JP3023068B2 - External preparation for skin disease treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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 and contact dermatitis. It is known to be highly effective (Monthly Pharmaceutical Affairs; 26, 8, 55, 1984). And Japanese Patent Application Laid-Open No. Sho 62-1496.
No. 20 discloses an external preparation containing corticosteroid as a main active ingredient.

[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. For this reason, in the Japanese Pharmacopoeia, the upper limit of the concentration of dexamethasone and prednisolone, which are typical corticosteroids, is regulated to about 0.1 to 0.5% by weight in the external preparation.

On the other hand, external preparations for treating skin diseases having few side effects include external preparations composed of non-steroidal anti-inflammatory drugs and antihistamines. However, for the above-mentioned intractable skin diseases, corticosteroids are used. Its effects are very weak compared to those containing (new drugs and treatments; 25,298,41,1984).

To solve these problems, Japanese Patent Laid-Open No.
No. 247852 discloses an external preparation for the treatment of skin diseases containing vitamin E and squalene. However, it is said that squalene has a fish oily smell and is not sufficiently stable for a long time because it is an unsaturated hydrocarbon. There are drawbacks.

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above problems, and it is an object of the present invention to provide a drug having an effect equal to or higher than that of an external preparation containing corticosteroid as an active ingredient, and having side effects. It is to provide an external preparation for treating skin diseases with a small amount.

[0007]

The external preparation for treating skin diseases of the present invention contains vitamin E and squalane. The above-mentioned vitamin E refers to tocopherol (vitamin E) and derivatives thereof. Examples of those listed in the Japanese Pharmacopoeia include dl-α-tocopherol, tocopherol acetate (vitamin E acetate), and tocopherol calcium succinate. (Vitamin E succinate) and the like. Examples not listed in the Japanese Pharmacopoeia include, for example, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol nicotinate (vitamin E nicotinate), tocopherol phosphate (vitamin E phosphate) and the like. Is mentioned.

The above-mentioned squalane is a saturated hydrocarbon obtained by reducing squalene present in deep-sea fish, particularly shark liver oil.

[0009] Vitamin E and squalane both have a therapeutic effect on skin diseases although both are weak. Even when the content of one is small, the therapeutic effect is synergistically manifested by increasing the content of the other. Even when the content of both is small, a clear therapeutic effect is exhibited by continuous use. Therefore, the content in each external preparation is preferably 0.1 to 98% by weight of vitamin E, more preferably more than 2% by weight and 98% by weight or less, further preferably 5 to 60% by weight, and most preferably. Is 10 to 50% by weight, and squalane is preferably 2 to 98% by weight, more preferably 2% by weight or more and less than 98% by weight, further preferably 5 to 60% by weight, and most preferably 10 to 50% by weight.
It is.

[0010] The external preparation for treating skin diseases of the present invention 4 contains a transdermal absorption enhancer in addition to vitamin E and squalane. The transdermal absorption enhancer is at least one selected from the group consisting of N-acyl sarcosine (salt), higher fatty acid ester, dicarboxylic acid (salt), hydroxycarboxylic acid ester, and fatty acid ethanolamide.

The N-acyl sarcosine includes, for example, N-lauroyl sarcosine, N-oleoyl sarcosine, N-palmitoyl sarcosine, coconut oil fatty acid sarcosine and the like.
-Sodium salts, potassium salts, magnesium salts, calcium salts, aluminum salts and the like of acylsarcosine.

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 since the higher fatty acid ester of the product becomes easier to volatilize when it becomes smaller, and the percutaneous absorption effect decreases when it becomes larger, and the carbon number of the alcohol is
If it becomes larger, the percutaneous absorption effect decreases, so it is 1 to 20. Examples of the higher fatty acids having 10 to 18 carbon atoms include saturated aliphatic monocarboxylic acids such as capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid; palmitoleic acid, oleic acid, vaccenic acid, linoleic acid, and linolenic acid. Unsaturated aliphatic monocarboxylic acids such as acids; and saturated aliphatic dicarboxylic acids such as sebacic acid.

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, and isopropyl stearate.

The carbon number of the above-mentioned dicarboxylic acid (salt) is 2 to 10 since the effect of transdermal absorption 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 number of carbon atoms of the hydroxycarboxylic acid is small, the hydroxycarboxylic acid ester of the product is liable to volatilize. When the carbon number is large, the transdermal absorption effect is reduced.
The alcohol has a carbon number of 1 to 20 because the effect of percutaneous absorption decreases as the number of carbon atoms increases.

Examples of the above-mentioned hydroxycarboxylic acids 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,
The above-mentioned ones are preferable, but not limited thereto, and conventionally known ones can be used.

Depending on the dosage form, the percutaneous absorption enhancer itself may be used as a base, and the total amount of vitamin E and squalane may be 100% by weight. Parts, preferably 0.1 to
10,000 parts by weight, more preferably 0.1 to 100 parts by weight, still more preferably 0.1 to 45 parts by weight.

The dosage forms of the external preparations of the present invention 1, 2, 3 and 4 are not particularly limited. For example, creams, pastes, jelly by dissolving or mixing and dispersing the above-mentioned drugs in a base. (Eg, ointment, liniment, lotion, etc.), or a solution prepared by dissolving or mixing and dispersing the above-mentioned drug in a base, spread on a support And a solution prepared by dissolving or mixing and dispersing the above-mentioned drug in an adhesive (a plaster, a tape, etc.). It should be noted that a liniment can be obtained even if a preparation is composed only of vitamin E and squalane without using a base.

As the base, any pharmaceutically acceptable base may be used, and conventionally known bases such as ointments, liniments, lotions and the like can be used. For example, sodium alginate, gelatin, Corn starch, tragacanth gum, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, dextrin, carboxymethylstarch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene
Polymers such as maleic anhydride copolymer, polyvinyl ether and polyvinyl pyrrolidone; beeswax, olive oil,
Fats and oils such as cocoa oil, sesame oil, soybean oil, camellia oil, peanut oil, beef oil, pork oil, lanolin; white petrolatum;
Paraffin; hydrocarbon gel ointment (for example, trade name Plastibase, manufactured by Taisho Pharmaceutical Co., Ltd.); higher fatty acids such as stearic acid; higher alcohols such as cetyl alcohol and stearyl alcohol; polyethylene glycol;

If necessary, inorganic fillers such as kaolin, bentonite, zinc oxide and titanium oxide, viscosity modifiers, antioxidants, pH regulators, and humectants such as glycerin and propylene glycol may be added. Good.

The support is appropriately selected depending on its dosage form (eg, poultice, plaster, tape, etc.), and is preferably a flexible material that is impermeable or hardly permeable to the active ingredient. , 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,
Examples include resin films such as polyvinylidene chloride, polyurethane, nylon, polyethylene terephthalate, and polybutylene terephthalate; aluminum sheets; woven fabrics and nonwoven fabrics; and laminated sheets thereof.

The above-mentioned pressure-sensitive adhesive may be any one which is pharmaceutically acceptable, and conventionally known pressure-sensitive adhesives may be used. Examples thereof include acrylic pressure-sensitive adhesives, rubber pressure-sensitive adhesives, silicone pressure-sensitive adhesives, and urethane-based pressure-sensitive adhesives. Agents and the like, and acrylic pressure-sensitive adhesives and rubber pressure-sensitive adhesives are suitably used. When the adhesive is spread on the support, the properties of the adhesive include solvent-based,
Any type such as an emulsion type and a hot melt type can be used.

Examples of the acrylic pressure-sensitive adhesive include pressure-sensitive adhesives mainly composed of polyalkyl (meth) acrylate obtained by copolymerizing alkyl (meth) acrylate. A copolymer with a functional monomer or another vinyl monomer may be used.

Examples of the alkyl (meth) acrylate include 2-ethylhexyl (meth) acrylate, dodecyl (meth) acrylate and the like. 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 and the like. A tackifier such as rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, cumarone resin, and cumarone-indene resin is added.

The amount of the external preparation for treating skin diseases according to the present invention 1, 2, 3 and 4 varies depending on the kind of the disease, the degree of the symptom, the size of the affected part and the like. Is 0.01 to 10 g, which is applied to the affected part once or in an appropriate number.

The diseases to be treated by the external preparations for treating skin diseases of the present invention 1, 2, 3 and 4 include, for example, rough skin, rash, heat rash, soreness, soybean, diaper rash, atopic dermatitis, contact Dermatitis, seborrheic dermatitis,
Lichen lichen, eczematous eczema, housewife eczema, sun dermatitis,
Insect sting, pruritus cutis, prurigo, drug eruption, poisoning eruption, psoriasis, psoriatic psoriasis, palmoplantar pustulosis, lichen planus, lichen planus, erythrocytic piliosis pylori, doubly psoriasis dystrophy, erythema Erythroderma, lupus erythematosus, lupus erythematosus, systemic lupus erythematosus, pemphigus, pemphigoid, juvenile herpes dermatitis, alopecia areata, vitiligo vulgaris, sarcoidosis, cutaneous amyloidosis, keloids, hypertrophic scars, Examples include wounds, pressure sores, skin ulcers, hair loss, hair growth and hair growth.

[0030]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described with reference to embodiments. (Examples 1 to 24 and Comparative Examples 1 to 10) Plastibase (manufactured by Taisho Pharmaceutical Co., Ltd.), vitamin E acetate (manufactured by Wako Pure Chemical Industries), vitamin E nicotinic acid ester (manufactured by Wako Pure Chemical Industries, Ltd.) shown in Tables 1 to 3 Vitamin E succinate (Sigma), squalane (Wako Pure Chemical), isopropyl myristate (Nacalai Tesque), dexamethasone (Wako Pure Chemical) and prednisolone (Wako Pure Chemical) Was supplied to a mortar and kneaded until the other additives were dissolved in the plastibase to obtain an ointment. Examples 13, 14, 16 and 17 are liniments because they do not contain plastibase.

The following ointments or liniments were tested for the ointment or liniment obtained above (however, the ointment obtained in Example 18 was not tested). In each test, five rats were used, and the obtained results were average values.

[Test Example 1] Effect on DNCB-induced skin primary irritation (non-allergic skin inflammatory reaction) [0032] The abdominal skin of 7-week-old Wistar rats was shaved and then 2% 2,4-dinitrochlorobenzene (DNCB, manufactured by Wako Pure Chemical Industries, Ltd.) 20 μl of an acetone solution was applied and dried well to induce non-allergic dermatitis. Next, the ointment or liniment obtained in the above Examples and Comparative Examples was treated with 0.1% ointment.
1 g of each of the test agents was applied to a rat skin DNCB reaction induction site on a piece of a circular polyethylene sheet having a radius of 1 cm.

Twenty-four 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 ointment base (Plastibase) was applied in the same manner in place of the test agent, and then the same operation was performed to measure the erythema intensity. From the measurement results of the erythema intensity (A) at the control application site and the erythema intensity (B) at the test agent application site, the erythema inhibition rate was calculated by the following formula. The results are shown in Tables 1 to 3. Erythema suppression rate (%) = {(AB) / A} × 100

[Test Example 2] Effect on PCA reaction (type I allergic reaction) (1) Preparation of rat anti-DNP-As serum Serum was prepared by the method of Tada and Okumura (Journal of
Immunology; 106,1002,1971) and rat anti-DNP
-As serum was prepared. Ascaris suum extract was extracted according to the method of Strejan and Campbell (Journal of Immunology; 98,893, 1967), and then extracted from the method of Eisen et al. (Journal of Ame).
rican Chemical Society; 75,4583,1953), and combined with 2,4-dinitrophenyl sulfate (DNP).
NP-linked Ascaris sum (DNP-As) was obtained.

1 mg of the above-mentioned DNP-As was dissolved in 1 ml of physiological saline in which 1 × 10 ¹⁰ pertussis-killed bacteria were suspended, and injected subcutaneously into the footpad of a female rat 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 rat anti-DNP-As serum was diluted with physiological saline, and 0.05 ml of the serum was injected into the back skin of male rats weighing 120-200 g. 45 hours later, 0.1 g of the ointment or liniment obtained in the above Examples and Comparative Examples
Were applied to the anti-DNP-As serum injection site of rat skin in the same manner as in Test Example 1 above. Three hours later, 0.5% Evans'blue saline solution containing DNP-As antigen was added to 2.
PCA reaction was induced by intravenous injection at a rate of 5 ml / kg.

After 30 minutes, the animals were sacrificed, and the dye leaked to the skin at the reaction site was analyzed by the method of Harada et al. (Journal of Pharmacy).
The reaction skin was minced in accordance with the method described in Aceutics Pharmacology (23, 218, 1971) and immersed in a mixed solution of 0.3% sodium sulfate aqueous solution: acetone = 3: 7 (volume ratio) for 48 hours or more to extract the leaked pigment. . The extracted dye was then colorimetrically determined at 620 nm. As a control, an ointment base (Plastibase) alone was applied in the same manner in place of the test agent, and then the same procedure was followed to perform colorimetric quantification of the extracted pigment. From the quantitative results of the dye extraction amount (C) at the control application site and the dye extraction amount (D) at the test agent application site, the dye leakage inhibition rate was calculated by the following equation.
The results are shown in Tables 1 to 3. Dye leakage inhibition rate (%) = {(CD) / C} × 100

Test Example 3 Effect on Rat Delayed Contact Skin Hypersensitivity Reaction (Type IV Allergic Reaction) The abdominal skin of 5-week-old Wistar rats was shaved, 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 preparations of the ointment or liniment obtained in the above-mentioned Examples and Comparative Examples was used in the same manner as in Test Example 1 above, using rat skin DNCB.
It was applied to the reaction induction site.

Twenty-four 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 ointment base (Plastibase) was applied in the same manner in place of the 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. The results are shown in Tables 1 to 3. Erythema suppression rate (%) = {(EF) / E} × 100

[Test Example 4] Influence on body weight due to body weight change The body weight of all the rats subjected to Test Example 3 and the control group before and after the test were measured, and the effect of side effects on the whole body was determined from the change. Examined. The results are shown in Tables 1 to 3.

[Test Example 5] Evaluation of feeling of use by sensory test The ointment or liniment obtained in Examples 1 to 17 and 19 to 24 was applied to five human skins. And the average was determined. The results are shown in Tables 1 and 2. Evaluation criteria 0: Stickiness, flow, etc. are remarkable, and usability is poor 1: Stickiness, flow, etc. are recognized. 2: No stickiness, no flow, etc., very good usability

[0042]

[Table 1]

[0043]

[Table 2]

[0044]

[Table 3]

In the types of "Vitamin E" in Tables 1 to 3, A is "Vitamin E acetate", B is "Vitamin E nicotinate", and C is "Vitamin E succinate". "IPM" represents "isopropyl myristate", "Dex" represents "dexamethasone", and "Pre" represents "prednisolone", respectively.

Further, the following tests were conducted on the ointments obtained in Examples 1, 2 and 18 having low contents of vitamin E and squalane.

Test Example 6 Effect of Continuous Administration on Rat Delayed Contact Skin Hypersensitivity Reaction (Type IV Allergic Reaction) The abdominal skin of 5-week-old Wistar rats was shaved 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 and 0.1 g of each of the ointments of Examples 1, 2 and 18 was applied once a day from 3 days before the induction in the same manner as in Test Example 1 above. did. 3 days after the start of application, 0.5% DNC
Contact dermatitis was induced by applying 20 μl of B acetone solution. Then, 0.1 g of the ointment of Examples 1, 2 and 18
Were applied to the site of rat skin DNCB reaction induction in the same manner as in Test Example 1 above.

Twenty-four hours after the induction of the reaction, the erythema intensity at the reaction site was measured using a colorimeter (CR-200, manufactured by Minolta). As a control, only the ointment base (Plastibase) was applied in the same manner in place of the test agent, and then the same operation was performed to measure the erythema intensity. From the measurement results of the erythema intensity (G) at the control application site and the erythema intensity (H) at the test agent application site, the erythema inhibition rate was calculated by the following formula. Table 4 shows the results. Erythema suppression rate (%) = {(GH) / G} × 100

[0049]

[Table 4]

Further, Examples 3 to 5, 8, 11, 1
The following tests were performed on the ointments obtained in 2, 19 to 24 and Comparative Examples 9 and 10. In each test, five rats were used, and the obtained results are average values.

Test Example 7 Effect on Type III Allergy Model (1) Preparation of Rabbit Anti-ovalbumin Serum Rabbit anti-ovalbumin serum was prepared according to the method of Eda et al. (Jpn Pharmacol. 66, 237, 1970). Prepared. Ovalbumin (Sigma) was dissolved in physiological saline at a concentration of 2 mg / ml. Emulsion mixture of equal volume of this solution and Freund's complete adjuvant (manufactured by Difco) was used as an antigen solution, and 0.5 ml of the emulsion was used as a male rabbit (New Zealand white breed).
Were injected into the right and left hip muscles four times a week. 7 of the last injection
One day later, blood was collected from the carotid artery, and serum was separated and collected to obtain rabbit anti-ovalbumin serum.

(2) Rat 4 hours xenogeneic passive cutaneous anaphylaxis reaction The above rabbit anti-ovalbumin serum was diluted 4-fold with physiological saline, and 0.05 ml thereof was intradermally injected into the back of Wistar male rats weighing around 200 g. Injected. Next, 0.1 g of each test agent of the ointment obtained in each of the above Examples and Comparative Examples was applied to an antiserum injection site of rat skin in the same manner as in Test Example 1. Four hours after the antiserum injection, 2.5% of a 0.5% Evans'blue saline solution containing 2 mg / ml of ovalbumin was added.
It was administered intravenously at a rate of 1 / kg to elicit a PCA response.

Thus, the leakage dye at the site where the intradermal reaction was induced was determined by the method of Harada et al. (Journal of Pharmaceuti
cs Pharmacology; 23,218,1971). Thirty minutes after the administration of Evans Blue, the animals were sacrificed, the skin at the reaction site was minced, and a 0.3% sodium sulfate aqueous solution:
Leakage dye was extracted by immersing in a mixed solution of acetone = 3: 7 (volume ratio) for 48 hours or more. The extracted dye was then colorimetrically determined at 620 nm. As a control, ointment base (Plastibase) instead of the above test agent
Only the same was applied in the same manner, and then the same procedure was followed to perform colorimetric quantification of the extracted dye. From the results of quantification of the dye extraction amount (I) at the control application site and the dye extraction amount (J) at the test agent application site, the dye leakage inhibition rate was calculated by the following equation. The results are shown in Tables 5 and 6. Dye leakage inhibition rate (%) = {(I−J) / I} × 100

[Test Example 8] Effect on rat delayed-type skin hypersensitivity reaction (tuberculin type IV allergic reaction) The test was carried out according to the method of Kuriyama et al. (Journal of the Pharmacological Society of Japan; 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 the company) in 1 ml of physiological saline was injected into two places in the skin on the back of the shaved rat. In addition, only one physiological saline without purified tuberculin was similarly injected into another place in the cut hide. Then, 0.1 g of each of the test preparations of the ointments obtained in the above Examples and Comparative Examples was used in the same manner as in the above Test Example 1 for one of the purified tuberculin injection sites on rat skin.
The ointment was applied so as to come into contact with the skin in several places. As a control, an ointment base (Plastibase) alone was similarly applied to another site of the tuberculin injection site on the rat skin instead of the test agent. 24 hours after the tuberculin injection, the diameter of the erythema was measured, and the erythema diameter was determined from the erythema diameter (K) at the control application site and the erythema diameter (L) at the test agent application site according to the following formula. The rate was calculated. The results are shown in Tables 5 and 6. Erythema suppression rate (%) = {(KL) / K} × 100

[Test Example 9] Action effect on sunlight dermatitis (ultraviolet erythema) The action effect on erythema induced by ultraviolet rays was examined according to the method of Tsuji et al. (Applied pharmacology 23,567,1982). Weight 2
50-300 g of guinea pig back skin was shaved. The skin was covered with a light-shielding cloth having three circular holes having a diameter of 7 mm.
Using a 2,000 watt ultraviolet lamp (manufactured by Toshiba Corporation),
Ultraviolet irradiation was performed for 30 seconds from a distance of cm. 0.1 g test agent of the ointment obtained in the above Examples and Comparative Examples,
It was applied to the site of UV erythema induction 3 hours before and immediately after irradiation. Five hours after the induction, the erythema intensity at the reaction site was measured with a colorimeter (CR-200, manufactured by Minolta). As a control, only the ointment base (Plastibase) was applied in the same manner in place of the test agent, and then the same operation was performed to measure the erythema intensity. Erythema intensity at the control application site (M) and erythema intensity at the test agent application site (N)
From the measurement results, the erythema suppression rate was calculated by the following equation.
The results are shown in Tables 5 and 6. Erythema suppression rate (%) = {(M−N) / M} × 100

Test Example 10 Effect on Wound Healing The effect on wounds was examined according to the method of Sakyo et al. (Applied pharmacology 43, 121, 1992). The skin of the back of a 5-week-old Wistar rat was shaved, and a 30 mm long incision along the midline was made with a scalpel under ether anesthesia. Immediately after making the incision, three places were sutured at equal intervals. Thereafter, 0.2 g of the test agent of the ointment obtained in the above Examples and Comparative Examples was cut into 2.5 cm × 5 cm gauze (three layers).
, Which was then applied by covering the incision site and fixing with an elastic adhesive bandage. The gauze to which the ointment was applied as described above was replaced once a day.

The thread was removed three days after the start of the test. On day 6, the skin surrounding the entire wound was removed from the rat, and a strip-shaped skin section (2 pieces / rat) having a width of 1 cm parallel to the wound was prepared. Connect both ends of this section to a tension measuring device RHEOMETE.
It was set on RNRM-3002D-L (manufactured by FUDOH) and the tension (g / cm) required for cutting at the cut was measured. The average value of the measured values of the two pieces was defined as the tension of one sample.
As a control, only the ointment base (Plastibase) was applied in the same manner in place of the test agent, and then the same operation was performed to measure the tension. The results are shown in Tables 5 and 6.

[0058]

[Table 5]

[0059]

[Table 6]

The external preparation for treating skin diseases of the present invention has the same effect as an external preparation containing an absorption enhancer or a corticosteroid, and also has a weight loss due to side effects such as an external preparation containing a corticosteroid. Was not found. In addition, a remarkable effect was observed by using vitamin E and squalane in combination as compared with the case where both were used alone.

(Examples 25 to 47) White Vaseline (manufactured by Maruishi Pharmaceutical Co., Ltd.), Vitamin E acetate (manufactured by Wako Pure Chemical Industries, Ltd.), Vitamin E nicotinic acid ester (manufactured by Wako Pure Chemical Industries, Ltd.) shown in Table 7 ), Vitamin E succinate (Sigma), squalane (Wako Pure Chemical Industries), N-lauroyl sarcosine (Nacalai Tesque), fumaric acid (Nacalai Tesque), cetyl lactate (VAN-DYK) ) And isopropyl myristate (Nacalai Tesque, Inc.) were supplied to a mortar and kneaded until the other additives were dissolved in white petrolatum to obtain an ointment.

[0062]

[Table 7]

In the column of "Vitamin E" in Table 7, A is "Vitamin E acetate", B is "Vitamin E nicotinate", and C is "Vitamin E succinate". "IPM" represents "isopropyl myristate", and "LS" represents "N-lauroyl sarcosine", respectively.

Example 48 40% by weight of vitamin E acetate (manufactured by Wako Pure Chemical Industries, Ltd.), 40% by weight of squalane (manufactured by Wako Pure Chemical Industries, Ltd.) and 20% by weight of olive oil were supplied to a beaker, and the whole was uniformly mixed. The mixture was stirred until it was compatible to obtain a liniment.

(Example 49) 20% by weight of vitamin E acetate (manufactured by Wako Pure Chemical Industries, Ltd.), 20% by weight of squalane (manufactured by Wako Pure Chemical Industries, Ltd.), and 60% by weight of olive oil were supplied to a beaker, and the whole was uniformly mixed. The mixture was stirred until it was compatible to obtain a liniment.

Example 50 40% by weight of vitamin E nicotinic acid ester (manufactured by Wako Pure Chemical Industries), 40% by weight of squalane (manufactured by Wako Pure Chemical Industries), and 20% by weight of olive oil were supplied to a beaker, and the whole was uniform. The mixture was stirred until it became compatible with the mixture to obtain a liniment.

Example 51 40% by weight of vitamin E succinate (manufactured by Sigma), 40% by weight of squalane (manufactured by Wako Pure Chemical Industries), and 20% by weight of olive oil were supplied to a beaker, and the whole was uniformly mixed. The mixture was stirred until dissolved to obtain a liniment.

Example 52 [Synthesis of Acrylic Adhesive] 301.1 parts by weight of 2-ethylhexyl methacrylate, 34.9 parts by weight of 2-ethylhexyl acrylate, 48. dodecyl methacrylate
3 parts by weight, 0.0384 parts by weight of 1,6-hexane glycol dimethacrylate, and 256.0 parts by weight of ethyl acetate are supplied to a separable flask equipped with a stirrer and a cooling device, and the mixture is heated to 70 ° C. while stirring and purging with nitrogen. Warmed.

A solution prepared by dissolving 2.0 parts by weight of lauroyl peroxide in 10.0 parts by weight of cyclohexane was divided into ten parts, and one part of the solution was added to a separable flask to initiate polymerization.
From the 5th hour after the start of the polymerization, the remaining 9 was added at hourly intervals, and the reaction was continued for an additional 19 hours after the addition was completed. After the start of the reaction for adjusting the viscosity, ethyl acetate was added every 5 hours.
Five parts by weight were added. After completion of the reaction, the mixture was cooled and then ethyl acetate was added to obtain a pressure-sensitive adhesive solution having a solid concentration of 50% by weight.

[Preparation of Tape] The above adhesive solution 120
Parts by weight, Vitamin E acetate (Wako Pure Chemical Industries) 20
Parts by weight and 20 parts by weight of squalane (manufactured by Wako Pure Chemical Industries, Ltd.) were supplied to a dissolver-type high-speed stirrer and uniformly stirred to obtain a mixed solution. The obtained mixture was applied on a silicon-treated polyethylene terephthalate film (thickness: 38 μm), and dried at 60 ° C. for 30 minutes to form an adhesive layer having a thickness of 80 μm. Next, the above-mentioned 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.

Example 53 A tape was prepared in the same manner as in Example 52 except that the pressure-sensitive adhesive solution was changed to 180 parts by weight, the vitamin E acetate was changed to 5 parts by weight, and the squalane was changed to 5 parts by weight.

Example 54 In Example 52, instead of 120 parts by weight of the adhesive solution and 20 parts by weight of vitamin E acetate, 20 parts by weight of vitamin E nicotinic acid ester (manufactured by Wako Pure Chemical Industries) and squalane were used. A tape preparation was obtained in the same manner except that the amount was 20 parts by weight.

Example 55 In Example 52, instead of 120 parts by weight of the adhesive solution and 20 parts by weight of vitamin E acetate, 20 parts by weight of vitamin E succinate (manufactured by Sigma) and 20 parts by weight of squalane were used. A tape preparation was obtained in the same manner except that the above composition was used.

[0074]

The external preparation for treating skin diseases according to the present invention is as described above, has a high therapeutic effect on skin diseases, and has fewer side effects as compared with external preparations mainly containing corticosteroids. Therefore, an external preparation useful for treating various skin diseases can be obtained.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-8-99821 (JP, A) JP-A-8-99825 (JP, A) JP-A-8-99830 (JP, A) JP-A-8-998 99827 (JP, A) JP-A-8-99831 (JP, A) JP-A-8-99855 (JP, A) JP-A-8-99856 (JP, A) JP-A-7-291868 (JP, A) JP-A-4-82835 (JP, A) JP-A-4-82834 (JP, A) JP-A-4-346917 (JP, A) JP-A-6-247852 (JP, A) JP-A-6-172165 (JP, A) JP-A-6-1779619 (JP, A) U.S. Pat. No. 4,981,681 (US, A) International publication 95/6482 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/355 A61K 31/01 A61K 47/14 A61K 47/16 CA (STN)

Claims (7)

(57) [Claims] 1. Mainly vitamin E and squalane only
A skin disease therapeutic external composition containing as an active ingredient
With a vitamin E content of 0.1-98% by weight, squalane
Is 2 to 98% by weight . 2. The method according to claim 1 , wherein the disease to be treated is rash, atopy.
Dermatitis, contact dermatitis, seborrheic dermatitis, Vidart
Lichen, eczema, housewife eczema, sun dermatitis, pruritus
Pruritus, prurigo, drug eruption, psoriasis, lichen planus, pityriasis piliosis,
Gibber Rose Pityriasis, Erythema, Erythroderma, Wounds, and Skin
The external preparation for treating skin diseases according to claim 1, wherein the external preparation is at least one selected from the group consisting of skin ulcers . 3. The content of vitamin E is more than 2% by weight and 9%.
8% by weight or less, squalane content is 2% by weight or more and 98%
2. The external preparation for treating skin diseases according to claim 1, wherein the amount is less than% by weight. 4. An N-acyl sarcosine (salt),
Higher fatty acid esters which are reaction products of higher fatty acids having 10 to 18 carbon atoms and alcohols having 1 to 20 carbon atoms, dicarboxylic acids (salts) having 2 to 10 carbon atoms, hydroxycarboxylic acids having 3 to 6 carbon atoms and carbon A hydroxycarboxylic acid ester which is a reaction product with an alcohol of Formulas 1 to 20, and one or more transdermal absorption enhancers selected from the group consisting of fatty acid ethanolamides, characterized in that it contains at least one transdermal absorption enhancer. 3. The external preparation for treating skin diseases according to 3. 5. A composition comprising vitamin E and squalane as components.
An external preparation for treating skin diseases, which contains Vitamin E content is 0.1-98% by weight, squalane
Is from 2 to 98% by weight, Diseases to be treated include rash, atopic dermatitis,
Tactile dermatitis, seborrheic dermatitis, lichen widard, monetary wet
Rash, housewife eczema, sun dermatitis, skin pruritus, prurigo, drug eruption,
Lichen planus, Piliosis hirsutism, Pitibillosis rosacea, Red
Selected from the group consisting of maculopathy, erythroderma, wounds, and skin ulcers
At least one selected Skin disease
External preparation for treatment of disease. 6. The content of vitamin E is more than 2% by weight and 9%.
8% by weight or less, squalane content is 2% by weight or more and 98%
6. Skin according to claim 5, characterized in that it is less than% by weight.
External preparation for disease treatment. 7. An N-acyl sarcosine (salt),
C10-C18 higher fatty acids and C1-C20 al fatty acids
Higher fatty acid ester, reaction product with carbon, carbon
Dicarboxylic acid (salt) having 2 to 10 carbon atoms, hydric having 3 to 6 carbon atoms
Reaction between roxycarboxylic acid and an alcohol having 1 to 20 carbon atoms
Hydroxycarboxylic acid esters and fats as reaction products
At least one selected from the group consisting of fatty acid ethanolamides
6. A transdermal absorption enhancer comprising:
Or an external preparation for treating skin diseases according to 6.