JP3150782B2 - External preparation for skin - Google Patents

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 containing a trans-4-guanidinomethylcyclohexanecarboxylic acid derivative and a salt thereof as an active ingredient, which is excellent in skin whitening effect, skin roughness prevention and improvement effect.

[0002]

2. Description of the Related Art Although there are some unclear points about the mechanism of the occurrence of skin spots and the like, melanin pigments are generally formed due to hormonal abnormalities and stimulation of ultraviolet rays from sunlight. It is believed to be abnormally deposited within. Treatment of such spots and bruises includes substances that suppress the production of melanin, such as a method of administering a large amount of vitamin C, a method of injecting glutathione, etc., or kojic acid,
A method of applying cysteine or the like in the form of an ointment, cream, lotion, or the like, and topically applying the composition is employed. In the United States and Europe, hydroquinone preparations are used as pharmaceuticals.

[0003]

However, these compounds, except for hydroquinone, exhibit very slow effects, so that the whitening effect is not sufficient, while hydroquinone has been recognized to be effective. Due to its sensitizing properties, its use is generally restricted.

In view of such circumstances, the present inventors have conducted intensive studies and as a result, have found that a specific trans-4-guanidinomethylcyclohexanecarboxylic acid derivative and a salt thereof exhibit a whitening effect more than hydroquinone.
The present inventors have recognized that the present invention has the effect of preventing and improving skin roughness, and completed the present invention.

[0005]

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

[0006]

Embedded image (Wherein, R ₁ R ₂ R ₃ are the same or different and each represents a hydrogen atom,
Lower alkyl group, lower alkoxy group, alkanoyl group,
Phenyl, halogen, trihalogenomethyl, nitro, acetamino, carbamoyl, sulfamoyl, benzoyl, phenoxy, benzyloxy, formyl or cyano)

Hereinafter, the configuration of the present invention will be described in detail. As the lower alkyl group in the compound of the present invention, methyl,
Ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl and the like, and the lower alkoxy group includes methoxy, ethoxy, propoxy, butoxy and the like, and the alkanoyl group includes acetyl, propionyl, butyryl group and the like. And the halogen atom includes chlorine, bromine, iodine and fluorine, and the trihalogenomethyl group includes a trifluoromethyl group.

The trans-4-guanidinomethylcyclohexanecarboxylic acid derivative and the salt thereof according to the present invention are:
For example, it can be easily synthesized by the methods described in JP-A-57-16856, JP-A-57-122059, JP-A-57-122061, and JP-A-57-122062. it can.
If desired, the synthesized compound of the present invention may be an inorganic acid salt such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid, or acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfone. An organic acid salt such as an acid can be used.

Specific examples of substance names include trans-
4-guanidinomethylcyclohexanecarboxylic acid phenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-methylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-ethylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid Acid 2'-methoxyphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-methoxyphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-ethoxyphenyl ester, trans-
4-guanidinomethylcyclohexanecarboxylic acid 2'-
Acetylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-acetylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-phenylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-phenylphenyl Ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-chlorophenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-chlorophenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-bromophenyl ester, trans- 4
-Guanidinomethylcyclohexanecarboxylic acid 4'-iodophenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 3 ', 4'-dichlorophenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 2', 4 ', 6' -Trichlorophenyl ester trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-trifluoromethylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-nitrophenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4 '
-Acetaminophenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-sulfamoylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-benzoylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 2 '-Phenoxyphenyl ester,
Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-benzyloxyphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 2 '
-Formylphenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-cyanophenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-cyanophenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-cyano Phenyl ester, trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-isopropyl-4'-chloro-5'-methylphenyl ester and the like.

The external preparation for skin of the present invention contains at least one or more of the trans-4-guanidinomethylcyclohexanecarboxylic acid derivatives and salts thereof obtained as described above. It is 20% by weight, preferably 0.01 to 7% by weight. If the amount is less than 0.001% by weight, the skin whitening effect and the skin roughening prevention and improvement effects are poor.

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, for example, oils, ultraviolet absorbers, antioxidants and surfactants. , Moisturizers, fragrances, water, alcohols, thickeners, coloring materials, skin nutritional agents (tocopherol acetate, pantothenyl ethyl ether, glycyrrhizinate) and the like can be appropriately compounded as necessary. .

[0012]

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

(1) Test method for whitening effect Test method: The subject was exposed to sunlight for 4 hours (2 hours a day for 2 days) for 50 hours on the inner skin of the upper arm of 50 subjects exposed to sunlight in summer. After the day, each sample was applied once in the morning and evening for 8 weeks. The panel was divided into 10 groups and divided into 5 groups, and the test was performed according to the following formulation.

Samples of Examples 1 to 3 and Comparative Examples 1 and 2 (alcohol phase)% by weight 95% ethyl alcohol 25.0 Polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 Antioxidant / preservatives Appropriate amount Perfume Appropriate amount Table 1) 1.0 (aqueous phase) Glycerin 5.0 Sodium hexametaphosphate Appropriate amount Ion-exchanged water Residue (Preparation method) Prepare aqueous and alcohol phases and solubilize.

(Evaluation Method) The lightening effect after use was determined based on the following criteria. (Judgment) ：: When the ratio of the effective and effective of the subjects is 80% or more ○: The ratio of the effective and effective among the subjects is 50 to 8
0%: △: 30% to 5% of the test subjects showed significant and effective
0%: ×: The proportion of subjects who show excellent and effective is 30% or less

[0016]

[Table 1]

As is clear from Table 1, the effect of the embodiment after exposure to sunlight is smaller in the example than in the comparative example. Admitted.

(2) Test Method for Preventing and Improving the Roughness of Skin Twice in the morning and at night, after washing the face, the appropriate amount of the cosmetics of Examples 1 to 3 was applied to the left side of the face and the appropriate amount of the cosmetic of Comparative Example 1 was applied to the right side of the face. This was done by applying for two weeks. The test was conducted by dividing the 30 female panels into 10 groups, each group comprising 10 groups. (Evaluation method) The effectiveness of three items (moisture of skin, firmness of skin, moisture of the next morning) was determined based on the following criteria. (Judgment) ：: When the ratio of the effective and effective of the subjects is 80% or more ○: The ratio of the effective and effective among the subjects is 50 to 8
0%: △: 30% to 5% of the test subjects showed significant and effective
0%: ×: The proportion of subjects who show excellent and effective is 30% or less

[0019]

[Table 2]

As is evident from Table 2, it was found that the effect of the skin moisture, the firmness of the skin and the effect of the moisture of the next morning were better in the example than in the comparative example.

Example 4 Cream Weight% Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-acetylphenyl ester hydrochloride 20.0 Caustic potash 0.2 Bisulfite Sodium 0.01 Preservatives Appropriate amount Fragrance Appropriate amount Ion-exchanged water residue (Preparation method) Add propylene glycol and caustic potash to ion-exchanged water, heat and maintain at 70 ° C (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is gradually added to the aqueous phase, and after the addition is completed, the temperature is maintained for a while to cause a reaction. Thereafter, the mixture is uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well.

Example 5 Cream% by weight Stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monostearate 1.5 Propylene glycol 10.0 trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-phenylphenyl ester hydrochloride Salt 7.0 Glycerin trioctanoate 10.0 Squalene 5.0 Sodium bisulfite 0.01 Ethyl paraben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Preparation method) Add propylene glycol to ion-exchanged water, heat and maintain at 70 ° C (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsified, homogenized with a homomixer, and cooled to 30 ° C. with good stirring.

Example 6 Cream% by weight 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'-chlorophenyl ester hydrochloride 0.005 Fragrance Appropriate amount Sodium bisulfite 0.03 Ethyl paraben 0.3 Ion-exchanged water Residue (Preparation method) Add propylene glycol to ion-exchanged water, heat and maintain at 70 ° C (water phase) ). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsified, homogenized with a homomixer, and cooled to 30 ° C. with good stirring.

Example 7 Emulsion Weight% 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-guanidinomethylcyclohexane carboxy Acid 4'-acetaminophenyl ester hydrochloride 10.0 Sodium bisulfite 0.01 Ethyl paraben 0.3 Carboxyvinyl polymer 0.05 Perfume Appropriate amount Ion exchange water residue (Preparation method) Dissolve the carboxyvinyl polymer in a small amount of ion exchange water (phase A). Polyethylene glycol 1500 and triethanolamine are added to the remaining ion-exchanged water, dissolved by heating, and maintained at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsification is performed, phase A is added, and the mixture is uniformly emulsified with a homomixer. After the emulsification, the mixture is cooled to 30 ° C. while stirring well.

Example 8 Emulsion weight% (oil phase) 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'-sulfamoylphenyl ester hydrochloride 1.0 trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-benzoylphenyl ester hydrochloride 1.0 Perfume ) Sodium bisulfite 0.01 Glycerin 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water Residue (Preparation method) Dissolve the oil phase at 70 ° C. 70 ° C in the aqueous phase
And the oil phase is mixed with the aqueous phase, emulsified by an emulsifier, and then cooled to 30 ° C. by a heat exchanger.

Example 9 Jelly wt% 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 2 ′ -Phenoxyphenyl ester hydrochloride 1.0 trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-formylphenyl ester hydrochloride 1.0 Methyl paraben 0.2 Perfume Appropriate amount Ion exchange water Residue (Preparation method) Uniformly dissolve carboxyvinyl polymer in ion exchange water Trans-4- in 95% ethanol
Dissolve guanidinomethylcyclohexanecarboxylic acid 2'-phenoxyphenyl ester hydrochloride, trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-formylphenyl ester hydrochloride, polyoxyethylene (50 mol) oleyl alcohol ether and add to aqueous phase I do. Then, after adding other ingredients, caustic soda,
Neutralize with L-arginine to thicken.

Example 10 Serum Weight% (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 mol) octyldodecanol 1.0 Methyl paraben 0.15 Pantothenyl ethyl ether 0.1 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'- Cyanophenylester hydrochloride 0.05 (B phase) 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) Dissolve phase A and phase C uniformly, A for C phase
Add phases and solubilize. Next, after the phase B is added, filling is performed.

Example 11 pack weight% (phase A) dipropylene glycol 5.0 polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (phase B) trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-ethylphenyl ester hydrochloride 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 3 ', 4'-dichlorophenyl ester hydrochloride 1.0 Olive oil 5.0 Tocophenol acetate 0.2 Ethylparaben 0.2 Fragrance 0.2 (Phase C) Sodium bisulfite 0.03 Polyvinyl alcohol (degree of saponification, degree of polymerization 2000 13.0 Ethanol 7.0 Purified water Residue (Preparation method) A phase, B phase, and C phase are each dissolved uniformly, and A
Add phase B to phase and solubilize. Then, after adding this to phase C, filling is performed.

The skin external preparations obtained in the present invention were tested in Examples 1 to 3 for whitening effect and for preventing skin roughness.
The effect was recognized in the improvement effect test.

[0030]

The skin external preparation containing the trans-4-guanidinomethylcyclohexanecarboxylic acid derivative and the salt thereof according to the present invention is a novel skin external preparation having both skin whitening effect and skin roughening prevention and improvement effects.

──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Yuki Yamase 1050 Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Inside Shiseido First Research Center Co., Ltd. (72) Naoe Akiyama 1050 Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Shares Shiseido Co., Ltd. 1st Research Center (72) Inventor Kenji Kitamura 1050 Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Shiseido Co., Ltd. 1st Research Center Co., Ltd. Examiner Ikuji Oya (56) References JP-A-57-16856 ( JP, A) JP-A-57-75921 (JP, A) JP-A-57-122059 (JP, A) JP-A-57-122062 (JP, A) JP-A-57-140713 (JP, A) (58) ) Fields surveyed (Int. Cl. ⁷ , DB name) A61K ⁷ /00-7/50 A61K 31/215-31/27 CA (STN)

Claims (1)

(57) [Claims] 1. A trans-4-compound represented by the following general formula 1.
An external preparation for skin comprising at least one or more of a guanidinomethylcyclohexanecarboxylic acid derivative and a salt thereof. Embedded image (Wherein, R ₁ R ₂ R ₃ are the same or different and each represents a hydrogen atom,
Lower alkyl group, lower alkoxy group, alkanoyl group,
Phenyl, halogen, trihalogenomethyl, nitro, acetamino, carbamoyl, sulfamoyl, benzoyl, phenoxy, benzyloxy, formyl or cyano)