JPH0680549A - Dermal medicine for external use - Google Patents

Abstract

PURPOSE:To provide a new dermal medicine for external use, containing a specified trans-4-guanidinomethylcyclohexanecarboxylic acid derivative, exhibiting a more excellent whitening effect than in hydroquinone and excellent in prevention and improvement of roughness of the skin. CONSTITUTION:A dermal medicine for external use, containing one or more kinds of compounds selected from trans-4-guanidinomethylcyclohexanecarboxylic acid derivatives of the formula (R is H, a lower alkyl, benzyl or phenyl; n=0 to 2) and their salts (e.g. trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-phenoxycarbonylphenyl ester). The amount of the compounds of the formula to be blended is preferably about 0.01 to 7wt.% based on the whole dermal medicine for external use.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a skin external preparation which contains a trans-4-guanidinomethylcyclohexanecarboxylic acid derivative and a salt thereof as an active ingredient and is excellent in skin whitening effect, skin roughening prevention and improvement effect.

[0002]

BACKGROUND OF THE INVENTION Although there are some unclear points about the mechanism of skin spots and the like, in general, melanin pigments are formed due to hormonal abnormalities and irritation of ultraviolet rays from the sun, and this is the skin. It is thought to be abnormally deposited inside. Such treatments for blemishes and bruises include substances that suppress the production of melanin, for example, a method of administering a large amount of vitamin C, a method of injecting glutathione or the like, or kojic acid,
Methods such as topical application of cysteine or the like in the form of ointment, cream, lotion and the like have been adopted. In Europe and America, hydroquinone preparations are used as medicines.

[0003]

However, these compounds, except for hydroquinone, show a very slow effect, so that the whitening effect is not sufficient, while hydroquinone has been confirmed to have an effect. Due to its sensitizing properties, its use is generally restricted.

In view of such circumstances, the inventors of the present invention have conducted extensive studies, and as a result, the trans-4-guanidinomethylcyclohexanecarboxylic acid derivative and its salt exert a whitening effect more than hydroquinone, and further, prevent rough skin. However, the present invention was completed by recognizing that it has an improving effect.

[0005]

That is, the present invention is an external preparation for skin characterized by containing a trans-4-guanidinomethylcyclohexanecarboxylic acid derivative represented by the following general formula 2 and a salt thereof.

[0006]

[Chemical 2] (In the formula, R is a hydrogen atom, a lower alkyl group, a benzyl group,
A phenyl group is shown and it is n = 0-2. )

The structure of the present invention will be described in detail below. As the lower alkyl group referred to in the compound of the present invention, methyl,
Examples thereof include ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl and the like.

The trans-4-guanidinomethylcyclohexanecarboxylic acid derivative and salts thereof according to the present invention are
For example, it can be easily synthesized by the methods described in JP-A-57-21360 and JP-A-57-48960. If desired, the synthesized compound of the present invention may be hydrochloric acid, sulfuric acid,
Inorganic acid salts such as phosphoric acid and hydrobromic acid, or organic acid salts such as acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid and p-toluenesulfonic acid can be used.

A specific example of the substance name is trans-
4-guanidinomethylcyclohexanecarboxylic acid 2'-
Phenoxycarbonyl phenyl ester, trans-4
-Guanidinomethylcyclohexanecarboxylic acid 4'-phenoxycarbonylphenyl ester, trans-4-
Guanidinomethylcyclohexanecarboxylic acid 3'-benzyloxycarbonylphenyl ester, trans-4
-Guanidinomethylcyclohexanecarboxylic acid 4'-benzyloxycarbonylphenyl ester, trans-
4-guanidinomethylcyclohexanecarboxylic acid 3'-
Carboxyphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-ethoxycarbonylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-carboxyphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-methoxy Carbonyl phenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-carboxymethylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-t-butyloxycarbonylmethylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid Acid 4 '-(2-carboxyethyl) phenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4 '- (2-ethoxycarbonylethyl) phenyl ester, and the like.

The skin external preparation of the present invention contains at least one trans-4-guanidinomethylcyclohexanecarboxylic acid derivative thus obtained and a salt thereof, and the compounding amount thereof is 0.001 to the total amount of the skin external preparation. It is 20% by weight, preferably 0.01 to 7% by weight. If it is less than 0.001% by weight, the skin whitening effect and skin roughening prevention and improvement effects are poor, and if it exceeds 20% by weight, the effect cannot be expected to increase.

The external preparation for skin of the present invention contains, in addition to the above-mentioned essential components, other components usually used in external preparations for skin such as cosmetics and pharmaceuticals, such as oil, ultraviolet absorber, antioxidant, and surfactant. , Moisturizers, fragrances, water, alcohols, thickeners, coloring materials, skin nutrients (tocopherol acetate, pantothenyl ether, glycyrrhizinate) and the like can be appropriately blended as necessary. .

[0012]

EXAMPLES Next, the present invention will be described in more detail with reference to examples. The present invention is not limited to this. The blending amount is% by weight. Prior to the examples, the effect test method and evaluation method of the present invention will be described.

(1) Whitening effect test Test method 50 subjects exposed to sunlight in the summer for 4 hours (2 hours a day for 2 days) 5 days on the day when the skin of the upper arm inner part was exposed to the sunlight From the day after, each sample was applied once in the morning and evening for 8 weeks. The panel was divided into 10 groups per group and divided into 5 groups, and the test was conducted according to the following formulation.

Samples of Examples 1 to 3 and Comparative Examples 1 and 2 (alcohol phase) wt% 95% ethyl alcohol 25.0 polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 antioxidant / preservative proper amount perfume proper amount drug ( Table 1) 1.0 (Aqueous phase) Glycerin 5.0 Sodium hexametaphosphate Appropriate amount Ion-exchanged water Residual (Production method) The aqueous phase and alcohol phase are solubilized after preparation.

(Evaluation method) The lightening effect after use was judged based on the following judgment criteria. (Judgment) ⊚: When the rate of marked efficacy and efficacy among the subjects is 80% or more ◯: The rate of marked efficacy and efficacy among the subjects is 50 to 8
In the case of 0% Δ: The ratio of markedly effective and effective in the subjects is 30 to 5
0% ×: When the ratio of markedly effective or effective in subjects is 30% or less

[0016]

[Table 1]

As is clear from Table 1, the effect after exposure to sunlight is greater in Example than in Comparative Example, in that excessive deposition of melanin pigment can be prevented and darkening can be prevented. Admitted.

(2) Skin Roughness Prevention and Improvement Effect Test Test Method After washing the face twice in the morning and at night, the cosmetics of Examples 1 to 3 on the left side of the face and the cosmetic of Comparative Example 1 on the right side of the face, It was carried out by applying for 2 weeks. The test was carried out by dividing a panel of 30 women into 10 groups per group into 3 groups. (Evaluation method) The effectiveness of three items (moisture of skin, firmness of skin, moisture of the next morning) was judged based on the following judgment criteria. (Judgment) ⊚: When the rate of marked efficacy and efficacy among the subjects is 80% or more ◯: The rate of marked efficacy and efficacy among the subjects is 50 to 8
In the case of 0% Δ: The ratio of markedly effective and effective in the subjects is 30 to 5
0% ×: When the ratio of markedly effective or effective in subjects is 30% or less

[0019]

[Table 2]

As is clear from Table 2, the effects of moisturizing the skin, firming the skin, and moisturizing the next morning were found to be superior in the Examples as compared with the Comparative Examples.

Example 4 Cream wt% stearic acid 5.0 stearyl alcohol 4.0 isopropyl myristate 18.0 glycerin monostearate 3.0 propylene glycol 10.0 trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-benzyloxycarbonylphenyl ester hydrochloride 20.0 caustic potash 0.2 Sodium bisulfite 0.01 Preservative Suitable amount Perfume Suitable amount Ion-exchanged water Residual (production method) Add propylene glycol and caustic potash to ion-exchanged water and heat to maintain at 70 ° C (water phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). The oil phase is gradually added to the water phase, and after the addition is completed, the temperature is kept for a while to cause the reaction. After that, the mixture is uniformly emulsified with a homomixer and cooled to 30 ° C while stirring well.

Example 5 Cream wt% stearic acid 6.0 sorbitan monostearate 2.0 polyoxyethylene (20 mol) sorbitan monostearate 1.5 propylene glycol 10.0 trans-4-guanidinomethylcyclohexanecarboxylic acid 4 '-(2-carboxy Ethyl) phenyl ester hydrochloride 7.0 Glycerin trioctanoate 10.0 Squalene 5.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Fragrance Suitable amount Ion-exchanged water Residual (preparation) Add propylene glycol to ion-exchanged water and heat to maintain at 70 ° C (water phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). The oil phase is added to the aqueous phase to carry out preliminary emulsification, and the mixture is uniformly emulsified with a homomixer and then cooled to 30 ° C. with thorough stirring.

Example 6 Cream wt% stearyl alcohol 7.0 stearic acid 2.0 hydrogenated lanolin 2.0 squalane 5.0 2-octyldodecyl alcohol 6.0 polyoxyethylene (25 mol) cetyl alcohol ether 3.0 glycerin monostearate 2.0 propylene glycol 5.0 trans-4 -Guanidinomethylcyclohexanecarboxylic acid 4 '-(2-ethoxycarbonylethyl) phenyl ester hydrochloride 0.005 Fragrance suitable amount sodium bisulfite 0.03 ethylparaben 0.3 ion-exchanged water residual (manufacturing method) Add propylene glycol to ion-exchanged water and heat. Keep at 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). The oil phase is added to the aqueous phase to carry out preliminary emulsification, and the mixture is uniformly emulsified with a homomixer and then cooled to 30 ° C. with thorough stirring.

Example 7 Emulsion wt% Stearic acid 2.5 Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic Acid 4'-Carboxymethylphenyl ester hydrochloride 10.0 Sodium bisulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume Suitable amount Ion-exchanged water Residual (production method) Dissolve carboxyvinyl polymer in a small amount of ion-exchanged water (phase A). Polyethylene glycol 1500 and triethanolamine are added to the remaining ion-exchanged water, and the mixture is heated and dissolved and kept at 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). The oil phase is added to the aqueous phase for preliminary emulsification, the phase A is added and the mixture is uniformly emulsified with a homomixer, and after emulsification, the mixture is cooled to 30 ° C. with thorough stirring.

Example 8 Emulsion wt% (oil phase part) Stearyl alcohol 1.5 Squalene 2.0 Vaseline 2.5 Deodorized liquid lanolin 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerin monooleate 2.0 Polyoxyethylene (60 mol) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-benzyloxycarbonylphenyl ester hydrochloride 1.0 trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-methoxycarbonylphenyl ester hydrochloride 1.0 perfume suitable amount (water phase Part) Sodium hydrogen sulfite 0.01 Glycerin 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water Residual (production method) The oil phase part is dissolved at 70 ° C. Aqueous phase 70 ℃
And the oil phase is mixed with the water phase, and the mixture is emulsified with an emulsifier and cooled to 30 ° C. with a heat exchanger.

Example 9 Jelly Weight% 95% Ethyl alcohol 10.0 Dipropylene glycol 15.0 Polyoxyethylene (50 mol) Oleyl alcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-Arginine 0.1 trans-4-guanidinomethylcyclohexanecarboxylic acid 4 ′ -T-Butyloxycarbonylmethylphenyl ester hydrochloride 1.0 trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-carboxyphenyl ester hydrochloride 1.0 methylparaben 0.2 Fragrance suitable amount ion-exchanged water residual (manufacturing method) uniform carboxyvinyl polymer in ion-exchanged water , 95% ethanol, trans-4-
Guanidinomethylcyclohexanecarboxylic acid 4'-t-
Butyloxycarbonylmethylphenyl ester hydrochloride, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-carboxyphenyl ester hydrochloride, polyoxyethylene (50 mol) oleyl alcohol ether are dissolved and added to the aqueous phase. Then, after adding other components, the mixture is neutralized with caustic soda and L-arginine to increase the viscosity.

Example 10 Beauty Serum Weight% (Phase A) Ethanol (95%) 10.0 Polyoxyethylene (20 mol) Octyldodecanol 1.0 Methylparaben 0.15 Pantothenylethyl ether 0.1 trans-4-guanidinomethylcyclohexanecarboxylic acid 4′- Ethoxycarbonylphenyl ester hydrochloride 0.05 (Phase B) Potassium hydroxide 0.1 (Phase C) Glycerin 5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 Purified water Residue (Production method) Phases A and C are uniformly dissolved. , A to phase C
Add phase and solubilize. Next, phase B is added and then filling is performed.

Example 11 Pack wt% (Phase A) Dipropylene glycol 5.0 Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (Phase B) trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-phenoxycarbonylphenyl ester hydrochloride 1.0 trans-4-guanidinomethylcyclohexanecarboxylic acid 4 '-(2-carboxyethyl) phenyl ester hydrochloride 1.0 olive oil 5.0 tocophenol acetate 0.2 ethylparaben 0.2 perfume 0.2 (phase C) sodium bisulfite 0.03 polyvinyl alcohol (saponification degree 90 , Degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water Residual (production method) Phase A, Phase B, Phase C are uniformly dissolved,
Phase B is added to the phase to solubilize it. Then, this is added to phase C and then filled.

All of the external preparations for skin obtained in the present invention were tested for whitening effect and prevention of rough skin, which were carried out in Examples 1 to 3.
The effect was recognized in the improvement effect test.

[0030]

The external preparation for skin containing the trans-4-guanidinomethylcyclohexanecarboxylic acid derivative and the salt thereof according to the present invention is a novel external preparation for skin having a skin whitening effect and a skin roughening preventing and improving effect.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Yuki Yamase, Inventor Yuki Yamase, 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Inside Shiseido Research Center 1, Inc. Shiseido Research Center No. 1 (72) Inventor Kenji Kitamura 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Within Shiseido Research Center No. 1

Claims (1)

[Claims] 1. Trans-4-represented by the following general formula 1
A skin external preparation containing at least one guanidinomethylcyclohexanecarboxylic acid derivative and a salt thereof. [Chemical 1] (In the formula, R is a hydrogen atom, a lower alkyl group, a benzyl group,
A phenyl group is shown and it is n = 0-2. )