JP3081030B2 - Skin whitening agent - 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 at least one gentisic acid ester derivative as an active ingredient and having a markedly improved skin bleaching effect.

[0002]

2. Description of the Related Art Although there are some unclear points about the mechanism of occurrence of skin spots and the like, it is generally caused by hormonal abnormalities and stimulation of ultraviolet rays from sunlight. It is believed that melanin is formed, which is abnormally deposited in the skin. Treatments for such spots and bruises include substances that inhibit melanin production,
For example, a method of administering a large amount of vitamin C, a method of injecting glutathione, or the like, or a method of injecting kojic acid, L-ascorbic acid and its derivatives (fatty acid, sulfuric acid, phosphate ester, etc.), cysteine or glutathione and its derivatives into an ointment, a cream, or the like. A method such as topical application in the form of a film or lotion is used. In the United States and Europe, hydroquinone preparations are used as pharmaceuticals. However, these compounds, except for hydroquinone, exhibit very slow effects, so that the whitening effect is not always sufficient. On the other hand, although hydroquinone has been recognized as having an effect, its use is not generally accepted in Japan due to its sensitizing properties. Therefore, in order to improve its safety, an attempt was made to use monoesters or alkyl monoethers of higher fatty acids (JP-A-58-1545).
No. 07), but esters are not always safe because they are decomposed by hydrolyzing enzymes in the body, and ethers which are sufficiently satisfactory in terms of safety have been obtained. Absent. In order to solve these problems, the present inventors have proposed a gentisic acid ester derivative which is said to have an antioxidant effect (Japanese Patent Laid-Open No. 24988/1990).
As a result of diligent studies on No. 5 publication, it has been found that these compounds, especially specific ones thereof, have a stronger skin bleaching and whitening effect than hydroquinone and can be applied as an external preparation for skin whitening.

[0003]

SUMMARY OF THE INVENTION Namely, the present invention is effective gentisic acid ester derivative represented by the following general formula 1
A whitening agent characterized by being a component .

Embedded image (In the formula, R represents a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms or an arylalkyl group.) Hereinafter, the constitution of the present invention will be described in detail.

The gentisic acid ester derivative used in the present invention is a substance represented by the above-mentioned general formula 1. These compounds are synthesized by a known synthesis method, for example, a linear or branched alcohol and gentisic acid with an acid catalyst (p. -Toluenesulfonic acid, sulfuric acid, etc.) and reacting to obtain gentisic acid ester. Specific examples of substance names include: methyl gentisate, ethyl gentisate, propyl gentisate, isopropyl gentisate, butyl gentisate, 2-butyl gentisate, 2-methyl-1-propyl gentisate, 2-methyl-2-propyl gentisate. Pentyl gentisic acid 2-pentyl gentisic acid 3-pentyl gentisic acid tert-amyl gentisic acid 2-methyl-1-butyl gentisic acid 3-methyl-2-butyl gentisic acid neopentyl gentisic acid hexyl gentisic acid 2-hexyl gentisic acid 3-hexyl 2-methyl-1-pentyl gentisate 2-methyl-2-pentyl gentisate 3-methyl-1-pentyl gentisate 3-methyl-2-pentyl gentisate 3-methyl-3-pentyl gentisate 4-methyl-1-pentyl gentisate heptyl gentisate heptyl gentisate 2-heptyl gentisate 3-heptyl gentisate 2,2-dimethyl-3-gentisate Pentyl 2,3-dimethyl-3-pentyl gentisate 2,4-dimethyl-3-pentyl gentisate 4,4-dimethyl-2-pentyl gentisate 3-ethyl-3-pentyl gentisate 2-methyl-2 gentisate -Hexyl gentisic acid 3-methyl-3-hexyl gentisic acid 5-methyl-2-hexyl gentisic acid 2-tetradecyl gentisic acid pentadecyl gentisic acid hexadecyl gentisic acid 2-hexadecyl gentisic acid heptadecyl gentisic acid octadecyl gentisic acid Nadeshiru gentisic acid eicosyl benzyl gentisic acid and the like. Of these, straight-chain or branched esters having 1 to 8 carbon atoms are desirable from the viewpoint of whitening effect and irritation, and among them, those having up to 6 carbon atoms are particularly preferred. The compounding amount is 0.001 to 1% of the total amount of the skin external preparation.
It is 20% by weight, preferably 0.01 to 10% by weight.
If the amount is less than 0.001% by weight, the whitening effect is poor.

Further, according to the present invention, at least one kind of the gentisic acid ester derivative represented by the above general formula 1 is added to vitamin C or its derivative or vitamin E
Alternatively, there is provided an external preparation for whitening skin characterized by blending with a derivative thereof. Vitamin C used in the present invention
Means L-ascorbic acid, which has cell respiratory action, enzyme activating action, collagen forming action and melanin reducing action due to its strong reducing action. Also, vitamin C
Examples of the derivatives of L-ascorbic acid monostearate, L-ascorbic acid monopalmitate, L
L-ascorbic acid monoalkyl esters such as ascorbic acid monooleate, L-ascorbic acid monoester derivatives such as L-ascorbic acid monophosphate magnesium and L-ascorbic acid-2-sodium sulfate;
L-ascorbic acid dialkyl esters such as L-ascorbic acid-2,6-distearate, L-ascorbic acid-2,6-dipalmitate and L-ascorbic acid-2,6-diolate; L-ascorbic acid diester derivatives such as ascorbic acid diphosphate, L
Trialkyl esters such as ascorbic acid tristearate, L-ascorbic acid tripalmitate and L-ascorbic acid trioleate; and ascorbic acid triester derivatives such as L-ascorbic acid triphosphate. In practicing the present invention,
One or more of these are appropriately selected and blended.

The vitamin E and derivatives thereof used in the present invention include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol acetate, and tocopherol nicotinate. And the like. In the present invention, any one or more of these are selected and used. These vitamin Es may be natural or synthetic. When naturally occurring vitamin E (d-α-tocopherol) is used, either crude vitamin E or a purified product may be used. Also, in addition to tocopherol, for example, triglyceride, lecithin,
Vitamin K, vitamin A, ubiquinone and the like may be contained. The compounding amount of vitamins C and vitamin E is about 0.01 to 5% by weight, preferably 0.05 to 3% by weight, based on the total amount of the external preparation for skin. The skin external preparation containing vitamin C or vitamin E according to the present invention has an enhanced whitening effect as compared with the case where a gentisic acid ester derivative is used alone. This is thought to be due to the fact that vitamin C or E enhances the ability to absorb into the skin.

[0007] In addition to the essential components described above, the skin external preparation of the present invention also contains other components usually used in skin external preparations such as cosmetics and pharmaceuticals, such as oils, ultraviolet absorbers, antioxidants, and surfactants. Humectants, fragrances, water, alcohols, thickeners, coloring materials, skin nutritional agents (pantothenylethyl ether, glycyrrhizinate) and the like can be appropriately compounded as necessary. Among them, as the ultraviolet absorber, benzoic acid-based para-aminobenzoic acid (hereinafter referred to as PA) is used.
BA), glyceryl PABA, ethyldihydroxypropyl PABA, cinnamic acid-based, octyl methoxycinnamate, 2-ethoxyethyl-p-methoxycinnamate, and benzophenone-based
2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-
Methoxy-4-methylbenzophenone, and others such as urocanic acid ethyl ester, 2-phenyl-5
-Methylbenzoxazole, 4-methoxy-4-t-butyldibenzoylmethane and the like are used.

[0008]

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. First, a synthesis example of the derivative used in the present invention will be described in detail. Synthesis Example 1 (n-hexyl gentisate) 15.4 g (0.1 mol) of gentisic acid under a nitrogen atmosphere
l) and 12.3 g of n-hexyl alcohol (0.12 m
ol) and 0.4 g of p-toluenesulfonic acid were suspended in 100 ml of xylene and reacted at 140 ° C. for 24 hours with stirring. After completion of the reaction, the mixture was washed with 10 ml of a saturated aqueous solution of sodium hydrogen carbonate and then with distilled water, the xylene layer was dried over anhydrous sodium sulfate, and xylene was removed under reduced pressure to obtain a pale yellow transparent viscous oil.
1.8 g (91.6% yield) was obtained. Infrared absorption spectrum KBr (liquid film): 3292, 2957, 2932, 2
860,1678,1487,1467,1404,1
080 (cm ^-1 )

Synthesis Example 2 (3-methyl-1 gentisate)
-Butyl) 10.8 g (0.07 mol) of gentisic acid in a nitrogen atmosphere
l) and 7.1 g of 3-methyl-1-butanol (0.08
mol) and 0.5 g of p-toluenesulfonic acid were suspended in 100 ml of xylene and stirred at 140 ° C. for 48 hours.
The reaction was carried out for a period of time to obtain 15.3 g (97% yield) of the ester as a viscous oil in the same manner as in Synthesis Example 1. Infrared absorption spectrum KBr (liquid film): 3418, 2960, 2
932, 1678, 1620, 1489, 1467, 1
082 (cm ^-1 )

Synthesis Example 3 (2-ethylhexyl gentisic acid) Under a nitrogen atmosphere, 7.7 g of gentisic acid (0.05 mol)
l) and 7.8 g of 2-ethylhexanol (0.06 mol)
l) and 0.4 g of p-toluenesulfonic acid were suspended in 100 ml of xylene, and reacted at 140 ° C. for 10 hours with stirring. 11.4 g of the ester was obtained as a viscous oil as in Synthesis Example 1 (yield). 85%). Infrared absorption spectrum KBr (liquid film): 3408, 2960, 293
0,2874,1678,1620,1487,146
6,1080 (cm ^-1 )

Examples 1-6, Comparative Examples 1-2 (Alcohol phase) 95% ethyl alcohol 55.0 Polyoxyethylene (25 mol) 2.0 Hardened castor oil ether Antioxidant / preservative qs perfume qs drugs (Table 1) 1.0 (aqueous phase) 5.0 glycerin 5.0 sodium hexametaphosphate qs ion exchanged water balance preparation aqueous phase, alcohol - after preparation Le phase, solubilized.

Test Method for Whitening Effect Conducted on the inner skin of the upper arm of 70 subjects exposed to sunlight in the summer for 4 hours (2 hours a day for 2 days), starting 5 days after the sun exposure. Each sample of Examples 1 to 6 and Comparative Examples 1 and 2 was applied once in the morning and evening for 8 weeks. Panels in groups of 10
Each group was divided into five groups and tested. Judgment of the whitening effect場合: When the ratio showing the significant effect and effectiveness among the subjects is 80% or more ○: The ratio showing the significant effect and effectiveness among the subjects is 50 to 8
0%: △: The proportion of the test subjects showing excellent and effective was 50 to 3
0%: ×: The proportion of the test subjects showing excellent and effective is 30% or less. Table 1 shows the results based on the above criteria.

[0013]

[Table 1] ─────────────────────────────────── Compound name Whitening effect ───────比較 Comparative Example 1 None × Comparative Example 2 Hydroquinone △ Example 1 Methyl gentisate ◎ Example 2 Gentisic acid Decyl ○ Example 3 Eicosyl gentisate ○ Example 4 2-Ethyl-hexyl gentisate ◎ Example 5 2-hexadecyl gentisate ○ Example 6 3-methyl-1-butyl gentisate ◎ ────────効果 As is clear from Table 1, the effect after exposure to sunlight was It was found that the examples prevent the deposition of excessive melanin pigment and prevent the color from becoming dark.

Example 7 (Cream) Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 Hexyl gentisate 20 .0 Caustic potash 0.2 propylene glycol to sodium bisulfite 0.01 preservative qs perfume qs ion-exchanged water balance preparation of ion-exchanged water - Le and potassium hydroxide was added, dissolved, kept heated to 70 ° C. (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is gradually added to the water phase, and after the addition is completed, the temperature is maintained for a while to cause a reaction. Then, a homomixer
Emulsify uniformly and cool to 30 ° C with good stirring.

Example 8 (Formulation of cream and vitamin C) Stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monostearate 1.5 Propylene glycol 10. 0 gentisic acid propyl 5.0 glycerin trioctanoate Noe - DOO 10.0 squalene 5.0 vitamin C 0.1 sodium bisulfite 0.001 ethylparaben 0.3 perfume qs ion exchanged water balance preparation propylene glycol in deionized water - And heat to 70 ° C (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, preliminarily emulsified, uniformly emulsified by a homomixer, and cooled to 30 ° C. with good stirring. The obtained skin external preparation had a more excellent whitening effect than that of the formulation containing no vitamin C.

Example 9 (Blend of cream and vitamin E) Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanolin 2.0 Squalane 5.0 2-Octyldodecyl alcohol 6.0 Polyoxy Ethylene (25 mol) Cetyl alcohol ether 3.0 Glycerin monostearate 2.0 Propylene glycol 5.0 Methyl gentisate 0.01 Vitamin E (dl-α-tocopherol) 0.05 Perfume Appropriate amount of bisulfite Sodium 0.03 Ethyl paraben 0.3 Ion-exchanged water Residual production method Propylene glycol is added to ion-exchanged water, and heated to 70 ° C. (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, preliminarily emulsified, uniformly emulsified by a homomixer, and cooled to 30 ° C. with good stirring. The resulting skin external preparation is
The whitening effect was superior to that of the formulation containing no vitamin E.

Example 10 (Cream) Solid paraffin 5.0 Beeswax 10.0 Vaseline 15.0 Liquid paraffin 41.0 Glycerin monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monolaurate 2 0.0 Soap powder 0.1 Borax 0.2 2-pentyl gentisate 0.05 3-Methyl-1-butyl gentisate 0.05 Ion-exchanged water Residual perfume Appropriate amount Sodium bisulfite 0.03 Ethyl paraben 0.3 Production method ion Add soap powder and borax to the replacement water, heat and dissolve.
Keep at 0 ° C. (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is gradually added to the aqueous phase while stirring, and the reaction is carried out. After the completion of the reaction, the mixture is uniformly emulsified with a homomixer, and cooled to 30 ° C. while stirring well after emulsification.

Example 11 (Emulsion) Stearic acid 2.5 Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) Monooleate 2.0 Polyethylene glycol 1500 0 Triethanolamine 1.0 Dodecyl gentisate 0.001 Sodium bisulfite 0.01 Ethyl paraben 0.3 Carboxyvinyl polymer 0.05 (trade name: Carbopol 941, BFGoodrich Chemical company) Fragrance Appropriate amount Ion Exchanged water Residual 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 dissolved by heating and maintained at 70 ° C. (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, preliminarily emulsified, the phase A is added, and the mixture is uniformly emulsified with a homomixer.

Example 12 (Emulsion, UV absorber formulation) (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 2.0 Glycerin monooleate 2.0 Polyoxyethylene (60 mol) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 3-Methyl-3-pentyl gentisate 1 0.0 Para-aminobenzoic acid 0.1 Perfume Appropriate amount (aqueous phase) Sodium bisulfite 0.001 Glycerin 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 (Product name: Carbopol 941, BFGoodrich Chemical company) dissolving 0.2 purified water balance preparation oil phase of potassium hydroxide at 70 ° C.. The aqueous phase is dissolved at 70 ° C., the oil phase is mixed with the aqueous phase, emulsified by an emulsifier, and then cooled to 30 ° C. by a heat exchanger.

Example 13 (Emulsion) Microcrystalline wax 1.0 Beeswax 2.0 Lanolin 20.0 Liquid paraffin 10.0 Squalane 5.0 Sorbitan sesquioleate 4.0 Polyoxyethylene (20 mol) Sorbitan mono Oleic acid ester 1.0 Propylene glycol 7.0 2,6-Dimethyl-4-heptyl gentisate 3.0 Ethylparaben 0.3 Sodium bisulfite 0.01 Perfume Appropriate amount Ion-exchanged water Residual process Ion-exchanged water with propylene Glycol is added and heated to 70 ° C. (aqueous phase). The other components are mixed, dissolved by heating and kept at 70 ° C. (oil phase). While stirring the oil phase, the aqueous phase is gradually added thereto, and the mixture is uniformly emulsified with a homomixer.
After emulsification, cool to 30 ° C with good stirring.

Example 14 (Jelly) 95% ethyl alcohol 10.0 dipropylene glycol 15.0 polyoxyethylene (50 mol) oleyl alcohol ether 2.0 carboxyvinyl polymer 1.0 ( Product name: Carbopol 940, BFGoodrich Chemical company) Caustic soda 0.15 L-arginine 0.1 Eicosyl gentisate 0.05 2-Hydroxy-4-methoxybenzophenone sodium sulfonate 0.05 Methyl paraben 0 .2 Ethylenediaminetetraacetate trisodium dihydrate 0.05 Perfume Appropriate amount Ion-exchange water Residual process Carbopol 940 is uniformly dissolved in ion-exchange water, while 95% ethanol is used. Dissolve eicosyl gentisate, polyoxyethylene (50 mol) oleyl alcohol ether, It is added to the phase. Next, after adding other components, the mixture is neutralized with caustic soda and L-arginine to increase the viscosity.

Example 15 (Serum) (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20) octyldodecanol 1.0 Methyl paraben 0.15 Pantothenyl ethyl ether 0.1 Hexyl gentisate 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerin 5.0 Cypropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 (Product name: K -Bopol 940, BFGoodrich Chemical company) Purified water Residual method Dissolve A phase and C phase uniformly, and add A phase to C phase for solubilization. Then, after adding the phase B, filling is performed.

Example 16 (Pack, Vitamin E formulation) (A phase) Dipropylene glycol 5.0 Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (B phase) Octyl gentisate 1.0 Gentisin 2-Tetradecyl acid 1.0 Octadecyl gentisate 1.0 Olive oil 5.0 Vitamin E (tocopherol acetate) 0.2 Ethyl paraben 0.2 Fragrance 0.2 (Phase C) Sodium bisulfite 0.03 Polyvinyl alcohol 13.0 (degree of saponification 90, degree of polymerization 2,000) Ethanol 7.0 Purified water Residual method A phase, B phase, and C phase are each dissolved uniformly, and B phase is added to A phase. In addition, it is solubilized. Then, after adding this to the C phase, filling is performed.

Example 17 (Pack with powder) (Alcohol phase) 95% Ethanol 10.0 Propylene glycol 5.0 2-Hexadecyl gentisate 10.0 Isopropyl gentisate 1.0 Perfume Appropriate colorant Appropriate amount (aqueous phase) Zinc flower 25.0 Kaolin 20.0 Methylparaben 0.3 Glycerin 5.0 Ion-exchange water Residual production method The aqueous phase is uniformly adjusted at room temperature. Next, the alcohol phase prepared at room temperature is added and mixed uniformly.

Example 18 (Cream) Solid paraffin 5.0 Beeswax 10.0 Vaseline 15.0 Liquid paraffin 41.0 Glycerin monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monolaurate 2.0 Soap powder 0.1 Borax 0.2 Benzyl gentisate 0.05 Ion-exchanged water Residual perfume Appropriate amount Sodium bisulfite 0.03 Ethylparaben 0.3 Manufacturing method Add soap powder and borax to ion-exchanged water, heat and dissolve.
Keep at 0 ° C. (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is gradually added to the aqueous phase while stirring, and the reaction is carried out. After completion of the reaction, the mixture is uniformly emulsified with a homomixer, and cooled to 30 ° C. while stirring well after emulsification.

[0026]

As described above, since the gentisic acid ester derivative used in the present invention has a stronger whitening effect than conventional ones, the desired effect can be obtained with a small amount of use, and it is safe. Compound. Accordingly, by blending the compound, an external preparation for skin whitening having excellent properties is provided.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Masako Naganuma 1050 Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Inside Shiseido Research Laboratories (72) Inventor Minoru Fukuda 1050 Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Shiseido Kenkyusha (56) References JP-A-4-273808 (JP, A) JP-A-4-208209 (JP, A) JP-A-3-153616 (JP, A) JP-A-61-122209 (JP, A) JP-A-1-249885 (JP, A) JP-A-4-502476 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 7/48 A61K 7/00

Claims (2)

(57) [Claims] 1. A whitening agent comprising a gentisic acid ester derivative represented by the following general formula as an active ingredient . Embedded image (In the formula, R represents a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms or an arylalkyl group.) 2. A skin whitening external preparation comprising at least one gentisic acid ester derivative according to claim 1 and vitamin C or a derivative thereof or vitamin E or a derivative thereof.