JPH0930964A - External preparation for treating skin disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an external preparation for treating skin diseases having effect nearly equivalent to or larger than that of external preparation containing an adrenal cortex hormone as an active ingredient and hardly having adverse effect. SOLUTION: This external preparation contains >=40wt.% and <=99.5wt % vitamin E (e.g. vitamin E acetate) and >=0.5wt.% and <60wt.% percutaneous absorbefacient (e.g. isopropyl millistate or isopropyl palmitate). Examples of the formulation include linimentum, ointment and tape and examples of the base include olive oil, hydrocarbon gel ointment and white waserin.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an external preparation for treating skin diseases.

[0002]

2. Description of the Related Art Conventionally, external preparations containing corticosteroids have been widely used for the treatment of skin diseases, especially for intractable skin diseases such as atopic dermatitis, contact dermatitis and psoriasis. It is known that its pharmacological effect is high (Monthly Pharmaceutical Affairs; 26, 8, 55, 1984).

[0003] However, topical corticosteroids are
For the application site, increased susceptibility, thinning of the skin,
The drug may cause side effects such as weakening of the blood vessel wall and abnormal activation of the pilosebaceous system.In addition, there is the possibility that transdermally absorbed drugs may cause systemic side effects. Attention is needed. Therefore, in the Japanese Pharmacopoeia, the upper limit of the concentration of dexamethasone and prednisolone, which are typical adrenocortical hormones, is limited to about 0.1% by weight in the external preparation.

On the other hand, as an external preparation for the treatment of skin diseases with few side effects, there is an external preparation comprising a nonsteroidal anti-inflammatory drug, an antihistamine, etc., but an adrenocortical hormone is used for the above-mentioned refractory skin diseases. Its effect is extremely weak compared to that containing it (new drug and treatment; 35,298,41,1984).

To solve these problems, Japanese Patent Laid-Open No.
JP-A-179619 discloses an external preparation for treating skin diseases, which contains 4 to 40% by weight of vitamin E and 0.3 to 10% by weight of a percutaneous absorption enhancer. However, the anti-inflammatory effect of the external preparation may be insufficient in some cases such as intractable skin disease.

[0006]

DISCLOSURE OF THE INVENTION The present invention is intended to solve the above-mentioned problems, and its object is to have an effect almost equal to or more than that of an external preparation containing an adrenocortical hormone as an active ingredient and to have few side effects. It is intended to provide an external preparation for treating skin diseases.

[0007]

The external preparation for treating skin diseases of the present invention contains vitamin E and a transdermal absorption enhancer as essential components.

The above-mentioned vitamin E used in the external preparation of the present invention means tocopherol (vitamin E) and its derivatives, and those listed in the Japanese Pharmacopoeia include, for example, dl-α-tocopherol and tocopherol acetate. (Vitamin E acetate ester), tocopherol succinate (vitamin E succinate ester) and the like. As those not listed in the Japanese Pharmacopoeia, for example, d-α-tocopherol, β-tocopherol, γ-tocopherol,
Examples include δ-tocopherol, tocopherol nicotinate (vitamin E nicotinate), tocopherol linolenate (vitamin E linolenate), and the like.

The content of vitamin E in the above external preparation is 4
0 wt% to 99.5 wt% or less, preferably 40 wt% to 80 wt%, and more preferably 40 wt% or less.
It is more than 70% by weight and not more than 70% by weight. When the content of vitamin E exceeds 40% by weight, the above-mentioned JP-A-6-1796 is used.
In comparison with the external preparation for treating skin diseases containing 4 to 40% by weight of vitamin E and 0.3 to 10% by weight of percutaneous absorption enhancer described in JP-A-19, the therapeutic effect is remarkably enhanced and the content of vitamin E is increased. The therapeutic effect also increases with the increase of.

The transdermal absorption enhancer used in the external preparation of the present invention is selected from the group consisting of N-acyl sarcosine (salt), higher fatty acid ester, dicarboxylic acid (salt), hydroxycarboxylic acid ester, and fatty acid ethanolamide. One or more types are preferred.

Examples of the N-acyl sarcosine include N-lauroyl sarcosine, N-oleoyl sarcosine, N-palmitoyl sarcosine, and coconut oil fatty acid sarcosine, and the salts thereof include, for example, the above N.
-Acylsarcosine sodium salts, potassium salts, magnesium salts, calcium salts, aluminum salts and the like.

The above higher fatty acid ester is a reaction product of a higher fatty acid and an alcohol. The carbon number of the higher fatty acid is 10 to 18 because the higher fatty acid ester of the product is easily volatilized when it is small and the transdermal absorption effect is reduced when it is large, and the carbon number of the alcohol is
The larger the value, the lower the transdermal absorption effect, and therefore 1 to 20. Examples of the higher fatty acid having 10 to 18 carbon atoms include saturated aliphatic monocarboxylic acids such as capric acid, lauric acid, myristic acid, palmitic acid and stearic acid; unsaturated aliphatic monocarboxylic acids such as palmitoleic acid and vaccenic acid. Acids; saturated aliphatic dicarboxylic acids such as sebacic acid and the like can be mentioned.

Examples of the alcohol having 1 to 20 carbon atoms include methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, caprylic alcohol, and nonyl alcohol. Examples include alcohols, decyl alcohol, lauryl alcohol, myristyl alcohol, palmityl alcohol, aliphatic saturated alcohols such as stearyl alcohol, and the like. Examples of the higher fatty acid ester include isopropyl myristate, isopropyl palmitate, isopropyl laurate, isopropyl stearate and the like.

The carbon number of the above dicarboxylic acid (salt) is 2 to 10 because the percutaneous absorption effect decreases as the carbon number increases.
As the dicarboxylic acid having 2 to 10 carbon atoms, for example,
Saturated aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid and suberic acid; unsaturated aliphatic dicarboxylic acids such as fumaric acid and maleic acid; phthalic acid, isophthalic acid, terephthalic acid And the salts thereof include, for example, the sodium, potassium, magnesium, calcium, and aluminum salts of the above dicarboxylic acids.

The above hydroxycarboxylic acid ester is
It is a reaction product of a hydroxycarboxylic acid and an alcohol. When the carbon number of the hydroxycarboxylic acid is small, the hydroxycarboxylic acid ester of the product is likely to be volatilized, and when it is large, the transdermal absorption effect is deteriorated.
Further, the carbon number of the alcohol is 1 to 20 because the transdermal absorption effect decreases as the alcohol number increases.

Examples of the hydroxycarboxylic acid having 3 to 6 carbon atoms include monocarboxylic acids such as lactic acid and glyceric acid, and dicarboxylic acids such as malic acid and tartaric acid. Examples of the alcohol having 1 to 20 carbon atoms include those similar to those used for the reaction of the higher fatty acid ester. Examples of the hydroxycarboxylic acid esters include myristyl lactate and cetyl lactate.

As the fatty acid ethanolamide, fatty acid monoethanolamide or fatty acid diethanolamide, and an alkylene oxide adduct thereof can be used. As the fatty acid ethanolamide,
For example, lauric acid monoethanolamide, lauric acid diethanolamide, lauroyl monoethanolamide, palmitic acid monoethanolamide, palmitic acid diethanolamide, myristic acid monoethanolamide, myristic acid diethanolamide, lauric acid / myristic acid monoethanolamide, coconut Oil fatty acid monoethanolamide, coconut oil fatty acid diethanolamide, polyoxyethylene added lauroyl monoethanolamide, polyoxyethylene added coconut oil fatty acid monoethanolamide and the like can be mentioned.

As the transdermal absorption enhancer, N-lauroyl sarcosine, isopropyl myristate, isopropyl palmitate, fumaric acid, maleic acid, myristyl lactate, cetyl lactate, lauric acid diethanolamide are particularly preferable. In addition, as a transdermal absorption enhancer,
As described above, the above-mentioned ones are preferable, but the present invention is not limited thereto, and conventionally known ones can be used.

The content of the above-mentioned percutaneous absorption enhancer in the external preparation is 0.5% by weight or more and less than 60% by weight, preferably 5% by weight or more and 40% by weight or less, more preferably 10% by weight or more 30%. It is less than or equal to weight%. If the content of the transdermal absorption enhancer is less than 0.5% by weight, the effect of treating skin diseases cannot be said to be sufficient even if the vitamin E concentration is increased.

The dosage form of the external preparation of the present invention is not particularly limited. For example, the above vitamin E and the percutaneous absorption enhancer are dissolved or mixed and dispersed in a base or a solvent to form a cream or paste. , Jelly, gel, emulsion,
In liquid form (cream, gel, ointment,
Emulsions, lotions, solutions, liniments, sprays, tinctures, etc.), bases prepared by dissolving or mixing and dispersing the above-mentioned vitamin E and transdermal absorption enhancer, and spreading them on a support (patches) Etc.), and those obtained by dissolving or mixing and dispersing the above-mentioned vitamin E and percutaneous absorption enhancer in an adhesive and spreading them on a support (plasters, tapes, etc.) and the like.

As the above-mentioned base or solvent, any pharmaceutically acceptable base may be used, and conventionally known bases such as ointments, liniments, lotions, sprays and tinctures may be used. Possible, for example, sodium alginate, gelatin, corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer,
Polymers such as polyvinyl ether and polyvinyl pyrrolidone; beeswax, olive oil, cacao oil, sesame oil, soybean oil, camellia oil, peanut oil, beef oil, pork oil, lanolin and other oils and fats; white petrolatum; paraffin; hydrocarbon gel ointment (eg, , Trade name Plastibase, manufactured by Taisho Pharmaceutical Co., Ltd.); higher fatty acids such as stearic acid; alcohols such as ethanol and isopropyl alcohol; higher alcohols such as cetyl alcohol and stearyl alcohol; propanediol; polyethylene glycol; water and the like. It is also possible to use the above-mentioned percutaneous absorption enhancer as a base.

If necessary, inorganic fillers such as kaolin, bentonite, zinc oxide and titanium oxide; viscosity modifiers; antiaging agents; pH modifiers; and moisturizers such as glycerin and propylene glycol are added. Good.

The above-mentioned support is appropriately selected according to its dosage form (eg, poultice, plaster, tape, etc.), but is preferably impermeable or hardly permeable to vitamin E and flexible, for example, , Cellulose acetate, ethyl cellulose, polyethylene, polypropylene, polyvinyl chloride,
Vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-carbon monoxide copolymer, polyvinylidene chloride, polyurethane, nylon, polyethylene Examples include resin films such as terephthalate and polybutylene terephthalate, aluminum sheets, woven fabrics and nonwoven fabrics, and laminated sheets of these.

The above-mentioned pressure-sensitive adhesive may be any one which is pharmaceutically acceptable, and conventionally known ones can be used. For example, acrylic pressure-sensitive adhesive, rubber pressure-sensitive adhesive, silicone pressure-sensitive adhesive, urethane pressure-sensitive adhesive. Examples thereof include acrylic adhesives and rubber adhesives. When the adhesive is spread on the support, the properties of the adhesive include solvent-based,
Any emulsion type or hot melt type can be used.

Examples of the above-mentioned acrylic pressure-sensitive adhesives include pressure-sensitive adhesives mainly composed of polyalkyl (meth) acrylate obtained by copolymerizing alkyl (meth) acrylate, which are copolymerizable with alkyl (meth) acrylate. It may be a copolymer with a functional monomer or another vinyl monomer.

Examples of the alkyl (meth) acrylate include 2-ethylhexyl (meth) acrylate and dodecyl (meth) acrylate. Examples of the polyfunctional monomer include 1,6-hexane glycol dimethacrylate and tetraethylene glycol diacrylate, and examples of the other vinyl monomer include N-vinyl-2-pyrrolidone and vinyl acetate. Is mentioned.

Examples of the rubber-based pressure-sensitive adhesive include pressure-sensitive adhesives mainly composed of natural rubber, styrene-isoprene-styrene block copolymer, styrene-olefin-styrene block copolymer, etc. Generally, rosin and hydrogenated A tackifier such as rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, coumarone resin, coumarone-indene resin is added.

The amount of the external preparation of the present invention to be used varies depending on the type of disease, the degree of symptoms, the size of the affected area, etc., but the amount of the preparation is preferably 0.01 to 10 g per day. Apply to the affected area once or in appropriate times.

The diseases to be treated by the external preparation of the present invention include, for example, atopic dermatitis, contact dermatitis, seborrheic dermatitis, Vidar lichen, coin-shaped eczema, housewife eczema, sun dermatitis, Insect bite, pruritus cutis, prurigo, drug eruption, poisoning eruption,
Psoriasis, psoriasis, palmoplantar pustulosis, lichen planus, lichen planus, erythema schizophrenia, gibber rose erythema glucose, erythema, erythroderma,
Discoid lupus erythematosus, systemic lupus erythematosus, pemphigus, pemphigus vulgaris, Juling herpes dermatitis, alopecia areata, vitiligo vulgaris, sarcoidosis, cutaneous amyloidosis, keloids, hypertrophic scars, cracks, cracks, Examples include rough skin, rashes, heat rashes, sores, frostbite and diaper rashes.

[0030]

Next, embodiments of the present invention will be described. (Examples 1 to 15 and Comparative Examples 1 to 4) Predetermined amounts (parts by weight) of olive oil (manufactured by Wako Pure Chemical Industries, Ltd.) shown in Table 1, vitamin E acetate (manufactured by Wako Pure Chemical Industries, Ltd.), isopropyl myristate ( Nacalai Tesque Co., Ltd.), isopropyl palmitate (Nacalai Tesque Co., Ltd.), dexamethasone (Wako Pure Chemical Industries, Ltd.) and prednisolone (Wako Pure Chemicals Co., Ltd.) were supplied to a mortar and thoroughly kneaded to obtain an external preparation.

In the table, "VE" is "vitamin E acetate", "IPM" is "isopropyl myristate", "IPP" is "isopropyl palmitate",
“Dx” represents “dexamethasone” and “Pr” represents “prednisolone”, respectively.

[0032]

[Table 1]

The following tests were conducted on the external preparations obtained above. In addition, in each test, 5 rats or 5 humans evaluated, and the obtained results are average values.

Test Example 1 Effects of action on PCA reaction (type I allergic reaction) (1) Preparation of rat anti-DNP-As serum Tada and Okumura method (Journal of
Immunology; 106,1002,1971), rat anti-DNP
-As serum was prepared. An extract of Ascaris suum was prepared according to the method of Strejan and Campbell (Journal of Immunology; 98,893,1967), which was then prepared by the method of Eisen et al. (Journal of Ame).
rican Chemical Society; 75,4583,1953) and combined with 2,4-dinitrophenylsulfate (DNP) to give D
NP-bound Ascaris suum (DNP-As) was obtained.

1 mg of the above DNP-As was dissolved in 1 ml of physiological saline in which 1 × 10 ¹⁰ pertussis killed bacteria were suspended, and the solution was subcutaneously injected into the foot pads of female rats weighing about 200 g. Five days later, 0.5 mg of DNP-As was dissolved in 0.5 ml of physiological saline, and injected into the right and left muscles of the back. Eight days after the first injection, blood was collected from the abdominal aorta and the serum was separated to obtain rat anti-DNP-As serum.

(2) PCA reaction The above-mentioned rat anti-DNP-As serum was diluted with physiological saline, and 0.05 ml thereof was intradermally injected into the dorsal skin of male rats weighing 120 to 200 g. After 45 hours, Example 1 above
15 to 15 and 0.1 g of each of the external preparations obtained in Comparative Examples 1 to 4 are placed on a circular polyethylene sheet piece having a radius of 1 cm, and the external preparation is brought into contact with the anti-DNP-As serum injection site of rat skin. Applied as. Three hours later, 0.5% Evans' blue physiological saline solution containing DNP-As antigen was intravenously injected at a rate of 2.5 ml / kg to induce a PCA reaction.

After 30 minutes, the animals were sacrificed and the dye leaked to the skin of the reaction part was analyzed by the method of Harada et al. (Journal of Pharm).
aceutics Pharmacology; 23,218,1971), and the reaction skin was cut into small pieces, and immersed in a mixed solution of 0.3% sodium sulfate aqueous solution: acetone = 3: 7 (volume ratio) for 48 hours or more to allow leakage dye to be extracted. . The extracted dye was then colorimetrically determined at 620 nm. As a control, only the base material (olive oil) was applied in the same manner in place of the above-mentioned test agent, and then the same operation was performed to perform colorimetric quantification of the extracted pigment. The dye leakage inhibition rate was calculated by the following formula from the quantitative results of the above-mentioned amount of extracted pigment (A) at the control application site and the amount of extracted pigment (B) at the test agent application site. Table 2 shows the results. Dye leakage inhibition rate (%) = {(AB) / A} × 100

[Test Example 2] Effect on rat delayed contact skin hypersensitivity reaction (type IV allergic reaction) 5 weeks old Wistar rats were shaved on the ventral skin, and then 20% 2,4-dinitrochlorobenzene ( DNCB,
20 μl of an acetone solution (manufactured by Wako Pure Chemical Industries, Ltd.) was applied and left for 2 weeks to sensitize. After creating the feeling, the back skin was shaved.
A contact dermatitis was induced by applying 20 μl of a 5% DNCB acetone solution. Then, 0.1 g of each of the test agents of the external preparations obtained in Examples 1 to 15 and Comparative Examples 1 to 4 was applied to the rat skin DNCB reaction-inducing site in the same manner as in Test Example 1 above.

Twenty-four hours after the reaction was induced, the erythema intensity at the reaction site was measured by a color difference meter (CR-200, manufactured by Minolta). As a control, only the base material (olive oil) was applied in the same manner in place of the above-mentioned test agent, and then the same operation was performed to measure the erythema intensity. From the measurement results of the erythema intensity (C) at the control application site and the erythema intensity (D) at the test agent application site, the erythema inhibition rate was calculated by the following formula. Table 2 shows the results. Erythema suppression rate (%) = {(CD) / C} × 100

[Test Example 3] Effects on the whole body due to changes in body weight About Examples 1 to 15 and Comparative Examples 1 to 4 The above Test Example 2
The body weight of all the rats subjected to the test and the rats of the control group before and after the test were measured, and the influence of the side effect on the whole body was examined from the amount of change. Table 2 shows the results.

[Test Example 4] Evaluation of feeling of use by sensory test The external preparations obtained in Examples 1 to 15 and Comparative Examples 1 to 4 were applied to the skin of five humans, and the feeling of use was as follows. Evaluation was performed according to the standard, and an average value was obtained. Table 2 shows the results. Evaluation criteria 0: Stickiness, flow etc. are remarkable and the feeling of use is bad. 1: Stickiness, flow etc. are observed. 2: There is no stickiness, flow etc. and the feeling of use is very good.

[Test Example 5] Effect on DNCB-induced primary skin irritation reaction (non-allergic skin inflammatory reaction) 7-week old Wistar rats were shaved on the abdominal skin, and then 2% 2,4-dinitrochlorobenzene 20 μl of an acetone solution (DNCB, manufactured by Wako Pure Chemical Industries, Ltd.) was applied and dried well. Then, 0.1 g of each of the test agents of the external preparations obtained in Examples 1 to 15 and Comparative Examples 1 to 4 was applied to the rat skin DNCB reaction-inducing site in the same manner as in Test Example 1 above.

24 hours after the induction of the reaction, the erythema intensity at the reaction site was measured with a colorimeter (CR-200, manufactured by Minolta). As a control, only the base material (olive oil) was applied in the same manner in place of the above-mentioned test agent, and then the same operation was performed to measure the erythema intensity. From the measurement results of the erythema intensity (E) at the control application site and the erythema intensity (F) at the test agent application site, the erythema inhibition rate was calculated by the following formula. Table 2 shows the results. Erythema suppression rate (%) = {(EF) / E} × 100

[Test Example 6] Effect of action on type II allergic reaction (1) Preparation of rabbit anti-rat serum Rabbit anti-rat serum was prepared according to the method of Eda et al. (Nippon Pharmacog., 66,237,1970). Serum was collected from male Wistar rats weighing 150 to 200 g. Equivalent mixture of this rat serum and Freund's complete adjuvant (manufactured by Difco) was used as an antigen solution, 0.5 ml of which was placed in the left and right gluteus muscle of a male rabbit (New Zealand White).
Four injections were given weekly. Seven days after the final injection, blood was collected from the carotid artery, and the serum was separated and collected to obtain rabbit anti-rat serum.

(2) Effect on intradermal reaction by anti-rat serum The effect on anti-dermal reaction by anti-rat serum was examined according to the method of Kuriyama et al. (Nippon Jpn Jpn., 95, 83, 1990). The rabbit anti-rat serum was diluted 4-fold with physiological saline, and 0.1 ml thereof was intradermally injected into the dorsal skin of Wistar male rats weighing about 200 g. Then, the above Examples 1 to 3,
0.1 g of the external preparation obtained in Examples 9 and 10 and Comparative Examples 3 and 4.
Each of these test agents was applied to the anti-rat serum injection site on rat skin in the same manner as in Test Example 1 above. Two hours later, 0.5% Evans' blue physiological saline solution was intravenously administered at a rate of 2.5 ml / kg.

Thus, the leakage dye at the site of the reaction was determined by the method of Harada et al. (Japan Journal of Pharmacology; 23,21).
Extraction and quantification according to 8,1971). 30 minutes after the administration of the Evans blue solution, the animals were sacrificed, and the dye leaked to the skin of the reaction part was finely cut into the reaction skin, and the mixture was mixed with a 0.3% sodium sulfate aqueous solution: acetone = 3: 7 (volume ratio) solution. To 4
Leakage dye was extracted by leaving it immersed for 8 hours or more. The extracted dye was then colorimetrically determined at 620 nm. As a control, only the base material (olive oil) was applied in the same manner in place of the above-mentioned test agent, and then the same operation was performed to perform colorimetric quantification of the extracted pigment. Dye extraction amount (G) at the control application site and dye extraction amount (H) at the test agent application site
From the quantification result of, the dye leakage suppression rate was calculated by the following formula. Table 2 shows the results. Dye leakage suppression rate (%) = {(GH) / G} × 100

[Test Example 7] Effect of action on anaphylactic reaction of heterologous skin in rat (type III allergic reaction) (1) Preparation of rabbit anti-ovalbumin serum Anti-ovalbumin serum According to the method of Eda et al. (Nippon Jakuzagaku; 66,237,1970). Rabbit anti-ovalbumin serum was prepared accordingly. Ovalbumin (Sigma) was dissolved in physiological saline to a concentration of 2 mg / ml. Emulsion mixed with an equal amount of this solution and Freund's complete adjuvant (manufactured by Difco) was used as an antigen solution, 0.5 ml of which was used for male rabbits (New Zealand white).
Were injected into the right and left gluteus muscle 4 times per week. 7 of the final injection
After a day, blood was collected from the carotid artery, and serum was separated and collected to obtain rabbit anti-ovalbumin serum.

(2) Rat 4 hours heterogeneous passive skin anaphylactic reaction The above rabbit anti-ovalbumin serum was diluted 4-fold with physiological saline, and 0.05 ml thereof was placed in the dorsal skin of male Wistar rats weighing about 200 g. I made an injection. Then, 0.1 g of each of the test agents of the external preparations obtained in Examples 1 to 3, 9 and 10 and Comparative Examples 3 and 4 was injected with antiserum into rat skin in the same manner as in Test Example 1 above. Applied to the site.
4 hours after injection of antiserum, ovalbumin 2 mg / m
A 0.5% Evans' blue physiological saline solution containing 1 was intravenously administered at a rate of 2.5 ml / kg to induce a PCA reaction.

Thus, the leaking dye at the site that elicited the intradermal reaction was determined by the method of Harada et al. (Japan Journal of Pharmacology;
23,218,1971). 30 minutes after the administration of Evans blue, the animals were sacrificed, and the dye leaked to the skin of the reaction part was finely cut into the reaction skin, which was then placed in a mixed solution of 0.3% sodium sulfate aqueous solution: acetone = 3: 7 (volume ratio). Four
Leakage dye was extracted by leaving it immersed for 8 hours or more. The extracted dye was then colorimetrically determined at 620 nm. As a control, only the base material (olive oil) was applied in the same manner in place of the above-mentioned test agent, and then the same operation was performed to perform colorimetric quantification of the extracted pigment. Dye extraction amount (I) at the control application site and dye extraction amount (J) at the test agent application site
From the quantification result of, the dye leakage suppression rate was calculated by the following formula. Table 2 shows the results. Dye leakage suppression rate (%) = {(I−J) / I} × 100

[Test Example 8] Effect of action on rat delayed skin hypersensitivity reaction (tuberculin type IV allergic reaction) It was carried out according to the method of Kuriyama et al. (Journal of the Japanese Pharmacological Society; 94, 113, 1989). A solution obtained by suspending 2.5 mg of BCG (Bacillus Calmette-Guerin) bacterium (manufactured by BCG Japan) in 1 ml of physiological saline was heated at 121 ° C. for 5 minutes.
ml was injected intraperitoneally into 9-week-old Wistar rats.
Seven days after injection of BCG bacteria, purified tuberculin (Japan BCG)
0.1 ml of a solution prepared by dissolving 200 μg (manufactured by Sharp Corporation) in 1 ml of physiological saline was injected into two places in the back skin of the above-mentioned rat. In addition, only physiological saline containing no purified tuberculin was similarly injected into the other place. Then, 0.1 g of each of the test agents of the external preparations obtained in Examples 1 to 3, 9 and 10 and Comparative Examples 3 and 4 was treated with the tuberculin injection site of rat skin in the same manner as in Test Example 1 above. Applied to one of them. As a control, only the base (olive oil) was applied to the other site of the tuberculin injection site in the rat skin instead of the above test agent. 24 hours after the tuberculin injection, the diameter of the erythema produced was measured, and the erythema diameter (K) at the control application site was measured.
And from the measurement results of the erythema diameter (L) of the test agent application site,
The erythema suppression rate was calculated by the following formula. Table 2 shows the results. Erythema suppression rate (%) = {(K−L) / K} × 100

[0051]

[Table 2]

From Table 2, the external preparation of the present invention has a transdermal absorption enhancer content of less than 0.5% by weight (Comparative Example 1) and a vitamin E content of 40% by weight or less (Comparative Example 2). ), A higher effect is obtained (Test Examples 1, 2, 5). Further, there were no side effects as compared with the preparation containing a steroid drug, and almost the same or higher effects were obtained for various allergic dermatitis models and non-allergic dermatitis models (Test Examples 3 and 5-8).

(Examples 16 to 23) Plastibase (manufactured by Taisho Pharmaceutical Co., Ltd.) in a predetermined amount (parts by weight) shown in Table 3, white petrolatum (manufactured by Maruishi Pharmaceutical Co., Ltd.), vitamin E acetate ester (manufactured by Wako Pure Chemical Industries, Ltd.) , Isopropyl myristate (manufactured by Nacalai Tesque) and isopropyl palmitate (manufactured by Nacalai Tesque) were supplied to a mortar and well kneaded to obtain an ointment.
In addition, "VE" in the table is "Vitamin E acetate ester",
"IPM" is "isopropyl myristate", "IP
“P” represents “isopropyl palmitate”, respectively.

[0054]

[Table 3]

(Example 24) [Synthesis of acrylic pressure-sensitive adhesive] 301.1 parts by weight of 2-ethylhexyl methacrylate, 34.9 parts by weight of 2-ethylhexyl acrylate, and dodecyl methacrylate 48.
3 parts by weight, 0.068 parts by weight of 1,6-hexane glycol dimethacrylate, and 256.0 parts by weight of ethyl acetate were supplied to a separable flask equipped with a stirrer and a cooling device, and the temperature was raised to 70 ° C. while stirring and purging with nitrogen. Warmed.

A solution prepared by dissolving 2.0 parts by weight of lauroyl peroxide in 100.0 parts by weight of cyclohexane was divided into 10 parts,
The 1 was added to the separable flask to start the polymerization. From the 5th hour after the initiation of the polymerization, the remaining 9 was added at 1-hour intervals, and the reaction was continued for 19 hours after the addition was completed. In addition,
For the purpose of adjusting the viscosity, 27 parts by weight of ethyl acetate was added 5 times every 5 hours after the reaction was started. After completion of the reaction, the mixture was cooled, and then ethyl acetate was added to obtain an adhesive solution having a solid content concentration of 50% by weight.

[Preparation of Tape Agent] 80 parts by weight of the adhesive solution, 50 parts by weight of vitamin E acetate ester (manufactured by Wako Pure Chemical Industries, Ltd.) and 10 parts by weight of isopropyl myristate (manufactured by Nacalai Tesque, Inc.) were placed in a dissolver type high speed stirrer. It was supplied and stirred uniformly to obtain a mixed solution. The obtained mixed solution was applied onto a polyethylene-treated polyethylene terephthalate film (thickness: 38 μm) and then dried at 60 ° C. for 30 minutes to form an adhesive layer having a thickness of 80 μm. Next, the pressure-sensitive adhesive layer was transferred onto the ethylene-vinyl acetate copolymer layer of a polyethylene terephthalate / ethylene-vinyl acetate copolymer laminated film having a thickness of 34 μm to obtain a tape agent.

[0058]

The external preparation for treating skin diseases of the present invention is as described above, and contains vitamin E as an essential component in an amount of more than 40% by weight and not more than 99.5% by weight and a transdermal absorption enhancer of 0.1%.
Since it is contained in an amount of 5% by weight or more and less than 60% by weight, it has a high therapeutic effect on skin diseases and has fewer side effects than an external preparation containing a corticosteroid as a main component. Therefore,
An external preparation useful for treating various skin diseases can be obtained.

Claims (1)

[Claims] 1. Vitamin E as an essential component 40% by weight
Over 99.5% by weight and transdermal absorption enhancer 0.5
An external preparation for the treatment of skin diseases, characterized by containing at least 50% by weight.