JPH08217662A - Skin preparation for external use - Google Patents

Abstract

PURPOSE: To obtain the subject preparation composed of a phenylglycine derivative having a specific structure and its salt, and excellent in beautifying effect such as prevention of spots, freckles, pigmentation into skin after sunburn, etc., with melanin production-suppressing effect and having excellent stability and high safety. CONSTITUTION: This preparation is composed of a phenylglycine derivative of the formula (X1 and X2 are each H, OH or methoxy; m and n are each a natura1 number; m+n=<=5; R1 , is carboxyl, alkoxycarbonyl, carbamoyl, etc.; R2 is H, an alkyl, benzoyl, etc.) and/or its salt. The compounding ratio of the compound is preferably 0.1-7wt.% based on the total weight of the preparation. Examples of the compound of the formula include L-p- hydroxyphenylglycine, 4-hydroxy-3-methoxy-D-phenylglycine, etc. Further, the external preparation is preferably formulated into a cream, an ointment, a gel, a lotion, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has a melanin production inhibitory effect, is excellent in skin whitening effects such as preventing pigmentation on the skin such as spots, freckles and after sunburn, and is stable and safe. Related to a high skin external preparation.

[0002]

BACKGROUND OF THE INVENTION Although there are some unclear points about the mechanism of skin stains, freckles, and pigmentation on the skin after sunburn, it is generally caused by hormonal abnormalities and ultraviolet ray stimulation from sunlight. It is believed that melanin pigment is formed, which is abnormally deposited in the skin.

[0003] For the treatment of such blemishes, freckles, and pigmentation on the skin after sunburn, a substance which suppresses 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, cysteine, etc. in the form of ointment, cream, lotion, etc.
Methods such as topical application are taken. In Europe and America, hydroquinone preparations are used as medicines. In addition, other various skin external preparations such as β-
Branched phenylalanine derivative (JP-A-6-32727) and α-branched tyrosine derivative (JP-A-6-1282).
No. 03), a phenylalaninol derivative, a tyrosinol derivative (JP-A-6-227958) and the like are known.

[0004]

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. This also has a problem in the safety (irritation and sensitization) of the substance itself, and therefore its use is generally limited.

In view of such circumstances, as a result of intensive studies, the present inventors have found that the phenylglycine derivative having a specific structure and its salt exhibit a whitening effect more than hydroquinone, and completed the present invention. Came to do.

[0006]

That is, the present invention is an external preparation for skin characterized by containing a phenylglycine derivative represented by the following general formula 2 and / or a salt thereof.

[0007]

Embedded image [In the formula, X ₁ and X ₂ represent a hydrogen atom, a hydroxyl group or a methoxy group, respectively, and m and n represent natural numbers.
+ N ≦ 5. R ₁ represents a carboxyl group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group or an alkylcarbamoyl group. R ₂ represents a hydrogen atom, an alkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, a benzyloxycarbonyl group, a benzoyl group, a substituted benzoyl group or a fluorenylmethyloxycarbonyl group. ]

The structure of the present invention will be described in detail below. The phenylglycine derivative and the salt thereof according to the present invention are known substances, and are synthesized by a conventional method using phenylglycine as a starting substance, or SIGMA, Aldri.
It can be easily obtained by a method such as purchasing a commercial product such as ch company.

If desired, the above-mentioned compounds of the present invention are inorganic acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, or acetic acid,
Organic acid salts such as lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid and p-toluenesulfonic acid,
Or sodium salt, potassium salt, ammonium salt,
Inorganic salts such as magnesium salt and calcium salt, monoethanolamine, dietanolamine, and triethanolamine
It may be an organic salt such as ruamine and dicyclohexylamine.

Specific examples of the substance names are L-p-hydroxyphenylglycine, D-p-hydroxyphenylglycine, N-benzyloxycarbonyl-Lp-hydroxyphenylglycine and N-benzyloxycarbonyl-D. -P-hydroxyphenylglycine, N-benzoyl-L-p-hydroxyphenylglycine, N-
Benzoyl-D-p-hydroxyphenylglycine, N
-(P-methoxybenzoyl) -Lp-hydroxyphenylglycine, N- (p-methoxybenzoyl) -D
-P-hydroxyphenylglycine, N- (p-hydroxybenzoyl) -Lp-hydroxyphenylglycine, N- (p-hydroxybenzoyl) -Dp-hydroxyphenylglycine, N-acetyl-Lp-hydroxy Phenylglycine, N-acetyl-Dp-hydroxyphenylglycine, N-acetyl-Lp-hydroxyphenylglycine ethyl ester, N-acetyl-Dp-hydroxyphenylglycine ethyl ester, N-acetyl-Lp -Hydroxyphenylglycinamide, N-acetyl-D-p-hydroxyphenylglycinamide, Lp-methoxyphenylglycine,
D-p-methoxyphenylglycine, L-p-methoxyphenylglycine hydrochloride, D-p-methoxyphenylglycine hydrochloride, 4-hydroxy-3-methoxy-L-phenylglycine, 4-hydroxy-3-methoxy-D −
Phenylglycine, L-p-hydroxyphenylglycine ethylamide, D-p-hydroxyphenylglycine ethylamide, N-tert-butoxycarbonyl-L
-P-hydroxyphenylglycine, N-tert-butoxycarbonyl-D-p-hydroxyphenylglycine, N-tert-butoxycarbonyl-Lp-methoxyphenylglycine, N-tert-butoxycarbonyl-Dp-methoxyphenyl Glycine, N-9-fluorenylmethyloxycarbonyl-Lp-methoxyphenylglycine, N-9-fluorenylmethyloxycarbonyl-Dp-methoxyphenylglycine, N-
9-fluorenylmethyloxycarbonyl-L-p-methoxyphenylglycine benzyl ester hydrochloride, N-
9-Fluorenylmethyloxycarbonyl-D-p-methoxyphenylglycine benzyl ester hydrochloride, L-
p-Hydroxyphenylglycine amide, D-p-hydroxyphenylglycine amide, L-p-hydroxyphenylglycine allyl ester p-toluenesulfonate, D-p-hydroxyphenylglycine allyl ester p-toluenesulfonate, L- p-Hydroxyphenylglycine benzyl ester p-toluenesulfonate, D-p-hydroxyphenylglycine benzyl ester p-toluenesulfonate, L-p-hydroxyphenylglycine ethyl ester, D-p-hydroxyphenylglycine ethyl ester, L-p-hydroxyphenylglycine ethyl ester hydrochloride, D-p
-Hydroxyphenylglycine ethyl ester hydrochloride,
L-p-hydroxyphenylglycine methyl ester,
Examples thereof include D-p-hydroxyphenylglycine methyl ester.

The skin external preparation of the present invention contains at least one kind of the phenylglycine derivative thus obtained and a salt thereof, and the compounding amount thereof is 0.00 based on the total amount of the skin external preparation.
It is 1 to 20% by weight, preferably 0.01 to 10% by weight, particularly preferably 0.1 to 7% by weight. If it is less than 0.001% by weight, the skin whitening effect is poor, and if it exceeds 20% by weight, the effect cannot be expected to increase.

The external preparation for skin of the present invention can be adjusted into various forms by conventional methods, but generally, cream, ointment, gel, lotion, emulsion, stick, pack, organic It is preferable that the solution form a solvent.

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, powder components, liquid oils and fats, solid oils and fats, waxes and hydrocarbons. , Higher fatty acids, higher alcohols, esters, silicones, anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, humectants, water-soluble polymer compounds, thickeners, film agents, ultraviolet rays Absorbents, sequestering agents, lower alcohols, polyhydric alcohols, sugars, amino acids, organic amines, synthetic resin emulsions, pH adjusting agents, skin nutrients, vitamins, antioxidants, antioxidant aids, fragrances, Water or the like can be appropriately added if necessary. Each of these components may be used alone or in combination of two or more.

As powder components, talc, carion, mica, sericite, muscovite, phlogopite, synthetic mica, phlogopite, biotite, lithia mica, permiculite,
Magnesium carbonate, calcium carbonate, aluminum silicate, barium silicate, calcium silicate, magnesium silicate, strontium silicate, tungstate metal salt, magnesium, silica, zeolite, barium sulfate, calcined calcium sulfate, (calculated gypsum), calcium phosphate , Fluorapatite, Hydroxyapatite, Ceramic powder, Metal soap (Zinc myristate, Calcium palmitate, Aluminum stearate), Inorganic powder such as boron nitride, Polyamide resin powder (Nylon powder), Polyethylene powder, Polymethylmethacrylate powder, Polystyrene powder, styrene-acrylic acid copolymer resin powder, benzoguanamine resin powder, polytetrafluoroethylene powder, organic powder such as cellulose powder, titanium dioxide, inorganic white such as zinc oxide Pigments, iron oxide (red iron oxide),
Inorganic red pigments such as iron titanate, inorganic brown pigments such as γ-iron oxide, yellow iron oxide, inorganic yellow pigments such as ocher black iron oxide, carbon black, inorganic black pigments such as low order titanium oxide, Inorganic purple pigments such as mango violet and cobalt violet, inorganic green pigments such as chromium oxide, chromium hydroxide and cobalt titanate, inorganic blue pigments such as ultramarine blue and navy blue, titanium oxide coated mica, titanium oxide coated bismuth oxychloride. , Titanium oxide coated talc, colored titanium oxide coated mica, bismuth oxychloride, pearl pigments such as fish scale foil, aluminum powder,
Metal powder pigments such as copper powder, Red No. 201, Red No. 202, Red No. 204, Red No. 205, Red 220
No., Red 226, Red 228, Red 405, Orange 203, Orange 204, Yellow 205, Yellow 401
And organic pigments such as Blue No. 404, Red No. 3, Red No. 104, Red No. 106, Red No. 227, Red No. 230
No., Red No. 401, Red No. 505, Orange No. 205, Yellow No. 4, Yellow No. 5, Yellow No. 202, Yellow No. 203, Green No. 3
No. 1, Blue No. 1 and other organic pigments such as zirconium, barium or aluminum lake, chlorophyll, and natural pigments such as β-caroline. However, the powder is not limited to the above components as long as it is a powder applicable to general cosmetics.

The liquid oils and fats include avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, persic oil, wheat germ oil, southern oil, castor oil, linseed oil. Oil, safflower oil, cottonseed oil, eno oil, soybean oil, peanut oil, teaseed oil, kaya oil, rice bran oil, cinnamon oil, Japanese kiri oil, jojoba oil, germ oil, triglycerin,
Examples thereof include glycerin trioctanoate and glycerin triisopalmitate.

Examples of solid fats and oils are cacao butter, coconut oil, horse fat, hardened coconut oil, palm oil, beef tallow, sheep fat, hardened beef tallow, palm kernel oil, pork fat, beef bone fat, sorghum kernel oil, hardened oil, Examples include beef tallow, mokuro, hydrogenated castor oil, and the like.

Examples of the waxes include beeswax, candelilla wax, cotton wax, carnauba wax, bayberry wax, ivota wax, spermaceti wax, montan wax, nuka wax, lanolin, capock wax, lanolin acetate, liquid lanolin, sugar cane wax, lanolin fatty acid isopropyl, hexyl laurate, and reduction. Examples thereof include lanolin, jojoba wax, hard lanolin, shellac wax, POE lanolin alcohol ether, POE lanolin alcohol acetate, POE cholesterol ether, lanolin fatty acid polyethylene glycol, and POE hydrogenated lanolin alcohol ether.

Examples of the hydrocarbon oil include liquid paraffin, ozokerite, squalene, pristane, paraffin, ceresin, squalene, petrolatum, microcrystalline wax and the like.

Examples of higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, 12-hydroxystearic acid, undecylenic acid, tall acid, isostearic acid, linoleic acid and linolein. Acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and the like.

Examples of higher alcohols include linear alcohols such as lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol and cetostearyl alcohol, monostearyl glycerin ether (batyl alcohol), 2-decyltetradecyl alcohol. Examples thereof include branched chain alcohols such as knoll, lanolin alcohol, cholesterol, phytosterol, hexyldodecanol, isostearyl alcohol, and octyldodecanol.

As synthetic ester oils, isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate,
Decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, 1
Cholesteryl 2-hydroxystearate, ethylene glycol di-2-ethylhexylate, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, glycerin di-2-heptylundecanoate , Trimethylolpropane tri-2-ethylhexylate, trimethylolpropane triisostearate, pentaneerythritol tetra-2-ethylhexylate, glycerin tri-2-ethylhexylate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, 2 -Ethylhexyl palmitate, Glycerin trimyristate, Glyceride tri-2-heptylundecanoate, Fatty acid methyl ester of castor oil, Oleic acid oil, Cetostearyl Cole, acetoglyceride, 2-heptylundecyl palmitate, diisobutyl adipate, N-lauroyl-L-glutamic acid-2-octyldodecyl ester, di-2-heptylundecyl adipate, ethyl laurate, di-2 sebacate -Ethylhexyl, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, diisopropyl sebacate, 2-ethylhexyl succinate,
Examples thereof include ethyl acetate, butyl acetate, amyl acetate, triethyl citrate and the like.

Examples of the silicone include chain polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, and methylhydrogenpolysiloxane, cyclic chains such as decamethylpolysiloxane, dodecamethylpolysiloxane, and tetramethyltetrahydrogenpolysiloxane. Examples thereof include polysiloxane, silicon resin having a three-dimensional network structure, and silicon rubber.

Examples of the anionic surfactant include a soap base, a fatty acid soap such as sodium laurate and sodium palmitate, a higher alkyl sulfate ester salt such as sodium lauryl sulfate and K lauryl sulfate,
POE lauryl sulfate triethanolamine, POE sodium lauryl sulfate and other alkyl ether sulfate salts,
N-acyl sarcosinic acid such as lauroyl sarcosine sodium, N-myristoyl-N-methyl taurine sodium,
Higher fatty acid amide sulfonates such as coconut oil fatty acid methyl tauride sodium, lauryl methyl tauride sodium, POE oleyl ether sodium phosphate, POE
Phosphoric acid ester salts such as stearyl ether phosphoric acid, di-2
-Sodium ethylhexyl sulfosuccinate, monolauroyl monoethanolamide sodium polyoxyethylene sulfosuccinate, sulfosuccinates such as sodium lauryl polypropylene glycol sulfosuccinate, sodium linear dodecylbenzenesulfonate, triethanolamine linear dodecylbenzenesulfonate, linear dodecylbenzenesulfone Alkylbenzene sulfonates such as acids, N-lauroyl glutamate monosodium, N-stearoyl glutamate disodium, N-myristoyl-L-monosodium N-acylglutamates such as monosodium glutamate, hydrogenated coconut oil fatty acids higher fatty acids such as sodium glycerin sulfate Ester Sulfate ester salt, sulfated oil such as funnel oil, POE alkyl ether carboxylic acid, PO
E Alkyl allyl ether carboxylate, α-olefin sulfonate, higher fatty acid ester sulfonate, secondary alcohol sulfate ester salt, higher fatty acid alkylolamide sulfate ester salt, lauroyl monoethanolamide sodium succinate, N-palmitoyl asparagine Examples thereof include acid ditriethanolamine and sodium caseinate.

Examples of the cationic surfactant include alkyl trimethyl ammonium salts such as stearyl trimethyl ammonium chloride and lauryl trimethyl ammonium chloride, distearyl dimethyl ammonium dialkyl dimethyl ammonium chloride, and poly (N, N'-dimethyl chloride).
-3,5-methylenepiperidinium), alkylpyridinium salts such as cetylpyridinium chloride, alkyl quaternary ammonium salts, alkyldimethylbenzylammonium salts, alkylisoquinolinium salts, dialkylmorphonium salts, POE alkylamines, alkyls Examples thereof include amine salts, polyamine fatty acid derivatives, amyl alcohol fatty acid derivatives, benzalkonium chloride and benzethonium chloride.

Examples of the amphoteric surfactant include 2-undecyl-N, N, N- (hydroxyethylcarboxymethyl) -2-
Imidazoline sodium, 2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc., imidazoline-based amphoteric surfactants, 2-heptadecyl-N-carboxymethyl-N-hydroxyethylimidazolinium Examples thereof include betaine-based surfactants such as betaine, lauryldimethylaminoacetic acid betaine, alkyl betaine, amidobetaine and sulfobetaine.

Examples of lipophilic nonionic surfactants include sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, Penta-2-ethylhexyl diglycerol sorbitan,
Sorbitan fatty acid esters such as tetra-2-ethylhexylate diglycerol sorbitan, monocotton seed oil fatty acid glycerin, glyceryl monoerucate, glyceryl sesquioleate, glyceryl monostearate, α, α'-glyceryl pyroglutamate oleate, glyceryl monostearate Examples thereof include glycerin polyglycerin fatty acid such as malic acid, propylene glycol fatty acid ester such as propylene glycol monostearate, hydrogenated castor oil derivative, and glycerin alkyl ether.

Examples of hydrophilic nonionic surfactants include POE sorbitan monooleate, POE-sorbitan monostearate, POE-sorbitan monooleate, POE-sorbitan tetraoleate, and other POE sorbitan fatty acid esters, POE- POE-sorbit fatty acid esters such as sorbit monolaurate, POE-sorbit monooleate, POE-sorbit pentaoleate, POE-sorbit monostearate, POE-glycerin monostearate, POE-glycerin monoisostearate, POE- POE glycerin fatty acid esters such as glycerin triisostearate, POE monooleate, POE distearate,
POE monodioleate, POE fatty acid esters such as ethylene glycol distearate, POE lauryl ether, POE oleyl ether, POE stearyl ether,
POE alkyl ethers such as POE behenyl ether, POE2-octyldodecyl ether, POE cholestanol ether, POE octylphenyl ether, POE nonylphenyl ether, POE dinonylphenyl ether, etc.
E Alkyl phenyl ethers, Pluronic types such as Bourronic, POE / POP cetyl ether, POE / PO
P2-decyl tetradecyl ether, POE / POP monobutyl ether, POE / POP hydrogenated lanolin, POE / POP alkyl ethers such as POE / POP glycerin ether, tetra POE / tetra POP ethylenediamine condensates such as Tetronic, POE castor POE hydrogenated castor oil, POE hydrogenated castor oil monoisostearate, POE hydrogenated castor oil triisostearate, POE hydrogenated castor oil monopyroglutamic acid monoisostearate diester, POE hydrogenated castor oil maleic acid, etc.POE castor oil hydrogenated castor Oil derivatives,
POE Beeswax lanolin derivatives such as sorbit beeswax, coconut oil fatty acid diethanolamide, lauric acid monoethanolamide, alkanolamides such as fatty acid isopropanolamide, POE propylene glycol fatty acid ester, POE alkylamine, POE fatty acid amide,
Examples thereof include sucrose fatty acid ester, POE nonylphenylformaldehyde condensate, alkylethoxydimethylamine oxide, trioleylphosphoric acid and the like.

Examples of moisturizers include polyethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, caronic acid, atelocollagen and cholesteryl.
-12-hydroxy stearate, sodium lactate, bile salt, dl-pyrrolidone carboxylate, short-chain soluble collagen, diglycerin (EO) PO adduct, Issai rose extract,
Examples include the extract of Periwinkle, Merrilot extract and the like.

Examples of natural water-soluble polymers include, for example, araavia gum, tragacanth gum, galactan, guar gum, carob gum, karaya gum, carrageenan, pectin, agar, quince seed (quince), arge colloid (cassius extract), starch (rice, corn, Potato, wheat), plant-based polymers such as glycyrrhizinate, microbial-based polymers such as xanthan gum, dextran, succinoglucan, and vullan, collagen,
Animal-based polymers such as casein, albumin and gelatin can be mentioned.

As the semi-synthetic water-soluble polymer, for example,
Starch-based polymers such as carboxymethyl starch and methyl hydroxypropyl starch, methyl cellulose, nitrocellulose, ethyl cellulose, methyl hydroxypropyl cellulose, hydroxyethyl cellulose, sodium cellulose sulfate, hydroxypropyl cellulose, sodium carboxymethyl cellulose (CMC), crystalline cellulose, cellulose powder Cellulosic polymers such as
Examples thereof include alginic acid-based polymers such as sodium alginate and propylene glycol alginate.

As the synthetic water-soluble polymer, for example, polyvinyl alcohol, polyvinyl methyl ether, polyvinylpyrrolidone, vinyl polymers such as carboxyvinyl polymer (Carbopol), polyethylene glycol 2
0,000, 4,000,000, 600,000 polyoxyethylene-based polymers, polyoxyethylene polyoxypropylene copolymer copolymer-based polymers, sodium polyacrylate, polyethyl acrylate, polyacrylamide and other acrylic polymers, polyethyleneimine, Examples include cationic polymers.

Examples of the inorganic water-soluble polymer include bentonite, silicic acid A1Mg (veegum), laponite, hectorite, and silicic acid anhydride.

Examples of the thickener include gum arabic, carrageenan, karaya gum, tragacanth gum, carob gum, quince seed (quince), casein, dextrin, gelatin, sodium pectate, sodium alginate, methyl cellulose, ethyl cellulose, C.
MC, hydroxyethyl cellulose, hydroxypropyl cellulose, PVA, PVM, PVP, sodium polyacrylate, carboxyvinyl polymer, locust bean gum, guar gum, tamarind gum, dialkyldimethylammonium sulfate cellulose, xanthan gum, magnesium aluminum silicate, bentonite,
Hectorite and the like can be mentioned.

As the ultraviolet absorber, para-aminobenzoic acid (hereinafter abbreviated as PABA), PABA monoglycerin ester, N, N-dipropoxy PABA ethyl ester, N, N-diethoxy PABA ethyl ester, N, N-dimethyl PABA ethyl ester , N, N-dimethyl PABA butyl ester, N, N-dimethyl
Benzoic acid type UV absorbers such as PABA tyl ester, anthranilate type UV absorbers such as homomenthyl-N-acetylanthranilate, amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol Salicylic acid-based UV absorbers such as phenyl salicylate, octyl cinnamate, ethyl
-4-isopropyl cinnamate, methyl-2,5-diisopropyl cinnamate, ethyl-2,4-diisopropyl cinnamate, methyl-2,4-diisopropyl cinnamate,
Propyl-p-methoxycinnamate, isopropyl-p-
Methoxycinnamate, isoamyl-p-methoxycinnamate, octyl-p-methoxycinnamate (2-ethylhexyl-p-methoxycinnamate), 2-ethoxyethyl-p-methoxycinnamate, cyclohexyl-p-methoxycinnamate, ethyl -α-cyano-β-phenyl cinnamate, 2-ethylhexyl-α-cyano-β-
Cinnamic acid-based UV absorbers such as phenylcinnamate, glyceryl mono-2-ethylhexanoyl-diparamethoxycinnamate, 2,4-dihydroxybenzophenone, 2,2'-
Dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,2 ', 4,4'-
Tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-
Methylbenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonate, 4-phenylbenzophenone, 2-ethylhexyl-4'-phenyl-benzophenone-2
-Carboxylate, 2-hydroxy-4-n-octoxybenzophenone, 4-hydroxy-3-carboxybenzophenone and other benzophenone-based UV absorbers, 3- (4'-methylbenzylidene) -d, 1-camphor, 3- Benzylidene-d, 1
-Camphor, urocanic acid, urocanic acid ethyl ester, 2-phenyl-5-methylbenzoxazole, 2,2'-
Hydroxy-5-methylphenylbenzotriazole, 2-
(2'-Hydroxy-5'-t-octylphenyl) benzotriazole, 2- (2'-hydroxy-5'-methylphenylbenzotriazole, dibenzalazine, dianisoylmethane, 4-
Methoxy-4′-t-butyldibenzoylmethane, 5- (3,3-dimethyl-2-norbornylidene) -3-pentan-2-one and the like can be mentioned. By adding various ultraviolet absorbing substances such as these ultraviolet absorbing agents and various plant extracts having an ultraviolet absorbing effect, a skin external preparation having both a sunburn preventing effect and a therapeutic effect can be obtained.

Examples of sequestering agents include 1-hydroxyethane-1,1-diphosphonic acid, 1-hydroxyethane-1,1-diphosphonic acid tetrasodium salt, edetate disodium, edetate trisodium and edetate. Tetrasodium, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, phosphoric acid, citric acid, ascorbic acid, succinic acid, edetic acid and the like can be mentioned.

Examples of the lower alcohol include methanol, ethanol, propanol, isopropanol, isobutyl alcohol, t-butyl alcohol and the like.

Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, tetramethylene glycol, 2,3-butylene glycol, Divalent alcohols such as pentamethylene glycol, 2-butene-1,4-diol, hexylene glycol and octylene glycol, trivalent alcohols such as glycerin, trimethylolpropane and 1,2,6-hexanetriol, Tetrahydric alcohols such as pentaerythritol, pentavalent alcohols such as xylitol, hexahydric alcohols such as sorbitol and mannitol, diethylene glycol, dipropylene glycol, triethylene glycol, polypropylene glycol, tetraethylene glycol, diglycerin, polyethylene glycol. Lumpur, triglycerol, tetraglycerol, polyhydric alcohol polymers poly glycerin, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monohexyl ether,
Dihydric alcohol alkyl ethers such as ethylene glycol mono 2-methylhexyl ether, ethylene glycol isoamyl ether, ethylene glycol benzyl ether, ethylene glycol isopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, diethylene glycol monomethyl ether , Diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol butyl ether, diethylene glycol methyl ethyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, Dihydric alcohol alkyl ethers such as ropylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, propylene glycol isopropyl ether, dipropylene glycol methyl ether, dipropylene glycol ethyl ether and dipropylene glycol butyl ether, ethylene glycol monomethyl ether Acetate, ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether acetate, ethylene glycol monophenyl ether acetate, ethylene glycol diadibate, ethylene glycol disuccinate, diethylene glycol monoethyl ether state, diethylene glycol monobutyl ether acetate , Dihydric alcohol ether esters such as propylene glycol monomethyl ether acetate, propylene glycol monoethyl ether acetate, propylene glycol monopropyl ether acetate, propylene glycol monophenyl ether acetate, etc., glycerin monoalkyl such as xyl alcohol, ceracyl alcohol, batyl alcohol, etc. Ether, sorbitol, maltitol, maltotriose, mannitol, sucrose, erythritol,
Glucose, fructose, starch-degrading sugar, maltose, xylitose, starch-degrading sugar Sugar alcohol such as reducing alcohol, Glysolid, tetrahydrofurfuryl alcohol, POE tetrahydrofurfuryl alcohol, POP butyl ether, POP POE butyl ether, tripolyoxypropylene glycerin ether , POP glycerin ether, POP glycerin ether phosphate, POP
Examples include POE pentane erythritol ether and the like.

Examples of the monosaccharide include tricarbon sugars such as D-glyceryl aldehyde and dihydroxyacetone, tetracarbon sugars such as D-erythrose, D-erythrulose, D-threose and erythritol, L-arabinose and D-xylose. L-lyxose, D-arabinose, D-ribose, D-ribulose,
Pentose sugars such as D-xylulose and L-xylulose, D-glucose, D-talose, D-busicose, D-galactose, D-
Fructose, L-galactose, L-mannose, D-tagatose and other hexoses, aldoheptose, heptulose and other heptasaccharides, octulose and other octose sugars, 2-deoxy-D-ribose, 6-deoxy-L-galactose , 6-deoxy-L-
Deoxy sugars such as mannose, D-glucosamine, D-galactosamine, sialic acid, aminouronic acid, amino sugars such as muramic acid, D-glucuronic acid, D-mannuronic acid, L-guluronic acid, D-galacturonic acid, L-iduron Examples thereof include uronic acid such as acid.

Examples of oligosaccharides include sucrose, guanthianose, umbelliferose, lactose, planteose, isoliknoses, α, α-trehalose,
Raffinose, lychnose, umbilicin, stachyose bell bass course, etc. may be mentioned.

Examples of polysaccharides include cellulose, quince seed, chondroitin sulfate, starch, galactan, dermatan sulfate, glycogen, gum arabic, heparan sulfate, hyaluronic acid, tragacanth gum, keratan sulfate, chondroitin, xanthan gum, mucoitin sulfate, guar gum, dextran. , Keratosulfate, locust bingham, succinoglucan, caronic acid and the like.

Examples of amino acids include neutral amino acids such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, tryptophan, cystine, cysteine, methionine, proline and hydroxyproline, and aspartic acid, glutamic acid, asparagine, glutamine and other acidic acids. Amino acids and basic amino acids such as arginine, histidine, lysine and hydroxylysine are mentioned. Examples of the amino acid derivative include sodium acyl sarcosine (sodium lauroyl sarcosine), acyl glutamate, sodium acyl β-alanine, glutathione, and pyrrolidone carboxylic acid.

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

Examples of the synthetic resin emulsion include acrylic resin emulsion, polyethyl acrylate emulsion, acrylic resin solution, polyacrylic alkyl ester emulsion, polyvinyl acetate resin emulsion and the like.

As the pH adjusting agent, lactic acid-sodium lactate,
Examples include buffering agents such as citric acid-sodium citrate.

As vitamins, vitamins A, B1 and
Examples include B2, B6, E and derivatives thereof, pantothenic acid and derivatives thereof, biotin and the like.

As the antioxidant, tocopherols,
Examples thereof include dibutylhydroxytoluene, butylhydroxyanisole and gallic acid esters.

Examples of the antioxidant aid include phosphoric acid, citric acid, ascorbic acid, maleic acid, malonic acid, succinic acid, fumaric acid, kephalin, hexametaphosphate, phytic acid, ethylenediaminetetraacetic acid and the like.

[0048]

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 1 (Test method) 8-methoxypsoralen (8-Metho)
xypsoralen) treated phototoxic pigmentation Weise
Using a Maple guinea pig, 50 μl of each sample was applied to the shaved back once a day in the range of about 4 cm 2 for 8 weeks, and the depigmenting effect of pigmentation and the pigmentation enhancing effect that appeared as a side effect were evaluated by a 4-point evaluation method. (+ Indicates decolorizing effect, − indicates side effect). One group consists of 5 animals, and the following Example 1 is used.
-5, each sample of Comparative Examples 1-4 was tested.

(Evaluation Method) Based on the criteria, the average evaluation point of 5 animals after 8 weeks was calculated for each sample. (Judgment Criteria) Depigmentation effect of pigmentation (Evaluation point 3): Pigmentation became almost inconspicuous (Evaluation point 2): Pigmentation became very light (Evaluation point 1): Pigmentation became lighter (Evaluation) Point 0): No change Pigmentation enhancing effect (side effect) (Evaluation point 0): No change (Evaluation point -1): Pigmentation slightly darkened (Evaluation point-2): Pigmentation thickened (Evaluation) Point-3): Pigmentation became very dark

Samples of Examples 1 to 5 and Comparative Examples 1 to 4 (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 ( Chemicals described in Table 1 below) 1.0 (Aqueous phase) Glycerin 5.0 Sodium hexametaphosphate Suitable amount Ion-exchanged water Residual (Production method) The aqueous phase and alcohol phase are solubilized after preparation.

[0052]

[Table 1]

As is clear from Table 2 below, 8-methoxypsoralen (8-methoxysorale)
n) Treated Phototoxic Pigmentation It was observed that the depigmenting effect of pigmentation using Weiser Maple guinea pigs was superior in the Examples as compared with the Comparative Examples.

[0054]

[Table 2]

(2) Whitening effect test 2 (Test method) The skin of the inner part of the upper arm of 90 test subjects exposed to sunlight in the summer for 4 hours (2 hours per day for 2 days) was exposed to sunlight. From 5 days after the day, each sample was applied once in the morning and evening for 8 weeks. The panel was divided into 10 groups per group into 9 groups, and the test was conducted on each sample of Examples 1 to 5 and Comparative Examples 1 to 4 described above.

(Evaluation method) The lightening effect after use was judged based on the following judgment criteria. (Judgment Criteria) Effectiveness: Pigmentation became almost inconspicuous Effectiveness: Pigmentation became very thin Moderately effective: Pigmentation was lightened Ineffectiveness: No change (Judgment) ◎: Excellent effect among subjects When the effective rate is 80% or more, ∘: Remarkably effective and effective rate among 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

As is clear from Table 3 below, the whitening effect after exposure to sunlight was greater in Example than in Comparative Example in that excessive melanin pigment was prevented from being deposited and blackening was prevented. Was approved.

[0058]

[Table 3]

(3) Whitening effect test 3 (Test method) Subject 18 suffering from dark blacks, stains, freckles, etc.
Targeting 0 people, each sample once in the morning and evening for 3 months,
It was applied to the face every day. The panel was divided into 20 groups per group into 9 groups, and the test was performed on each of the samples of Examples 1 to 5 and Comparative Examples 1 to 4 described above.

(Evaluation method) The lightening effect after 3 months was judged based on the following judgment criteria. (Judgment Criteria) Effectiveness: Pigmentation became almost inconspicuous Effectiveness: Pigmentation became very thin Moderately effective: Pigmentation was lightened Ineffectiveness: No change (Judgment) ◎: Excellent effect among subjects When the effective rate is 80% or more, ∘: Remarkably effective and effective rate among 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

As is clear from Table 4 below, it was recognized that the whitening effect on the color black, stains, freckles and the like was better in the Examples than in the Comparative Examples.

[0062]

[Table 4]

Example 6 Cream% by weight Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 D-p-methoxyphenylglycine hydrochloride 20.0 Caustic potassium 0.2 Sodium bisulfite 0.01 Preservative Adequate perfume Adequate ion Exchanged water Residual (manufacturing method) Propylene glycol and caustic potash are added to ion-exchanged water, dissolved and heated to 70 ° C. (aqueous 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 7 Cream wt% Stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 moles) Sorbitan monostearate 1.5 Propylene glycol 10.0 L-p-hydroxyphenylglycinamide 7.0 Glycerin trioctanoate 10.0 Squalene 5.0 Sodium bisulfite 0.01 Ethyl paraben 0.3 Fragrance Suitable amount Ion-exchanged water Residual (production method) Propylene glycol is added to ion-exchanged water, dissolved and heated to 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, preliminarily emulsified, uniformly emulsified with a homomixer, and then cooled to 30 ° C. with thorough stirring.

Example 8 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 Dp -Hydroxyphenylglycine benzyl ester p-toluenesulfonate 0.001 Perfume proper amount sodium bisulfite 0.03 ethylparaben 0.3 ion-exchanged water Residue (production method) Propylene glycol is added to ion-exchanged water to dissolve and 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 9 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 L-p-hydroxyphenylglycine ethyl Amide 10.0 Sodium hydrogen sulfite 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 10 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 Ethyl paraben 0.2 Butyl paraben 0.1 N-9-fluorenylmethyloxycarbonyl-L-p-hydroxyphenylglycine 1.0 N-tert-butoxycarbonyl-L-p-hydroxyphenylglycine 1.0 Perfume proper amount (water phase part) sodium bisulfite 0.01 Glycerin 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water Residual (production method) Dissolve the oil phase 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 11 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 N-Acetyl-L-p-hydroxyphenylglycine amide 1.0 D-p-Hydroxyphenylglycinamide 1.0 Methylparaben 0.2 Fragrance Suitable amount Ion-exchanged water Residual (production method) Carboxyvinyl polymer is uniformly dissolved in ion-exchanged water, while N-acetyl-L is added to 95% ethanol.
-P-hydroxyphenylglycinamide, D-p-hydroxyphenylglycinamide, 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 12 Serum Serum Weight% (Phase A) Ethanol (95%) 10.0 Polyoxyethylene (20 mol) Octyldodecanol 1.0 Methylparaben 0.15 Pantothenyl ethyl ether 0.1 Lp-hydroxyphenylglycine 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 Purified water Residual (production method) Phases A and C are uniformly dissolved, and A is added to phase C
Add phase and solubilize. Next, phase B is added and then filling is performed.

Example 13 Pack wt% (Phase A) Dipropylene glycol 5.0 Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (Phase B) Dp-hydroxyphenylglycine 1.0 Dp-hydroxyphenylglycine ethyl ester hydrochloric acid Salt 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 Residue (Process) Phase A, Phase B, Phase C Dissolve each of the
Phase B is added to the phase to solubilize it. Then, this is added to phase C and then filled.

The external preparations for skin obtained by the present invention were all found to be effective in the whitening effect test conducted in Examples 1 to 5.

[0072]

The external preparation for skin containing the phenylglycine derivative and / or its salt according to the present invention has a melanin production inhibitory effect and prevents pigmentation on the skin such as spots, freckles and after sunburn, and It is a novel external preparation for skin which is excellent in skin whitening effect such as improving and / or improving, stable, and highly safe.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Masayuki Asaike 7-5-5 Ginza, Chuo-ku, Tokyo (72) Inventor Yuki Shibata 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Shiseido Daiichi Research Co., Ltd. Inside the center (72) Inventor Rumiko Kaku 1050 Shiba, Shinba-cho, Kohoku-ku, Yokohama, Kanagawa Shiseido Daiichi Research Center (72) Tsuneo Suehiro 1050 Shinba-cho, Kohoku-ku, Yokohama, Kanagawa Shiseido Inside the Daiichi Research Center

Claims (1)

[Claims] 1. A skin external preparation containing at least one kind of a phenylglycine derivative represented by the following general formula 1 and / or a salt thereof. Embedded image [In the formula, X ₁ and X ₂ represent a hydrogen atom, a hydroxyl group or a methoxy group, respectively, and m and n represent natural numbers.
+ N ≦ 5. R ₁ represents a carboxyl group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group or an alkylcarbamoyl group. R ₂ represents a hydrogen atom, an alkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, a benzyloxycarbonyl group, a benzoyl group, a substituted benzoyl group or a fluorenylmethyloxycarbonyl group. ]