halcinonide, budesonide, and alclometasone propionate as a medicinal effect ingredient.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an aqueous patch for the purpose of treating skin diseases for external use, which has diflucortron valerate, difluprednate, prednisolone valerate acetate, and hydrocortisone propionate butyrate as medicinal ingredients. , An aqueous patch containing an adrenal cortex hormone selected from diflorazone acetate, dexamethasone propionate, betamethasone dipropionate, amcinonide, dexamethasone valerate, halcinonide, budesonide, and alclomethasone propionate.

[0002]

Conventionally, eczema, dermatitis group, psoriasis, prurigo group,
Oral and injectable preparations mainly composed of corticosteroids for the treatment of allergic skin diseases such as erythema, insect bites, chronic discoid erythematosus, amyloid lichen, lichen planus and atopic dermatitis , External preparations, etc. are used.

[0003]

However, these preparations have some side effects and inconveniences in use. For example, there is a risk of forgetting to take or overdosing with an oral preparation, and administration with an injectable preparation. It causes great pain and stress at times, and is difficult to administer in individuals. External preparations such as ointments and lotions not only contaminate clothes but also have the drawback that it is difficult to administer a fixed dose. In addition, since most skin diseases are accompanied by itching in most cases, there is a problem that the symptoms are exacerbated by physical irritation. Further, there is also a problem that since the diseased part is not protected, the condition is exacerbated by an external antigen (external skin irritation and sensitizing substance). Therefore,
The present inventors have studied patches for the purpose of solving these problems and developing applications. Natural rubber, synthetic rubber, or acrylic adhesives are already known as the bases for patches, but these bases have rashes caused by the adhesives themselves and strong adhesive force, which causes keratinization during peeling. It had defects such as damage to the affected area accompanied by peeling. Therefore, as a result of further intensive studies, an aqueous patch having a moisturizing effect, having a significantly slight skin irritation, and having high adhesiveness to the skin was obtained, and it was excellent by using this aqueous patch. The inventors have found that it has a therapeutic effect and completed the present invention.

[0004]

Means for Solving the Problems That is, the aqueous patch of the present invention comprises diflucortron valerate, difluprednate, prednisolone valerate acetate, hydrocortisone propionate butyrate, diflorazone acetate, dexamethasone propionate, di- Containing an adrenal corticosteroid selected from betamethasone propionate, amcinonide, dexamethasone valerate, halcinonide, budesonide, alclomethasone propionate, a water-soluble polymer as a base, humectant, water, solubilizer and / or absorption enhancer Is blended.

The aqueous patch for skin diseases of the present invention will be described in detail below. The adrenocortical hormone agent which is the main component of the present invention includes diflucortron valerate, difluprednate, prednisolone valerate acetate, hydrocortisone propionate butyrate, diflorazone acetate, dexamethasone propionate, betamethasone dipropionate, amcinonide, dexamethasone valerate. , Halcinonide, budesonide, and alclomethasone propionate were raised, and the amount of these corticosteroids was 0.0005 in the base.
˜1% by weight, preferably 0.001 to 0.5% by weight, more preferably 0.005 to 0.1% by weight, and the blending ratio of these has a great influence on the drug efficacy expression. As the amount of the adrenal cortex hormone compound decreases, the drug effect tends to be difficult to develop. If it is less than 0.0005%, the onset of the drug effect is delayed, which is not preferable, and as the compounded amount increases, side effects may occur. There is a tendency for it to occur more easily,
If it exceeds 1%, side effects may occur concurrently depending on the patient, which is not preferable.

Examples of the water-soluble polymer include gelatin, casein, pullulan, dextran, dextrin, sodium alginate, soluble starch, agar, gum arabic,
Hydroxyethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyethylene oxide, polyacrylamide, polyacrylic acid, sodium polyacrylate, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl ether, methoxyethylene maleic anhydride One or more copolymers, isobutylene maleic anhydride copolymer, polyethyleneimine, etc. are preferably used. The content of the water-soluble polymer is 1 to 30% by weight, preferably 1 to 20% by weight, more preferably 1 to 15% by weight, based on the whole preparation. If it is less than 1% by weight, the viscosity becomes low and the shape retention cannot be maintained.
If the amount is larger, the viscosity becomes higher, and the workability at the time of kneading or coating decreases.

The moisturizing agent is selected from polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, isobutylene glycol, glycerin, diglycerin, sorbitol and the like. Alternatively, two or more kinds are appropriately selected, and the compounding amount thereof is 10 to 90% by weight, preferably 10 to 70% by weight,
It is more preferably 20 to 60% by weight. If it is less than 10% by weight, the moisturizing effect is insufficient, and if it is more than 90% by weight, the solubility of the water-soluble polymer is affected, which is not preferable.

The content of water is 10 to 90% by weight, preferably 20 to 80% by weight, and it is necessary to dissolve the water-soluble polymer and bring out the thickening property, cohesiveness and shape retention. Further, in the aqueous patch of the present invention, the drug is dissolved by appropriately blending a dissolving agent or an absorption enhancer, and the drug is uniformly dispersed in the base and promotes absorption into the skin, and further has a sustained effect of drug effect, etc. And a good patch can be obtained.

As the solubilizer, 3-l, which is a monoglycerin derivative of oleic acid, glycol salicylate, benzyl alcohol, isopropyl myristate, crotamiton, oleyl alcohol, peppermint oil, eucalyptus oil, limonene, isopulegol, and 1-menthol. -Mentoxypropane-1.2-diol, other essential oils, surfactants or the like are used. Further, as the absorption promoter, diisopropyl adipate, polyethylene glycol, dimethyl sulfoxide, isopropyl myristate, squalane, squalene, horse oil, crotamiton, azone, 1- (2-decylthioethyl) azacyclopentan-2-one, 1 -Mentone, l-menthol, peppermint oil, eucalyptus oil, limonene or other essential oils or surfactants as well as other known absorption enhancers are used. The above-mentioned solubilizers or absorption promoters are blended alone or in combination, and the blending amount is 0.0
It is used in the range of 1 to 10% by weight, preferably 0.05 to 5% by weight.

In addition to the above essential components, if necessary, a polyvalent metal compound as a cross-linking agent, specifically, aluminum hydroxide, calcium hydroxide, calcium chloride, aluminum sulfate, ammonium aluminum sulfate, potassium aluminum sulfate, metasilicate. Acid magnesium aluminate, dihydroxyaluminum aminoacetate and the like, and other crosslinking agents include compounds having at least two epoxy groups in the molecule, specifically ethylene glycol diglycidyl ether and polyethylene glycol diglycidyl. Ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, glycerol polyglycidyl ether, sorbitol Examples include glycidyl ether, sorbitan polyglycidyl ether, trimethylolpropane polyglycidyl ether, pentaerythritol polyglycidyl ether, resorcin diglycidyl ether, neopentyl glycol diglycidyl ether, and 1,6-hexanediol diglycidyl ether. 1 type or 2 types or more are suitably mix | blended suitably.

As other additives, kaolin,
Fillers such as zinc white, titanium dioxide, talc, bentonite, and hydrous aluminum silicate. Preservatives such as thymol, methylparaben, ethylparaben, isopropylmethylphenol. Ascorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, gallic acid ester,
Antioxidants such as vitamin E, vitamin E acetate, and disodium edetate. 2-hydroxy-4-methoxybenzophenone, ethyl p-aminobenzoate, 2- (2-
UV absorbers such as hydroxy-5-methylphenyl) benzotriazole, menthyl salicylate, and phenyl salicylate. Examples of the emulsifier include sorbitan fatty acid ester, glycerin fatty acid ester, decaglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, and polyoxyethylene alkyl ether. These various additives are suitably blended in one kind or two kinds or more. As the support of the patch of the present invention, non-stretchable or stretchable woven fabric, knitted fabric, non-woven fabric, non-woven paper and the like can be used.
The release coating can be appropriately selected from plastic films such as polyethylene, polypropylene or polyester and release paper.

Next, the method for producing the aqueous patch for skin diseases of the present invention will be described. First, (A) a drug selected from the above-mentioned corticosteroids is mixed with a solubilizer as needed to make it uniform. Next, (B) the water-soluble polymer is mixed and dispersed in water and a humectant, and additives are added as necessary to obtain a uniform kneaded product. Then, (A) may be added to (B) and uniformly dispersed and directly spread on a support, or may be once spread on a plastic film or paper and then pressure-bonded and transferred to a support to be used for production. . In addition, the order of mixing each of the bases, the medicinal components, and the other components in the above-mentioned production method is only one example, and the present invention is not limited to this mixing order.

[0013]

The aqueous patch for skin diseases of the present invention has the following excellent features. a. Since the medicinal component is lipophilic, drug release from the base can be improved. b. Good adhesion due to the use of a highly tacky base,
It can also be easily attached to flexed areas such as elbows, knees, and neck. c. Since the base is hydrophilic, the irritation to the skin is significantly reduced. d. Since it is a hydrous patch, it can enhance and maintain the moisturizing effect on the skin diseased part, and the treatment on the dry skin diseased part is effective. e. Since it contains a large amount of water having high thermal conductivity, the cooling effect of the affected part by the aqueous base is enhanced, and the cooling effect can be expected naturally. f. By applying it to a patch, the affected area can be protected from scratches and antigens. g. An excellent anti-inflammatory effect of a corticosteroid can be exhibited. h. Since the sustained-release base is used as a patch formulation, the duration of drug effect can be extended.

[0014]

【Example】

Example 1. Put 20.69 parts of purified water, 5 parts of gelatin, 3 parts of polyvinyl alcohol, and 5 parts of kaolin into the mixer,
Dissolve at about 50 ° C. to obtain a uniform dispersion. Next, a previously prepared dispersion of 50 parts of glycerin, 3 parts of sodium polyacrylate, 10 parts of purified water, and a solution of 3 parts of methoxyethylene maleic anhydride copolymer were added, stirred and mixed, and uniformly kneaded. Get things. To this, 0.01 part of diflucortron valerate and 0.3 part of crotamiton are mixed and dissolved to obtain a uniform kneaded product. 500 using a spreading machine
It was applied to a non-woven fabric so as to have g / m ^2, and then covered with a polypropylene film and cut into a predetermined size to obtain a product.

Example 2. Purified water (48.48 parts), gelatin (3 parts) and titanium oxide (2 parts) are put into a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid. Next, 20 parts of glycerin and polyethylene glycol 20 prepared in advance
Parts, sodium polyacrylate 3 parts, polyacrylic acid 3
Add 1 part of the dispersion and stir to mix. To this, 0.02 parts of difluprednate and 0.5 part of benzyl alcohol are added, mixed and dissolved to obtain a uniform kneaded product. This was applied to a non-woven fabric using a spreading machine so as to have a weight of 500 g / m ² , then covered with a polyester film, and cut into a predetermined size to obtain a product.

Embodiment 3. 37.37 parts of purified water, 5 parts of gelatin, 3 parts of polyvinylpyrrolidone and 5 parts of zinc white are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid. Next, propylene glycol 10 prepared in advance
Part, glycerin 30 parts, sodium polyacrylate 4
Parts, a dispersion of 4 parts of carboxymethyl cellulose and 1 part of potassium aluminum sulfate are added and mixed with stirring. To this, 0.03 parts of prednisolone valerate acetate and 0.5 of peppermint oil
Parts and 0.1 parts of thymol are mixed and dissolved to obtain a uniform kneaded product. This was applied to a non-woven fabric using a spreading machine so as to have a weight of 500 g / m ² , then covered with a polyester film, and cut into a predetermined size to obtain a product.

Embodiment 4 FIG. Purified water (57.96 parts), gelatin (2 parts), aluminum silicate (1 part) and polyvinyl alcohol (2 parts) are put into a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion. Next, glycerin 2 prepared in advance
0 part, 6 parts sodium polyacrylate dispersion and 10 parts purified water, methoxyethylene maleic anhydride copolymer 2
Add 1 part of the solution and stir to mix. 0.05 part of hydrocortisone butyrate propionate, 1 part of isopropyl myristate, and 0.1 part of isopropylmethylphenol were added to this, and mixed and dissolved to obtain a uniform kneaded product. This was applied using a spreading machine so as to be 500 g / m ² , then covered with a polyester film, and cut into a predetermined size to obtain a product.

Example 5. Purified water 32.2 parts, gelatin 3
Parts, 2 parts of polyvinyl alcohol and 3 parts of kaolin are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion. Next, 41 parts of glycerin prepared in advance, a dispersion of 3 parts of sodium polyacrylate, 12 parts of purified water, and a solution of 3 parts of methoxyethylene maleic anhydride copolymer were added, and mixed by stirring to obtain a uniform kneading. Get things. 0.5 parts of dexamethasone propionate and 0.3 parts of crotamiton are added to this and mixed and dissolved to obtain a uniform kneaded product. This was applied to a non-woven fabric using a spreading machine so as to have a weight of 500 g / m ² , then covered with a polypropylene film, and cut into a predetermined size to obtain a product.

Example 6. Purified water 42.8 parts, gelatin 3
Parts, 2 parts of polyvinyl alcohol and 3 parts of kaolin are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion. Next, 33 parts of a glycerin prepared beforehand, a dispersion of 3 parts of sodium polyacrylate, 10 parts of purified water, and a solution of 3 parts of methoxyethylene maleic anhydride copolymer were added, and mixed by stirring to obtain a uniform kneading. Get things. 0.001 part of diflorazone acetate and 0.2 part of crotamiton are added to this and mixed and dissolved to obtain a uniform kneaded product. This was applied to a non-woven fabric using a spreading machine so as to have a weight of 500 g / m ² , then covered with a polypropylene film, and cut into a predetermined size to obtain a product.

Example 7. Purified water 39.2 parts, gelatin 2
Parts and 2 parts of titanium oxide are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid. Next, 25 parts of glycerin and polyethylene glycol 25 prepared in advance
Parts, sodium polyacrylate 3 parts, polyacrylic acid 3
Add 1 part of the dispersion and stir to mix. Add 0.005 parts of betamethasone dipropionate and 0.7 of benzyl alcohol.
95 parts are added and mixed and dissolved to obtain a uniform kneaded product. This was applied to a non-woven fabric using a spreading machine so as to have a weight of 500 g / m ² , then covered with a polyester film, and cut into a predetermined size to obtain a product.

Example 8. Purified water 52.9 parts, gelatin 2
Parts and 2 parts of titanium oxide are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid. Next, 18 parts of glycerin and polyethylene glycol 18 prepared in advance
Parts, sodium polyacrylate 3 parts, polyacrylic acid 3
Part of the dispersion is added and mixed with stirring. To this, 0.1 part of amcinonide and 1.0 part of benzyl alcohol are added, mixed and dissolved to obtain a uniform kneaded product. 500 using a spreading machine
It was applied to a non-woven fabric so as to have g / m ^2, and then covered with a polyester film and cut into a predetermined size to obtain a product.

Example 9. Purified water 46.4 parts, gelatin 4
Parts, 3 parts of polyvinylpyrrolidone and 4 parts of zinc white are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid. Next, propylene glycol 10 prepared in advance
Parts, glycerin 25 parts, sodium polyacrylate 3
Part, a dispersion of 3 parts of carboxymethyl cellulose and 0.8 part of potassium aluminum sulfate are added and mixed with stirring. To this, 0.02 part of halcinonide, 0.7 part of peppermint oil, and 0.08 part of thymol are added, mixed and dissolved to obtain a uniform kneaded product. This was applied to a non-woven fabric using a spreading machine so as to have a weight of 500 g / m ² , then covered with a polyester film, and cut into a predetermined size to obtain a product.

Example 10. 40.4 parts of purified water, 5 parts of gelatin, 3 parts of polyvinylpyrrolidone and 3 parts of zinc white are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid. Next, propylene glycol 8 prepared in advance
Part, glycerin 30 parts, sodium polyacrylate 4
Parts, a dispersion of 5 parts of carboxymethyl cellulose and 0.5 part of potassium aluminum sulfate are added and mixed with stirring. Dexamethasone valerate 0.05 parts, peppermint oil 0.9
Parts and 0.15 parts of thymol are mixed and dissolved to obtain a uniform kneaded product. This was applied to a non-woven fabric using a spreading machine so as to have a weight of 500 g / m ² , then covered with a polyester film, and cut into a predetermined size to obtain a product.

Example 11. 32.3 parts of purified water, 5 parts of gelatin, 1.5 parts of aluminum silicate and 5 parts of polyvinyl alcohol are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid. Next, 35 parts of a glycerin prepared in advance, a dispersion of 5 parts of sodium polyacrylate, 10 parts of purified water, and a solution of 3 parts of methoxyethylene maleic anhydride copolymer are added and mixed with stirring. Budesonide (0.05 parts), isopropyl myristate (3 parts) and isopropylmethylphenol (0.15 parts) were added to this, and mixed and dissolved to obtain a uniform kneaded product. 500g using a spreading machine
/ M ² and then covered with a polyester film and cut into a predetermined size to obtain a product.

Example 12 50.4 parts of purified water, 3 parts of gelatin, 1 part of aluminum silicate and 3 parts of polyvinyl alcohol are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid. Next, glycerin 2 prepared in advance
0 part, dispersion of sodium polyacrylate 5 parts and purified water 10 parts, methoxyethylene maleic anhydride copolymer 2
Add 1 part of the solution and stir to mix. 0.5 parts of alclomethasone propionate, 5 parts of isopropyl myristate and 0.1 part of isopropylmethylphenol were added to this, and mixed and dissolved to obtain a uniform kneaded product. This was applied using a spreading machine so as to be 500 g / m ² , then covered with a polyester film, and cut into a predetermined size to obtain a product.

Reference Example 1. In the same manner as in Example 1, the amount of the adrenocortical hormone agent added was set to 0 part to obtain a drug-free patch.

Test Example 1. Skin pallor test The efficacy of the patches of Examples 1 to 4 and Reference Example 1 was evaluated by a skin pallor test. The patch was punched into a circle having a diameter of 15 mm to prepare a sample. These samples are used for healthy adult boys 2
It was attached to the inside of the forearm of 0 person. The application time is 4 hours,
After removing the test, wipe the test site with gauze soaked in lukewarm water,
Skin pallor was evaluated and evaluated at 2 hours, 4 hours, and 24 hours. The evaluation was performed by the skin paleness index of the medical department, and the results are shown in Table 1. -The following criteria were set as the judgment criteria. ++: Remarkable pallor is recognized (3 points) +: Clear pallor is recognized (2 points) ±: Slight pallor is recognized (1 point) −: No pallor is recognized (0 point)

[0028]

[Table 1] As is clear from Table 1, the patch of this example has a remarkable pallorizing effect, and its effectiveness was recognized. Test example 2. Skin safety test The skin safety test of the preparations shown in the examples was carried out. In the test, a closed patch test was conducted by 20 healthy adults for 48 hours, and the skin irritation state was observed 1 hour and 24 hours after peeling, and evaluated according to the following criteria. The results are shown in Table 2.
It was shown to. -Judgment criteria −: No change is observed on the skin ±: Slight redness is found on the skin +: Clear redness is found on the skin ++: Severe feel on the skin is found.

[0029]

[Table 2] As is clear from Table 2, this formulation was found to exhibit extremely weak skin irritation, which is equal to or lower than that of Japanese Vaseline.

[0030]

INDUSTRIAL APPLICABILITY As described above, the present invention has an excellent drug release property, a long-lasting effect, a cooling effect based on an aqueous base and a moisturizing effect on a skin diseased part, and an irritation to the skin. Is also significantly reduced. Furthermore, by using an aqueous patch as the dosage form, it is possible to enhance scratching action on the diseased site and protection from antigens. Therefore, the present invention can provide a pharmaceutical preparation useful as a therapeutic agent for external skin diseases.

Claims (1)

[Claims] 1. A base component comprising a water-soluble polymer, a moisturizing agent, water, a solubilizer and / or an absorption enhancer, and diflucortron valerate, difluprednate, prednisolone valerate acetate, and propione butyrate as medicinal components. An aqueous patch containing an adrenocortical hormone selected from hydrocortisone acid, diflorazone acetate, dexamethasone propionate, betamethasone dipropionate, amcinonide, dexamethasone valerate, halcinonide, budesonide, and alclomethasone propionate.