JP2722309B2 - 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 an external preparation for skin, and more particularly to an improvement in a whitening active ingredient.

[0002]

2. Description of the Related Art There are various pigment abnormalities on the skin, from cosmetics such as spots and freckles to skin disorders such as liver spots and sparrow eggs. The mechanism of action of these pigment abnormalities is unknown in many ways, but in general, melanin pigments are formed by stimulating hormonal abnormalities and ultraviolet rays from sunlight, which are abnormally deposited in the skin. It is believed that. In the treatment of such pigment abnormalities, a melanin production inhibitor is used as a symptomatic treatment. For example, a method of orally administering vitamin C, a method of injecting glutathione or the like, or a method of injecting kojic acid, vitamin C and the like. A method of topically applying a derivative, cysteine, or the like in the form of an ointment, cream, lotion, or the like has been adopted. However, the fact is that these methods have not yet obtained a sufficient effect. On the other hand, in Europe and the United States, hydroquinone and its derivatives, which are melanin production inhibitors, are used as pharmaceuticals for the purpose of depigmenting pigment spots.

[0003]

However, the effects of the hydroquinone derivative are extremely slow, and its whitening effect is not sufficient. Although hydroquinone itself has a lightening effect, its use is restricted due to safety problems. Derivatives that reduce the side effects of hydroquinone and have an excellent whitening effect have been studied, but none of them have sufficient effects and safety. The present invention has been made in view of the above technical problems, and an object of the present invention is to provide a skin external preparation having an excellent whitening effect and high safety.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems of the prior art, and as a result, certain alkoxysalicylic acids have a melanin production inhibitory action, Have been found to have an excellent whitening effect of improving and preventing abnormal deposition of the present invention, and have completed the present invention.

That is, the external preparation for skin according to claim 1 of the present invention is characterized by containing one or more of alkoxysalicylic acid and / or a salt thereof represented by the following general formula (A). . General formula (A):

Embedded image (In the formula, R represents an alkoxy group.)

A skin external preparation according to claim 2 of the present invention is characterized in that, in the skin external preparation according to claim 1, the alkoxy group is a methoxy group. The external preparation for skin according to claim 3 of the present invention is characterized in that, in the external preparation for skin according to claim 1, the alkoxy group is an ethoxy group. The external preparation for skin according to claim 4 of the present invention is claim 1 to claim 1.
3. The external preparation for skin according to item 3, wherein one or more acidic mucopolysaccharides are blended.

A skin external preparation according to claim 5 of the present invention is characterized in that one or more vitamin E esters are blended in the skin external preparation according to claims 1 to 4. The external preparation for skin according to claim 6 of the present invention is claim 1 to claim 1.
5. The external preparation for skin according to 5, wherein one or more of paraoxybenzoic acid esters are blended. The external preparation for skin according to claim 7 of the present invention is claim 1
6. The skin external preparation according to 6, wherein an alkylenediamine carboxylic derivative is blended.

Hereinafter, the configuration of the present invention will be described in detail. The alkoxysalicylic acid used in the external preparation for skin of the present invention is a known substance. For example, 5-methoxysalicylic acid is Be
il, 10227, 4-methoxysalicylic acid is Bei
1, 10379, and can be easily synthesized. Also, it is commercially available as a reagent from Aldrich (Germany) or the like, and this can also be used.

The alkoxysalicylic acid used in the present invention is obtained by substituting any of the 3-, 4- or 5-hydrogen atoms of salicylic acid with an alkoxy group.
The alkoxy group as a substituent is preferably a methoxy group,
It is any one of an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and an isobutoxy group, and more preferably a methoxy group or an ethoxy group. To give a concrete example of the compound name,

3-methoxysalicylic acid (2-hydroxy-3-me
thoxybenzoic acid) 3-ethoxy-3-ethoxybenzoic
acid) 4-methoxy-4-methoxybenzoic acid
acid) 4-Ethoxysalicylic acid
acid) 4-propoxysalicylic acid
ic acid) 4-Hydroxy-4-isopropoic acid
xybenzoic acid) 4-butoxysalicylic acid (2-hydroxy-4-butoxybenzoic)
acid) 5-methoxysalicylic acid
acid) 5-ethoxy-5-ethoxybenzoic
acid) 5-propoxysalicylic acid (2-hydroxy-5-propoxybenzo
ic acid).

The above-mentioned alkoxysalicylic acid can be converted into a salt by a known method. However, the external preparation for skin of the present invention may contain alkoxysalicylic acid in the form of a salt. Such salts are not particularly limited, for example,
In addition to alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, and calcium salts, salts such as ammonium salts and amino acid salts are exemplified. Although the above-mentioned alkoxysalicylic acid or a salt thereof is an existing substance, its whitening effect is not known at all, and it was first clarified by the present inventors, and was once added to a skin external preparation for the purpose of whitening. There is no example.

In order to obtain an effective whitening effect in the skin external preparation of the present invention, the amount of the alkoxysalicylic acid and / or its salt is preferably 0.001 to 20% by weight based on the total amount of the skin external preparation. Preferably 0.
01 to 10% by weight. If the amount is less than 0.001% by weight, the whitening effect is poor, and if it exceeds 20% by weight, the whitening effect reaches a plateau, and the effect corresponding to the increase in the amount cannot be expected.

By the way, the present inventors proceeded with the research on the above-mentioned external preparation for skin and found that acidic mucopolysaccharides, vitamin E esters, p-hydroxybenzoic acid esters, and alkylenediamine carboxylic acid derivatives were substituted with the alkylsalicylic acid of the present invention or the alkylsalicylic acid or its derivatives. It has been found that when it is mixed with a skin-containing external preparation containing salt, the whitening effect is enhanced. These are known as moisturizers, blood flow enhancers, preservatives, and bactericides, respectively, and are incorporated in cosmetics and the like, but the whitening effect enhancing effect has not been known until now. . Examples of the acidic mucopolysaccharide used in the present invention include sodium hyaluronate, sodium chondroitin sulfate, and the like, and the amount thereof is preferably 0.01 to 10% by weight, more preferably 0.1 to 10% by weight, based on the external preparation for skin. 01-3
% By weight.

The vitamin E esters used in the present invention include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol acetate, tocopherol nicotinate and the like. Examples of paraoxybenzoic acid include: Methyl paraben, ethyl paraben, butyl paraben, and the like. As the alkylene diamine carboxylic acid derivative, ethylene diamine tetraacetic acid or a salt thereof is preferable. As alkylenediamine carboxylate, sodium salt, potassium salt,
In addition to alkali metal salts such as magnesium salts and the like, alkaline earth metal salts, ammonium salts, alkanol salts and the like can be mentioned, with preference given to sodium salts.

The amount of the vitamin E ester and / or paraoxybenzoic acid ester and / or alkylenediamine carboxylic acid derivative is preferably 0.01 to 3% by weight, more preferably 0 to 3% by weight, based on the external preparation for skin. 0.05 to 0.3% by weight. The dosage form of the external preparation for skin of the present invention can be arbitrarily selected as long as the effect can be sufficiently exerted.
In addition to emulsified systems such as emulsions and creams and dispersed systems such as makeup cosmetics, packs, jellies, ointments and the like can be mentioned.

In addition to the above-mentioned essential components, the skin external preparation of the present invention contains, in addition to the components usually used in skin external preparations such as cosmetics and pharmaceuticals, other whitening agents, moisturizing agents, antioxidants, etc. An oil component, an ultraviolet absorber, a surfactant, a humectant, a thickener, an alcohol, a powder component, a coloring material, an aqueous component, water, various skin nutrients, and the like can be appropriately compounded as necessary.

Examples of the oily component include camellia oil, macadamia nut oil, olive oil, castor oil, safflower oil, soybean oil, teaseed oil, cocoa butter, coconut oil, hydrogenated coconut oil,
Palm oil, mokuro, hardened castor oil, beeswax, candelilla wax, carnauba wax, lanolin, liquid lanolin,
Natural oils and fats such as jojoba wax, rigid lanolin, polyoxyethylene lanolin alcohol ether, polyoxyethylene cholesterol ether, liquid paraffin, ozokerite, squalene, paraffin, ceresin, petrolatum, hydrocarbon oils such as microcrystalline wax, myristic acid Isopropyl, octyldodecyl myristate, isopropyl palmitate, cholesteryl 12-hydroxystearate, ethylene glycol di-2-ethylhexylate, dipentaerythritol fatty acid ester, pentaerythritol tetra-2-ethylhexylate, glycerin tri-2-ethylhexylate,
Synthetic oil components such as trimethylolpropane triisostearate, cetyl-2-ethylhexanoate, castor oil fatty acid methyl ester, chain polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane and methylhydrogenpolysiloxane, decamethyl Examples thereof include cyclic polysiloxanes such as polysiloxane, dodecamethylpolysiloxane, and tetramethyltetrahydrogenpolysiloxane, silicones capable of forming a three-dimensional network structure, and silicones such as silicone rubber.

Examples of the ultraviolet absorber include benzoic acid-based ultraviolet rays such as paraaminobenzoic acid, paraaminobenzoic acid monoglycerin ester, N, N-dipropoxyparaaminobenzoic acid ethyl ester, and N, N-dimethylparaaminobenzoic acid ethyl ester. Absorbent, homomenthyl-N
-Anthranilic acid UV absorbers such as acetylanthranilate, amyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate,
Salicylic acid type ultraviolet absorbers such as benzyl salicylate and p-isopropanol phenyl salicylate, octyl cinnamate, ethyl-4-isopropyl cinnamate, methyl-2,5-diisopropyl cinnamate, ethyl-2,4-diisopropyl cinnamate, propyl- p-methoxycinnamate, isoamyl-p-methoxycinnamate, octyl-p-methoxycinnamate (2-ethylhexyl-p-methoxycinnamate),
2-ethoxyethyl-p-methoxycinnamate, 2-
Ethylhexyl-α-cyano-β-phenylcinnamate, glyceryl mono-2-ethylhexanoyl-di-p
-Cinnamic acid ultraviolet absorbers such as methoxycinnamate,
2,4-dihydroxybenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone, 2,2 ′,
4,4′-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonate,
-Phenylbenzophenone, 2-ethylhexyl-4 '
Benzophenone ultraviolet absorbers such as -phenylbenzophenone-2-carboxylate, 3- (4'-methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l-camphor, urocanic acid, urocanic acid ethyl ester, 2,2′-hydroxy-5-methylphenylbenzotriazole, 2- (2′-hydroxy-
5'-t-octylphenyl) benzotriazole, dibenzarazine, dianisoylmethane, 4-methoxy-
4'-t-butyldibenzoylmethane, 5- (3,3-
Dimethyl-2-norbornylidene) -3-pentane-2
-On and the like.

Examples of the lipophilic nonionic surfactant include sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, and penta-2. -Sorbitan fatty acid esters such as diglycerol sorbitan ethylhexylate, glycerin or polyglycerol esters such as glycerin monostearate, glycerin α, α'-oleate pyroglutamate, glyceryl monostearate, propylene monostearate Examples include propylene glycol fatty acid esters such as glycol, hydrogenated castor oil derivatives, and glycerin alkyl ether.

Examples of the hydrophilic nonionic surfactant include polyoxyethylene sorbitan monooleate,
Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monostearate, polyoxyethylene sorbite monolaurate, polyoxyethylene sorbite monooleate, polyoxyethylene sorbite fatty acid esters such as polyoxyethylene sorbite monostearate, Polyoxyethylene glycerin fatty acid ester such as polyoxyethylene glycerin monostearate, polyoxyethylene glycerin monoisostearate, polyoxyethylene glycerin triisostearate, polyoxyethylene monooleate, polyoxyethylene distearate, etc. Polyoxyethylene fatty acid esters, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether,
Polyoxyethylene alkyl ethers such as polyoxyethylene stearyl ether, polyoxyethylene-2-octyldodecyl ether, polyoxyethylene cholestanol ether, polyoxyethylene octyl phenyl ether, polyoxyethylene nonyl phenyl ether, polyoxyethylene dinonyl Phenyl ether,
Polyoxyethylene alkyl phenyl ethers such as
Pluronic type surfactant such as Pluronic, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene polyoxypropylene-2-decyltetradecyl ether, polyoxyethylene polyoxypropylene monobutyl ether, polyoxyethylene polyoxypropylene, hydrogenated Lanolin, polyoxyethylene polyoxypropylene alkyl ethers such as polyoxyethylene polyoxypropylene glycerin ether, tetrapolyoxyethylene / tetrapolyoxypropylene ethylene diamine condensates such as tetronic, polyoxyethylene castor oil, polyoxyethylene cured Castor oil, polyoxyethylene hydrogenated castor oil monoisostearate, polyoxyethylene hydrogenated castor oil triisostearate, polyoxy Styrene hydrogenated castor oil mono-pyroglutamic acid monoisostearate diester, polyoxyethylene castor oil derivative or a polyoxyethylene hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil maleic acid ester, coconut oil fatty acid diethanolamide,
Lauric acid monoethanolamide, alkanolamides such as fatty acid isopropanolamide, polyoxyethylene propylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene fatty acid amide, sucrose fatty acid ester, polyoxyethylene nonyl phenyl formaldehyde condensate, Examples thereof include alkylethoxydimethylamine oxide and trioleyl phosphoric acid.

Examples of the anionic surfactant include, for example,
Fatty acid soaps such as sodium laurate and sodium palmitate; higher alkyl sulfates such as sodium lauryl sulfate and potassium lauryl sulfate; alkyl ether sulfates such as polyoxyethylene lauryl sulfate triethanolamine and polyoxyethylene sodium lauryl sulfate; N-acyl sarcosine acids such as sodium lauroyl sarcosine, N-myristoyl-N-methyl taurine sodium, higher fatty acid amide sulfonates such as coconut oil fatty acid methyl tauride sodium, sodium lauryl methyl tauride sodium, polyoxyethylene oleyl ether phosphoric acid Sodium, phosphate salts such as sodium polyoxyethylene stearyl ether phosphate, sodium di-2-ethylhexylsulfosuccinate, monolauroyl Monosulfonates such as monoethanolamide sodium polyoxyethylene sodium sulfosuccinate, sodium lauryl polypropylene glycol sodium sulfosuccinate, alkylbenzene sulfonates such as sodium linear dodecylbenzenesulfonate, and linear ethanol dodecylbenzenesulfonate triethanolamine; mono-N-lauroylglutamic acid Sodium, N-acyl glutamic acid such as N-stearoyl glutamate, higher fatty acid ester sulfate such as hydrogenated coconut fatty acid sodium glycerin sulfate, polyoxyethylene alkyl ether carboxylate, α-olefin sulfonate, higher fatty acid ester Sulfonate, secondary alcohol sulfate, higher fatty acid alkylolamide sulfate, lauroyl monoethanol Sodium Amidokohaku acid, N- palmitoyl aspartate, ditriethanolamine, coconut oil fatty acid collagen hydrolyzate alkali salts.

Examples of the cationic surfactant include alkyltrimethylammonium salts such as stearyltrimethylammonium chloride and lauryltrimethylammonium chloride, dialkyldimethylammonium salts such as distearyldimethylammonium chloride, and poly (N, N 'chloride).
-Dimethyl-3,5, -methylenepiperidinium), alkylpyridinium salts such as cetylpyridinium chloride, alkyl quaternary ammonium salts, alkyldimethylbenzylammonium salts, alkylisoquinolinium salts, dialkylmorphonium salts, polyoxy Ethylene alkylamine, alkylamine salt, polyamine fatty acid derivative, amyl alcohol fatty acid derivative, benzalkonium chloride, benzethonium chloride, cationic polymer, acrylic acid β-
N-N-dimethyl-N-ethylammonioethyl vinylpyrrolidone chloride copolymer and the like.

Examples of the amphoteric surfactant include 2-undecyl-N, N, N,-(hydroxyethylcarboxymethyl) -2-imidazoline sodium and 2-cocoyl-2-imidazolinium hydroxide-1-carboxylate. Imidazoline amphoteric surfactants such as ethyloxy disodium salt; betaine such as 2-heptadecyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, lauryl dimethylaminoacetic acid betaine, alkyl betaine, amido betaine and sulfobetaine; Examples include an amphoteric surfactant.

As the humectant, for example, cholesteryl-
12-hydroxystearate, sodium lactate, dl
-Pyrrolidone carboxylate, urea, diglycerin ethylene oxide / propylene oxide adduct, and the like. Particularly, when an acidic mucopolysaccharide such as chondroitin sulfate or hyaluronic acid is blended, the whitening effect of alkoxysalicylic acid and / or a salt thereof. Has an enhancing effect on

Examples of the thickener include gum arabic,
Carrageenan, tragacanth gum, quince seed (quince), casein, sodium caseinate, dextrin, gelatin, sodium alginate, methylcellulose, ethylcellulose, carboxymethylcellulose,
Examples include hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, sodium polyacrylate, carboxyvinyl polymer, guar gum, xanthan gum, aluminum magnesium silicate, bentonite, hectorite and the like.

Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycerin,
Erythritol, trimethylolpropane, pentaerythritol, sorbitol, maltitol, diglycerin, polyethylene glycol and the like can be mentioned.

The higher alcohols include, for example, lauryl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, cetostearyl alcohol, monostearyl glycerin ether (batyl alcohol), lanolin alcohol, cholesterol, phytosterol, isostearyl alcohol, octyldodeca Knol and the like.

As the powder component, for example, talc, kaolin, mica, sericite (sericite), phlogopite, synthetic mica, magnesium carbonate, calcium carbonate, aluminum silicate, silica, zeolite, barium sulfate, calcined calcium sulfate ( Calcined gypsum), calcium phosphate, fluoroapatite, hydroxyapatite, ceramic powder, metal soap (zinc myristate, calcium palmitate, aluminum stearate, etc.), inorganic powders such as boron nitride, polyamide resin powder (nylon powder), polyethylene powder, Polymethyl methacrylate powder, polystyrene powder, copolymer resin powder of styrene and acrylic acid,
Organic powders such as polymethysilsesquioxane powder and cellulose powder, titanium dioxide, zinc oxide, iron oxide (bengara), iron titanate, yellow iron oxide, black iron oxide, carbon black, lower titanium oxide, mango violet, Inorganic pigments such as cobalt violet, chromium oxide, ultramarine, navy blue, etc.
Titanium oxide coated mica, titanium oxide coated bismuth oxychloride, colored titanium oxide coated mica, bismuth oxychloride, pearl pigments such as fish scale foil, metal powder pigments such as aluminum powder, red No. 201,
Red No. 202, Orange No. 203, Yellow No. 205, Yellow 40
Organic pigments such as No. 1, Blue No. 404, Red No. 3, Yellow No. 4
No. 3, Green No. 3, Blue No. 1, etc., zirconium, barium,
Organic pigments such as aluminum lake, chlorophyll, β-
And natural pigments such as carotene. As the synthetic resin emulsion, for example, acrylic resin emulsion,
Examples include a polyvinyl acetate resin emulsion.

As amino acids, glycine, leucine,
Examples include phenylalanine, tyrosine, aspartic acid, glutamic acid, sodium glutamate, arginine, histidine, lysine, cystine, cysteine, acyl sarcosine sodium (lauroyl sarcosine sodium), acyl glutamate, glutathione, and pyrrolidone carboxylic acid.

Examples of the organic amine include monoethanolamine, diethanolamine, triethanolamine, morpholine, triisopropanolamine, 2-amino-2-methyl-1,3-propanediol, and 2-amino-2-methyl-1. -Propanol and the like.

In addition, sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannin, verapamil, tranexamic acid and derivatives thereof, and licorice extract Products, glabridine, hot water extract of fire thorn fruit, various crude drugs, tocopherol acetate,
Drugs such as glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate,
Other whitening agents such as ascorbic acid glucoside, arbutin, kojic acid, glucose, fructose, mannose,
Saccharides such as sucrose and trehalose can also be appropriately blended. Particularly, when vitamin E esters such as tocopherol acetate are blended, the whitening effect of alkoxysalicylic acid and / or its salt is enhanced.

[0032]

(Preparation of reagent)

1) L-DOPA solution 10 mg of L-DOPA (special reagent grade) was dissolved at the time of use with 20 ml of the phosphate buffer of 3) to obtain a 0.05% L-DOPA solution. 2) Tyrosinase solution Mushroom tyrosinase (50,000 units / 1)
1.7 mg protein (manufactured by SIGMA) 11.7
mg in 25 ml of distilled water and 2,000 units / m
1 solution. 3) 0.1 M phosphate buffer The pH was adjusted to 6.8 by a conventional method.

[Preparation of sample solution] Each sample shown in Table 1 was diluted with ethanol to three levels of concentration to obtain a sample solution. [Test method] Tyrosinase activity was measured by Pomeran.
The method of tz was slightly modified, and L-DOP was used as a substrate.
A (reagent grade) was used to measure the absorbance at 475 nm based on the reaction product, dopachrome. That is, 1.0 ml of the L-DOPA solution and 1.8 ml of the phosphate buffer were taken, and 0.1 ml of the sample solution was added thereto. Next, 0.1 ml of a tyrosinase solution was added and mixed, and reacted at room temperature for 1.5 minutes. Spectrophotometer (Spectrophotometer 220 manufactured by Hitachi, Ltd.)
A) was used to measure the absorbance at 475 nm, and the value was taken as T. L-DOPA as a reagent blank
1.0 ml of distilled water was used instead of the solution, 1.8 ml of the phosphate buffer and 0.1 ml of the sample solution were added and mixed, and the same operation was performed to measure the absorbance. did.

The control was L-DOPA solution 1.0
0.1 ml of ethanol instead of the sample solution was added to 0.1 ml of the phosphate buffer and 1.8 ml of the phosphate buffer. The control reagent blank is L-DOP
1.0 ml of distilled water was used in place of the solution A, and 1.8 ml of a phosphate buffer and 0.1 ml of ethanol were added thereto.
Hereinafter, similarly, the value was set to C ′. The tyrosinase activity inhibition rate at each sample concentration was calculated by the following equation, and the horizontal axis of the semilogarithmic graph was the sample concentration (log) and the vertical axis was the activity inhibition rate. From this graph, the tyrosinase activity 50% inhibition concentration (ID 50) I asked. In addition, T, T ', C, and C' were measured three times, and the average value of each was used.

Tyrosinase activity inhibition rate (%) = 100 × [1
− (TT ′) / (CC ′)]

(2) Whitening Effect Test [Preparation of Sample] Using each sample, a lotion was prepared according to the following formulation. The preparation was carried out by preparing an alcohol phase and an aqueous phase according to a conventional method and then solubilizing the same. (Alcohol phase) 95% ethanol 55.0 wt% Polyoxyethylene (40 mol) hydrogenated castor oil 2.0 Sample 1.0 (Aqueous phase) Dipropylene glycol 5.0 Sodium hexametaphosphate Appropriate amount Ion-exchanged water balance

[Test Method] Ten subjects were exposed to the sunlight in summer for 4 hours (2 hours a day for 2 days). Each lotion was applied to the skin once in the morning and evening for 8 weeks. After the application, whether or not there was an inhibitory effect on pigmentation induced by ultraviolet irradiation was examined, and the degree thereof was evaluated based on the following criteria. ◎: Eight or more panelists (80%
○: Excellent or effective panelists 5-7 (50%
△: Less than 70%) Δ: 3-4 panelists who were extremely effective or effective (30%
×: Less than 50%) ×: Not more than 2 panelists who were extremely effective or effective (30%
Less than)

Examples 1 to 4 and Comparative Examples a to d (Firoshi
Nase activity inhibitory action and whitening effect) First, in order to alkoxysalicylic acid of the present invention inhibit the activity of essential tyrosinase melanogenesis, to make sure that actually have a whitening effect on human skin, Table 1
The tyrosinase activity inhibition test and the whitening effect test using a human body panel were performed using the samples shown in FIG. As a result, as is clear from Table 1, the alkoxysalicylic acids of the present invention all have a tyrosinase inhibitory action,
It was confirmed that methoxysalicylic acid and 5-methoxysalicylic acid inhibited the activity even at extremely low concentrations of 1.0 mM and 4.5 mM, respectively.

On the other hand, in the whitening effect test, the panelists who judged that the effect was remarkable or effective in all of the lotions of Examples 1 to 4 accounted for 80% or more of the whole.
The whitening effect was clearly superior to any of the lotions of Comparative Examples a to d. Ascorbic acid of Comparative Example c had an extremely high tyrosinase activity inhibitory action, but was not easily absorbed into the skin because of its water solubility, and the whitening effect on the human body panel tended to be slightly lower.

The hydroquinone of Comparative Example a and the gentisic acid of Comparative Example b are known to have side effects, and have a problem in safety. In contrast, Examples 1 to
With the alkoxysalicylic acid of No. 4, no abnormalities in the skin such as erythema, eczema, and swelling and no side effects such as pain and itch were recognized in any group, and the safety was very high.

Although the data is omitted, the alkoxysalicylic acid and / or its salt of the present invention other than those used in the present Example also have the same tyrosinase activity inhibitory activity and excellent whitening effect, indicating that the safety is high. It was very expensive. For example, in the case of a lotion containing potassium 4-methoxysalicylate, 80% or more of the panelists were markedly effective or effective in the whitening effect test.
From the above, it was confirmed that the external preparation for skin of the present invention is a highly safe external preparation for skin, while preventing melanin pigment deposition and exerting a remarkable whitening effect by inhibiting tyrosinase activity.

[0041]

[Table 1] ID Sample ID 50 (mM) Whitening effect Safety ── ─────────────────────────────── Example 1 3-methoxysalicylic acid 21.0 ◎ Example 2 4-methoxysalicylic acid 1.0 ◎ ○ Example 3 5-methoxysalicylic acid 4.5 ◎ ○ Example 4 4-ethoxysalicylic acid 2.0 ◎ ○ ───────────────────────────── ──── Comparative Example a Hydroquinone 4.2 △ × Comparative Example b Gentisic acid 13.6 △ △ Comparative Example c Ascorbic acid 0.3 ○ ○ Comparative Example d No additive − × − ─────────────── ───────────────────

Examples 5 to 13 and Comparative Example e (whitening effect)
Next, the enhancing effect of various additives on the whitening effect of the alkoxysalicylic acid and / or salt thereof of the present invention was examined. First, a whitening effect test was performed using 3-methoxysalicylic acid as alkoxysalicylic acid and sodium hyaluronate as acidic mucopolysaccharide. The lotion for the test was prepared by adding 0.5% by weight of 3-methoxysalicylic acid as a sample in the alcohol phase and sodium hyaluronate in the aqueous phase in the formulation of the lotion for the whitening effect test.
Was prepared so as to have a concentration shown in Table 1 below, and used for the test.

As a result, as is apparent from Table 2, 3-
When 0.01% or more of sodium hyaluronate was added to 0.5% of methoxysalicylic acid, the whitening effect was clearly improved as compared with the case where no sodium hyaluronate was added. However, when sodium hyaluronate is added in an amount of 10% or more, not only the lotion becomes sticky, but the function at the time of use deteriorates, and problems such as poor handling at the time of preparation of the lotion arise. Therefore, the compounding amount of sodium hyaluronate is
It is preferably 0.01 to 10% by weight, more preferably 0.01 to 3% by weight, based on the total amount of the external preparation for skin.

In this example, 3-methoxysalicylic acid was used, but sodium hyaluronate also has a whitening effect enhancing effect on other alkoxysalicylic acids and / or salts thereof according to the present invention. In addition, other acidic mucopolysaccharides such as sodium chondroitin sulfate also showed a whitening effect enhancing effect as in the case of sodium hyaluronate.

[0045]

[Table 2] Sample Amount (% by weight) Comparative Example e Example 5 Example 6 Example 7 Example 8 Example 9メ ト キ シ 3-methoxysalicylic acid 0.5 0.5 0.5 0.5 0.5 0.5 Sodium hyaluronate 0.0 0.01 0.1 0.5 3.0 10.0 ────────────────────────── ────────── [Effect] Whitening effect ○ ◎ ◎ ◎ ◎ ◎ Sensory / usability ◎ ◎ ◎ ◎ ○ × ─────────────────── ─────────────────

Furthermore, as a result of examining the tocopherol acetate, methylparaben, ethylparaben and disodium ethylenediaminetetraacetate shown in Examples 10 to 13 of Table 3, as shown in Table 3, it was remarkable in all Examples. A whitening effect enhancing effect was observed. Example 10
In Examples 13 to 13, 3-methoxysalicylic acid was used, but the whitening effect was similarly enhanced with respect to other alkoxysalicylic acids and / or salts thereof according to the present invention.

Vitamin E other than Examples 10 to 13
Esters, paraaminobenzoic esters, and alkylenediamine carboxylic acid derivatives also had a whitening enhancing effect on the alkoxysalicylic acid and / or salt thereof of the present invention. The amounts of these vitamin E esters and / or paraaminobenzoic acid esters and / or alkylenediamine carboxylic acid derivatives are as follows:
It was preferably 0.01 to 3% by weight, more preferably 0.05 to 0.3% by weight, based on the total amount of the external preparation for skin. When the amount was 0.01% by weight or less, the whitening effect was not enhanced, and even when added in an amount exceeding 3% by weight, no enhancement of the whitening effect commensurate with the increased amount was observed.

[0048]

[Table 3] ──────────────────────────────────── Sample Amount in lotion (% by weight) Comparative Example e Example 10 Example 11 Example 12 Example 13 ── 3-methoxysalicylic acid 0.5 0.5 0.5 0.5 0.5 Tocopherol acetate 0.0 0.5 0.0 0.0 0.0 Methyl paraben 0.0 0.0 0.5 0.0 0.0 Ethyl paraben 0.0 0.0 0.0 0.5 0.0 Ethylenediaminetetraacetic acid 0.0 0.0 0.0 0.0 0.5 Disodium salt ──────── ──────────────────────────── Whitening effect ○ ◎ ◎ ◎ ◎ ─────────────── ─────────────────────

The following skin external preparations of Examples 14 to 28 were prepared by the respective methods, and subjected to a whitening effect test in the same manner as in Examples 1 to 4. All the skin external preparations showed excellent whitening effects. In addition, no abnormality was found in the skin, and it was a highly safe external preparation for skin. In addition, in the following prescriptions, the compounding amounts are all% by weight.

Example 14 Cream A cream was prepared according to the following formulation. The preparation method is that propylene glycol, caustic potassium and ethylenediaminetetraacetic acid tetrasodium salt are added to ion-exchanged water and dissolved,
Maintained at 70 ° C. (aqueous phase). The other components are mixed and dissolved by heating and maintained at 70 ° C (oil phase). The oil phase is gradually added to the aqueous phase, pre-emulsification is performed at 70 ° C, and the mixture is uniformly emulsified by a homomixer. While cooling to 30 ° C. Stearic acid 6.0 Cetostearyl alcohol 3.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 4-Butoxysalicylic acid 15.0 Caustic potash 0.2 Ethylenediaminetetraacetic acid tetrasodium salt 0.01 Tocopherol acetate 0.1 butyl paraben qs perfume qs deionized water balance

Example 15 Cream A cream was prepared according to the following formulation. The preparation method was as follows: propylene glycol and disodium ethylenediaminetetraacetate were added to ion-exchanged water and dissolved, and kept at 70 ° C. (aqueous phase). Mix and heat and melt other ingredients 7
Keep at 0 ° C (oil phase), gradually add oil phase to water phase and add 70 ° C
After pre-emulsification, the mixture was uniformly emulsified by a homomixer, and then cooled to 30 ° C. while stirring well. Stearic acid 5.0 Sorbitan monostearate 2.5 Polyoxyethylene (20 mol) Sorbitan monostearate 1.5 Propylene glycol 10.0 3-Isobutoxysalicylic acid 4.0 Glycerin trioctanoate 10.0 Squalene 5.0 Octyl paradimethylaminobenzoate 3.0 Ethylenediaminetetraacetic acid disodium salt 0.01 Ethylparaben 0.3 Perfume Appropriate amount Deionized water balance

Example 16 Cream A cream was prepared according to the following formulation in the same manner as in Example 15. Stearyl alcohol 7.5 Stearic acid 1.5 Hydrogenated lanolin 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 mol) cetyl ether 3.0 Glycerin monostearate 2.0 Propylene glycol 5.0 Sodium hyaluronate 0.1 Octylcinnamate 4.0 4-Methoxysalicylic acid 3.0 Ethylenediaminetetraacetic acid disodium salt 0.03 Ethylparaben 0.3 Perfume Appropriate amount Deionized water residue

Example 17 Cream A cream was prepared in the same manner as in Example 15 according to the following formulation. Stearic acid 6.5 Sorbitan monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monostearate 1.5 Propylene glycol 10.0 5-Ethoxysalicylic acid 8.5 Glycerin trioctanoate 10.0 Squalene 5 0.0 Sodium hyaluronate 1.0 Trisodium ethylenediaminetetraacetate 0.01 Glucose 0.5 Ethylparaben 0.3 Perfume Appropriate amount Deionized water balance

Example 18 Cream A cream was prepared according to the following formulation in the same manner as in Example 15. Stearyl alcohol 5.5 Stearic acid 2.5 Hydrogenated lanolin 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 mol) cetyl ether 3.0 Glycerin monostearate 2.0 Propylene glycol 5.0 5-Methoxysalicylic acid 4.0 Glycerin 5.0 Sodium bisulfite 0.03 Ethylparaben 0.3 Perfume Appropriate amount Ion-exchanged water balance

Example 19 Cream A cream was prepared according to the following formulation in the same manner as in Example 15. Stearyl alcohol 5.0 Stearic acid 2.5 Hydrogenated lanolin 2.5 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 mol) cetyl ether 3.0 Glycerin monostearate 2.0 Propylene glycol 7.0 Sodium L-ascorbate 0.5 3-Methoxysalicylic acid 0.8 Sodium bisulfite 0.03 Ethylparaben 0.3 Perfume Appropriate amount Ion-exchanged water balance

Example 20 Cream A cream was prepared in the same manner as in Example 15 according to the following formulation. Stearyl alcohol 6.0 Stearic acid 3.0 Hydrogenated lanolin 2.0 Squalane 5.0 2-Octyldodecyl alcohol 6.0 Polyoxyethylene (25 mol) cetyl ether 3.0 Glycerin monostearate 2.0 Propylene glycol 5.0 5-Propoxysalicylic acid 0.05 Vitamin A palmitate 0.3 Sodium bisulfite 0.03 Ethyl paraben 0.3 Perfume Appropriate amount Ion-exchanged water balance

Example 21 Emulsion An emulsion was prepared according to the following formulation. The preparation method is to dissolve the carboxyvinyl polymer in a small amount of ion-exchanged water (A
Phase), polyethylene glycol in the remaining ion-exchanged water 1
500, triethanolamine and sodium sulfite were added, and the mixture was dissolved by heating and kept at 70 ° C (aqueous phase). Mix the other ingredients, heat and melt and maintain at 70 ° C (oil phase), add the oil phase to the aqueous phase, pre-emulsify, add phase A, emulsify uniformly with a homomixer, and stir well. Cooled to 30 ° C. Stearic acid 2.0 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 Sodium hyaluronate 0.0 05 4-Methoxysalicylic acid 2.0 Carboxyvinyl polymer 0.05 (Product name: Carbopol 941, BF Goodrich Chemical company) Sodium bisulfite 0.01 Ethylparaben 0.3 Perfume Appropriate amount Ion-exchanged water balance

Example 22 Emulsion An emulsion was prepared in the same manner as in Example 21 according to the following formulation. Stearic acid 2.5 Cetyl alcohol 1.0 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 3-Methoxysalicylic acid 5 0.0 Glycyrrhizic acid 0.5 Amino acid 0.3 Carboxyvinyl polymer 0.05 (Product name: Carbopol 941, BF Goodrich Chemical company) Sodium bisulfite 0.01 Ethyl paraben 0.3 Perfume Appropriate amount Ion-exchanged water balance

Example 23 Emulsion An emulsion was prepared according to the following formulation. The preparation method was such that the oil phase and the aqueous phase were each dissolved at 70 ° C., the oil phase was mixed with the aqueous phase, emulsified with an emulsifier, and then cooled to 30 ° C. with a heat exchanger. [Oil phase] Stearyl alcohol 2.0 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) cured Castor oil 2.0 Tocopherol acetate 0.05 5-Methoxysalicylic acid 2.0 Ethyl paraben 0.2 Butyl paraben 0.1 Appropriate amount of perfume [Aqueous phase] Glycerin 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.0 2 (Product name: Carbopol 941, BF Goodrich Chemical company) Potassium hydroxide 0.2 Sodium bisulfite 0.01 Purified water Residue

Example 24 Emulsion An emulsion was prepared in the same manner as in Example 23, according to the following formulation. [Oil phase] Stearyl alcohol 1.4 Squalene 2.0 Vaseline 2.5 Deodorized liquid lanolin 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.5 Glycerin monooleate 2.0 Polyoxyethylene (60 mol) cured Castor oil 1.5 Tocopherol acetate 0.05 4-butoxysalicylic acid 1.5 Ethylparaben 0.2 Butylparaben 0.1 Perfume Appropriate amount [Aqueous phase] Glycerin 5.0 Chondroitin sodium sulfate 0.01 Carboxyvinyl polymer 0.0 2 (Product name: Carbopol 941, BF Goodrich Chemical company) Potassium hydroxide 0.2 Citric acid 0.01 Sodium citrate 0.1 Purified water Residue

Example 25 Jelly A jelly was prepared according to the following formulation. The preparation method was such that Carbopol 940 was uniformly dissolved in ion-exchanged water (aqueous phase). Polyoxyethylene (50 mol) oleyl ether was dissolved in 95% ethanol and added to the aqueous phase. Further, other components were added, and finally, sodium hydroxide and L-arginine were added to neutralize and thicken. [Prescription] 95% ethanol 10.0 dipropylene glycol 12.5 polyoxyethylene (50 mol) oleyl ether 2.0 carboxyvinyl polymer 1.0 (trade name: Carbopol 940, BF Goodrich Chemical company) 4-propoxysalicylic acid 0.05 caustic soda 0.15 L-arginine 0.1 2-hydroxy-4-methoxybenzophenone 0.05 sodium sulfonate methylparaben 0.2 ethylenediaminetetraacetate trisodium 2 water 0.05 perfume appropriate amount ion exchange water residue Extra

Example 26 Serum A serum was prepared according to the following formulation. In the preparation method, the phase A and the phase C were each uniformly dissolved, and the phase A was added to the phase A to solubilize the same. Then, phase B was added and dissolved. [Phase A] 95% ethanol 10.0 Polyoxyethylene (20 mol) octyldodecanol 1.1 Methyl paraben 0.2 Pantothenyl ethyl ether 0.1 4-Methoxysalicylic acid 0.05 [Phase B] Potassium hydroxide 0. 1 [C phase] Glycerin 5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 (trade name: Carbopol 940, BF Goodrich Chemical company) Purified water residue

Example 27 Pack A pack was prepared according to the following recipe. The preparation method is A
The phase, phase B and phase C were uniformly dissolved, respectively, and phase B was added to phase A for solubilization, and then this was added to phase C and filled. [A phase] Dipropylene glycol 6.0 Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 [Phase B] 3-methoxysalicylic acid 1.3 4-methoxysalicylic acid 1.5 5-methoxysalicylic acid 0.7 Olive oil 5 2.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume Appropriate amount [Phase C] Polyvinyl alcohol (degree of saponification 90, degree of polymerization 2,000) 13.0 Ethanol 7.0 Sodium bisulfite 0.03 Purified water Residue

Example 24 Pack containing powder A pack containing powder was prepared according to the following formulation. The preparation method is to uniformly dissolve the aqueous phase and alcohol phase at room temperature,
The alcohol phase was added to the aqueous phase and mixed uniformly. [Alcohol phase] 95% ethanol 10.0 Propylene glycol 5.0 4-Methoxysalicylic acid 5.0 4-Ethoxysalicylic acid 5.0 Perfume Appropriate amount Coloring material Appropriate amount [Aqueous phase] Zinc flower 25.0 Kaolin 20.0 Glycerin 5.0 Methyl paraben 0.2 Deionized water residue

[0065]

The skin external preparation of the present invention has an excellent whitening effect of preventing or improving abnormal deposition of melanin pigments on the epidermis by inhibiting melanin production based on inhibition of alkoxysalicylic acid and / or its salt tyrosinase activity. And a skin external preparation highly safe for the skin. The whitening effect of the external preparation for skin of the present invention is enhanced by acidic mucopolysaccharides, vitamin E esters, paraaminobenzoic acid esters and alkylenediamine carboxylic acid derivatives.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location A61K 31/60 AED A61K 31/60 AED (72) Inventor Yuki Yamase Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture 1050 Shiseido Co., Ltd. 1st Research Center (72) Inventor Yoshihiro Yokokawa 1050 Nippacho, Kohoku-ku, Yokohama, Kanagawa Prefecture Shiseido Co., Ltd. 1st Research Center (72) Inventor Hisayuki Komazaki Kohoku-ku, Yokohama, Kanagawa 1050 Nippacho Shiseido Co., Ltd. First Research Center

Claims (7)

(57) [Claims] 1. An external preparation for skin, comprising one or more of alkoxysalicylic acid represented by the general formula (A) and / or a salt thereof. General formula (A): (In the formula, R represents an alkoxy group.) 2. The external preparation for skin according to claim 1, wherein the alkoxy group is a methoxy group. 3. The external preparation for skin according to claim 1, wherein the alkoxy group is an ethoxy group. 4. The external preparation for skin according to claim 1, further comprising one or more acidic mucopolysaccharides. 5. The external preparation for skin according to claim 1, further comprising one or more vitamin E esters. 6. The external preparation for skin according to claim 1, further comprising one or more paraoxybenzoic acid esters. 7. The external preparation for skin according to claim 1, further comprising an alkylenediamine carboxylic acid derivative.