JP6752551B2 - Tyrosinase activity inhibitor and topical skin preparation - Google Patents

Description

The present invention relates to a tyrosinase activity inhibitor consisting of an α-lipoic acid derivative and ascorbic acids, and a skin external preparation containing the tyrosinase activity inhibitor.

α-Lipoic acid (also known as thioctic acid or 6,8-dithiooctanoic acid) is an important coenzyme that is abundant in mitochondria and has antioxidant capacity, so it can be used for various pathological conditions due to oxidative stress. It is attracting attention as a therapeutic drug. In addition, reduced dimercaptooctanoic acid has the effect of reducing and regenerating oxidized glutathione, vitamin C, and the like. Focusing on the antioxidant capacity of α-lipoic acid, studies on using α-lipoic acid as a raw material for pharmaceuticals and cosmetics have been conventionally conducted. For example, in Patent Document 1, a metal chelate compound of α-lipoyl amino acid (an acid amide formed by α-lipoic acid and an amino acid) or a pharmacologically acceptable salt thereof is used as an enzyme involved in the production of melanin. It has the effect of inhibiting the activity of known tyrosinase and the activity of elastase, which is an enzyme that decomposes elastin present in skin tissues, and is a preventive / therapeutic agent for skin stains, buckwheat, and sunburn. It is described that it is useful as a whitening agent, a skin-beautifying agent, an anti-wrinkle agent, and the like.

Patent Document 2 states that an unchelated α-lipoyl amino acid or a pharmacologically acceptable salt thereof has an elastase inhibitory effect and a melanin production inhibitory effect, and for skin beautification containing the same. , Skin external preparations suitable for whitening, sun protection / treatment, etc. are described (hereinafter, α-lipoyl amino acids and metal chelate compounds thereof described in Patent Documents 1 and 2 and their pharmacology. The acceptable salts are collectively abbreviated as α-lipoic acid derivative). Further, Patent Document 3 describes that a metal chelate compound of α-lipoyl amino acid has an effect of eliminating melanin pigment aggregation (stains, freckles, moles) generated on the skin. Among these α-lipoic acid derivatives, the α-lipoic acid derivative described in Patent Document 1 has a particularly excellent ability to inhibit tyrosinase activity, but in recent cosmetics, it has a higher tyrosinase activity. The development of a material having an inhibitory ability is desired.

On the other hand, ascorbic acid is also widely known as an antioxidant. Ascorbic acid has optical isomers, and the L form is known as vitamin C and is involved in various redox reactions in the living body. In the field of cosmetics, it is blended in many products as ascorbic acid and its derivatives or salts thereof, and in particular, there are many proposals to blend it in whitening cosmetics for the purpose of improving dark skin, age spots, freckles, etc. Can be seen.

In addition, attempts to use α-lipoic acid and ascorbic acid in combination have been conventionally known. For example, Patent Document 4 proposes a drug containing lipoic acid compounds such as α-lipoic acid and dihydrolipoic acid and vitamins, and specific examples of vitamins include vitamin A, vitamin B1, and vitamin B6. Vitamin C is also listed along with vitamin B12 and vitamin E (see claim 2). It is described that ampoules and tablets containing equal amounts of α-lipoic acid and vitamin C (L-ascorbic acid) were prepared (see Examples 3 and 4). However, this patent document does not disclose anything about combining α-lipoic acid and vitamin C to make a cosmetic.

Patent Document 5 proposes a skin external preparation containing a lipoic acid compound and a compound selected from vitamin A, carotenoids, vitamin B6, vitamin C, etc., and eliminates reactive oxygen species by a combination thereof. It is described that the action of the skin is synergistically improved, and effective rough skin and skin aging symptoms can be improved and a whitening action can be exerted (see paragraph 0006). In the examples of the patent document, the skin is rough in both the system containing lipoic acid and ascorbic acid (Example 1) and the system containing dihydrolipoic acid and retinol palmitate (vitamin A derivative) (Example 4). Symptoms and pigmentation have been reported to be improved (see Table 7). However, as is clear from the description of the comparative example described later, the external preparation for skin described in the patent document does not necessarily have a sufficient ability to inhibit tyrosinase activity, and further improvement has been desired. ..

International Publication No. 2002/076935 Japanese Unexamined Patent Publication No. 2003-286168 International Publication No. 2004/024139 Japanese Unexamined Patent Publication No. 6-135832 Japanese Unexamined Patent Publication No. 10-007541

As a result of diligent studies under such background technology, the present inventors, when a specific α-lipoic acid derivative and a specific ascorbic acid are used in combination, are far more than when each is used alone. We have found that it exerts an excellent tyrosinase activity inhibitory action, and have completed the present invention.

A main object of the present invention is to provide a tyrosinase activity inhibitor having a highly excellent tyrosinase activity inhibitory ability, and another object is a whitening agent capable of suppressing the activity of tyrosinase contained in the skin. The purpose is to provide a skin external preparation useful as such.

Such an object of the present invention is achieved by using a specific α-lipoyl amino acid metal chelate compound or a pharmacologically acceptable salt thereof in combination with a specific ascorbic acid as a tyrosinase activity inhibitor.

Thus, according to the present invention, the first invention is selected from histidine dithiooctanamide (Na / zinc) (A), ascorbic acid, ascorbic acid glucoside, ascorbic acid phosphoric acid monoester, and alkali metal salts thereof. A tyrosinase activity inhibitor consisting of one or a combination of two or more ascorbic acids (B) is provided. In addition, as a second invention, one or two selected from histidine dithiooctanamide (Na / zinc) (A), ascorbic acid, ascorbic acid glucoside, ascorbic acid phosphoric acid monoester, and alkali metal salts thereof. An external preparation for skin containing the above ascorbic acids (B) is provided.

According to the present invention, a tyrosinase activity inhibitor having an excellent tyrosinase activity inhibitory ability can be obtained by using a specific α-lipoic acid derivative and a specific ascorbic acid in combination. Further, by blending a specific α-lipoic acid derivative and a specific ascorbic acid as active ingredients, the tyrosinase activity can be effectively suppressed, and a skin external preparation having an excellent whitening effect can be prepared.

Hereinafter, the present invention will be described in detail.
<Tyrosinase activity inhibitor>
The tyrosinase activity inhibitor of the present invention is one or 2 selected from histidine dithiooctanamide (Na / zinc) (A), ascorbic acid, ascorbic acid glucoside, ascorbic acid phosphoric acid monoester, and alkali metal salts thereof. It is a combination of ascorbic acids (B) of more than one species. Both components may be mixed in advance and used as a composition, but each component may be stored separately and may be separately blended when preparing a target product such as an external preparation for skin.

<Α-lipoic acid derivative>
The tyrosinase activity inhibitor of the present invention uses histidine dithiooctanamide (Na / zinc) as a main active ingredient. Histidine dithiooctanamide (Na / zinc) is a sodium salt of a chelate compound in which dithiooctanoic acid, which is an α-lipoic acid, and histidine, which is an amino acid, are amide-bonded and zinc is chelated.

Histidine dithiooctanamide (Na / zinc) is monohydrate, dihydrate, 1/2 hydrate, 1/3 hydrate, 1/4 hydrate, 2/3 hydrate, It can also be used as a 3/2 hydrate or a 6/5 hydrate.

Heat scan cytidine dithio octa cyanamide (Na / zinc) is there is record of use as a cosmetic raw material, preferably used as compound safety has been confirmed. As the histidine dithiooctanamide (Na / zinc), a commercially available product such as “DM-His. Zn” manufactured by Oga Research Co., Ltd. can be used.

A metal chelate compound of α-lipoyl amino acid or a pharmacologically acceptable salt thereof can be obtained by synthesizing an intermediate α-lipoyl amino acid and reducing it with a metal and an acid.

α-Lipoyl amino acids are usually protected by esterifying the carboxyl group, which is the acidic group of the amino acid, and then reacted with α-lipoic acid using a dehydration condensing agent to form an acid amide, which is finally saponified. Although it is common, it can be obtained in a higher yield by using the mixed acid anhydride method. More specifically, α-lipoic acid is first dissolved in an organic solvent (eg, chloroform, tetrahydrofuran, acetonitrile, etc.), and -15 in the presence of tertiary amines (triethylamine, tributylamine, N-methylmorpholin, etc.). Reacting a halogenated carbonate (ethyl chlorocarbonate, butyl chlorocarbonate, etc.) and a mixed acid anhydride reagent (isobutyloxycarbonyl chloride, diethylacetyl chloride, trimethylacetyl chloride, etc.) at ° C to -5 ° C to produce α-lipoic acid. Synthesize mixed acid anhydride. The reaction time at this time is about 1 to 2 minutes to several tens of minutes.

Next, in the presence of a base (sodium hydroxide, potassium hydroxide, triethylamine, tributylamine, or other tertiary amine), amino acids dissolved in a solvent such as alcohol, water, or a mixture thereof are added, and α-lipoic acid is mixed. After reacting with acid anhydride, it can be recrystallized from a suitable solvent such as water or alcohol to obtain α-lipoyl amino acids in high yield.

Then, by reducing the α- Ripoiruamino acid zinc and acid, through dihydro body, to obtain a metal chelate compound. Examples of the acid used in the reduction reaction of α-lipoyl amino acid include inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as acetic acid and citric acid. The metal used in the reduction reaction, for example, etc. Zinc dust and the like. In the case of a zinc chelate compound, it is considered that two SH groups (mercapto groups) in the molecule are bonded to one atom of metal and chelated.

<Ascorbic acids>
The ascorbic acids used as the component (B) in the present invention are one or a combination of two or more selected from ascorbic acid, ascorbic acid glucoside, ascorbic acid phosphoric acid monoester, and alkali metal salts thereof. .. The ascorbic acid glucoside refers to 2-O-α-D-glucopyranosyl-L-ascorbic acid, and the ascorbic acid phosphoric acid monoester refers to the hydroxyl group at the 2- or 3-position of ascorbic acid and the phosphoric acid. Refers to those with an ester bond. Among the ascorbic acid phosphoric acid monoesters, ascorbic acid-2-phosphate ester in which the hydroxyl group at the 2-position and the phosphoric acid are ester-bonded is preferable.

Ascorbic acid, as the alkali metal salts of ascorbic acid glucoside or ascorbyl phosphate monoester, e.g., sodium salt, etc. potassium salts.

Among the ascorbic acids, ascorbic acid and ascorbic acid salts such as sodium ascorbate and potassium ascorbate have a high ability to inhibit tyrosinase activity in the initial stage, but the ability to inhibit tyrosinase activity decreases with the passage of time. I have a problem. Therefore, in the present invention, a tyrosinase activity inhibiting ability and its stability standpoint, ascorbic acid glucoside, sodium ascorbate 2-phosphate, etc. ascorbic acid-2-phosphoric acid potassium are particularly preferably used.

In the present invention, it is important to use both the components (A) and (B) in combination, and the ratio R used thereof is R = [concentration of the component (A) (μg / mL)] / [( B) Concentration of component (mg / mL)], R is usually 0.0001 to 1,000, preferably 0.001 to 300, and more preferably 0.01 to 50. If the ratio of the component (A) is excessively low, the tyrosinase activity inhibitory ability cannot be enhanced, and conversely, if the ratio is excessively large, the effect of improving the tyrosinase activity inhibitory ability by using the component (B) in combination is obtained. In addition to the decrease, the amount of the expensive component (A) used increases, which is economically disadvantageous.

According to the present invention, the combined use of the component (A) and the component (B) exerts an excellent tyrosinase activity inhibitory effect, and therefore, an external preparation for skin for the purpose of whitening and skin beautification, for example, milky lotion, cream, and makeup. It is possible to provide skin care cosmetics such as water, packs and cleaning agents, makeup cosmetics such as makeup bases and liquid foundations, and non-medicinal products such as ointments, dispersions, creams and external liquids.

<External skin preparation>
The external preparation for skin of the present invention can be prepared according to a conventional method except that the component (A) and the component (B) constituting the tyrosinase activity inhibitor are contained. The blending amount (content) of the component (A) (α-lipoic acid derivative) in the external preparation for skin is preferably 1 × 10 ^-5 to 1% by mass, more preferably 5 × 10 as a dry solid content. ^{-4 to} 0.5% by mass. If the content of the component (A) is excessively small, a sufficient whitening effect by suppressing the activity of tyrosinase cannot be obtained, and conversely, if the content is excessively large, a higher whitening effect cannot be obtained.

On the other hand, the blending amount (content) of the component (B) (ascorbic acid) is preferably 0.001 to 5.0% by mass, more preferably 0.1 to 3.0% by mass. If the content of the component (B) is excessively small, a sufficient whitening effect cannot be obtained by suppressing the activity of tyrosinase, and conversely, if the content is excessively large, problems are likely to occur in terms of the stability of the preparation. ..

Examples of the form of the external preparation for skin are not particularly limited, and for example, skin care cosmetics such as emulsions, creams, lotions, packs and cleaning agents, makeup cosmetics such as makeup bases and liquid foundations, ointments, dispersions, etc. It can be a non-medicinal product such as a cream or an external liquid. The dosage form is also not particularly limited, and may be solid, paste, mousse, gel, powder, solution system, solubilization system, emulsification system, powder dispersion system, multilayer form, aerosol, or the like. it can.

The emulsification system is not particularly limited, and for example, O / W (water-in-water type), W / O (water-in-oil type), W / O / W (water-in-water type), O / W / O. (Oil type in oil) and the like. Among these dosage forms, when the water-in-water oil-in-water type is adopted, the component (A) is blended in the innermost aqueous phase, and the component (B) is blended in the outermost aqueous phase, the components (A) and (B) are blended. ) The contact of the component can be suppressed, the stability of the preparation can be improved, and the deterioration of the component (A) due to oxidation can be prevented.

In addition to the above-mentioned α-lipoic acid derivatives and ascorbic acids, the external preparation for skin of the present invention is usually used in preparations such as cosmetics and non-pharmaceutical products as long as the effects of the present invention are not impaired. Ingredients: water (purified water, hot spring water, deep water, etc.), oils, surfactants, metal keratins, gelling agents, powders, alcohols, water-soluble polymers, film-forming agents, resins, UV protection agents , Inclusion compounds, antibacterial agents, fragrances, deodorants, salts, PH adjusters, refreshing agents, animal / microorganism-derived extracts, plant extracts, blood circulation promoters, astringents, antilipoic agents, active oxygen scavengers , Cell activator, moisturizer, keratolytic agent, enzyme, hormones, vitamins and the like can be added as appropriate.

As an oil agent, hydrocarbons may be natural oils, synthetic oils, solids, semi-solids, liquids, etc., as long as they are used in ordinary cosmetics. Any oil such as waxes, waxes, fatty acids, higher alcohols, ester oils, silicone oils, and fluorine-based oils can be used. For example,
Hydrocarbons such as squalane, squalene, selecin, paraffin, paraffin wax, liquid paraffin, pristane, polyisobutylene, microcrystalline wax, petrolatum;
Waxes such as beeswax, carnauba wax, candelilla wax, whale wax;
Animal oils such as beef tallow, beef tallow, beef tallow, hardened beef tallow, hardened oil, turtle oil, lard, horse fat, mink oil, cod liver oil, egg yolk oil;
Lanolin derivatives such as lanolin, liquid lanolin, reduced lanolin, lanolin alcohol, hard lanolin, lanolin acetate, lanolin fatty acid isopropyl, POE lanolin alcohol ether, POE lanolin alcohol acetate, lanolin fatty acid polyethylene glycol, POE hydrogenated lanolin alcohol ether;
Fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, oleic acid, arachidonic acid, docosahexaenoic acid (DHA), isostearic acid, 12-hydroxystearic acid;

Lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, behenyl alcohol, hexadecyl alcohol, oleyl alcohol, isostearyl alcohol, hexyldodecanol, octyldodecanol, cetostearyl alcohol, 2-decyltetradecinol, cholesterol, phytosterol, citosterol , Lanosterol, POE cholesterol ether, monostearyl glycerin ether (batyl alcohol) and other higher alcohols;

Diisobutyl adipate, -2-hexyldecyl adipate, -di-2-heptylundecyl adipate, -N-alkylglycol monoisostearate, isosetyl isostearate, trimethylpropane triisostearate, di-2-ethylhexanoic acid Ethylene glycol, cetyl 2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, pentaerythritol tetra-2-ethylhexanoate, cetyl octanoate, cetyl octyldodecyl gum ester, oleyl oleate, octyldodecyl oleate, olein Decyl acid, neopentyl glycol dicaprate, triethyl citrate, -2-ethylhexyl succinate, amyl acetate, ethyl acetate, butyl acetate, isosetyl stearate, butyl stearate, diisopropyl sebacate, di-2-ethylhexyl sebacate, lactic acid Cetyl, myristyl lactate, isopropyl palmitate, -2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptylundecyl palmitate, cholesteryl 12-hydroxystearyl, dipentaerythritol fatty acid ester, isopropyl myristate, myristic acid Octyldodecyl, -2-hexyldecyl myristate, myristyl myristate, hexyldecyl dimethyloctanoate, ethyl laurate, hexyl laurate, N-lauroyl-L-glutamate-2-octyldodecyl ester, diisostearyl malate, etc. Ester oil;

Glyceride oils such as acetoglyceride, triisooctanoic acid glyceride, triisostearic acid glyceride, triisopalmitate glyceride, tri-2-ethylhexanoic acid glyceride, monostearic acid glyceride, di-2-heptylundecanoic acid glyceride, trimyristic acid glyceride ;
Higher alkoxy modifications such as dimethylpolysiloxane, methylphenylpolysiloxane, methylhydrogenpolysiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, tetramethyltetrahydrogencyclotetrasiloxane, stearoxysilicone, etc. silicone;
Silicone-based oils such as higher fatty acid-modified silicones, silicone resins, silicone rubbers, and silicone oils;
Fluorine-based oils such as perfluoropolyether, perfluorodecalin, and perfluorooctane can be mentioned.

As the surfactant, anionic, cationic, nonionic and amphoteric activators are used. Examples of the anionic surfactant include fatty acid sulpene such as sodium stearate and triethanolamine palmitate, alkyl ether carboxylic acid and its salt, carboxylate such as condensate of amino acid and fatty acid, alkyl sulfonic acid, and alkene sulfonate. , Sulfate of fatty acid ester, sulfonate of fatty acid amide, sulfonate of alkyl sulfonate and its formalin condensate, alkyl sulphate, secondary higher alcohol sulphate, alkyl and allyl ether sulphate , Sulfate ester salt of fatty acid ester, Sulfate ester salt of fatty acid alkylolamide, Sulfate ester salts such as funnel oil, Alkyl phosphate, Ether phosphate, Alkyl allyl ether phosphate, Amid phosphate, N-acyl amino acid Examples include system activators.

Examples of the cationic surfactant include amine salts such as alkylamine salts, polyamines and aminoalcohol fatty acid derivatives, alkyl quaternary ammonium salts, aromatic quaternary ammonium salts, pyridium salts, and imidazolium salts.

Examples of nonionic surfactants include sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyethylene glycol fatty acid ester, sucrose fatty acid ester, polyoxyethylene alkyl ether, polyoxypropylene alkyl ether, and poly. Oxyethylene alkyl phenyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene propylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene Hardened castor oil, polyoxyethylene phytostanol ether, polyoxyethylene phytosterol ether, polyoxyethylene cholestanol ether, polyoxyethylene cholesteryl ether, polyoxyalkylene-modified organopolysiloxane, polyoxyalkylene-alkyl co-modified organopolysiloxane, alkanol Examples thereof include amide, sugar ether and sugar amide. Examples of the amphoteric surfactant include betaine, an aminocarboxylic acid salt, and an imidazoline derivative.

Metallic stakes include aluminum 12-hydroxystearate, zinc stearate, aluminum stearate, calcium stearate, magnesium stearate, zinc myristate, magnesium myristate, zinc cetyl phosphate, calcium cetyl phosphate, sodium zinc cetyl phosphate, zinc laurate. , Zinc undecylenate and the like.

Examples of the gelling agent include amino acid derivatives such as N-lauroyl-L-glutamic acid and α, γ-di-n-butylamine, and dextrins such as dextrinpylumitate, dextrin stearate, and dextrin 2-ethylhexanoic acid palmitinate. Sucrose fatty acid esters such as fatty acid esters, sucrose palmitate, sucrose stearate, benzylidene derivatives of sorbitol such as monobenzylidene sorbitol and dibenzylidene sorbitol, dimethylbenzyldodecylammonium montmorillonite clay, dimethyldioctadecylammonium montmorillonite clay and the like. Examples include organically modified clay minerals.

As the powder, if it is used for ordinary cosmetics, its shape (spherical, needle-like, plate-like, etc.), particle size (foam-like, fine particles, pigment grade, etc.), particle structure (porous, Any of inorganic powder, organic powder, pigment, etc. can be used regardless of the non-porous material. For example, inorganic powders include magnesium oxide, barium sulfate, calcium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, talc, synthetic mica, mica, kaolin, sericite, white mica, synthetic mica, phlogopite, and red mica. Black mica, Lithia mica, silicic acid, anhydrous silicic acid, aluminum silicate, magnesium silicate, aluminum magnesium silicate, aluminum silicate containing sulfur, calcium silicate, barium silicate, strontium silicate, metal tungate, hydroxy Examples thereof include apatite, vermiculite, hygilite, montmorillonite, zeolite, ceramic powder, dicalcium phosphate, alumina, aluminum hydroxide, boron nitride, boron nitride and the like.

Organic powders include polyamide powder, polyester powder, polyethylene powder, polypropylene powder, polystyrene powder, polyurethane, benzoguanamine powder, polymethylbenzoguanamine powder, tetrafluoroethylene powder, polymethylmethacrylate powder, silk powder, nylon powder, 12 nylon, 6 Nylon, styrene / acrylic acid copolymer, divinylbenzene / styrene copolymer, vinyl resin, urea resin, phenol resin, fluororesin, silicon resin, acrylic resin, melamine resin, epoxy resin, polypropylene resin, microcrystalline fiber powder Examples include the body and lauroyl lysine.

Colored pigments include inorganic red pigments such as iron oxide, iron hydroxide and iron titanate, inorganic brown pigments such as γ-iron oxide, inorganic yellow pigments such as yellow iron and ocher, black iron oxide and carbon black. Inorganic black pigments, inorganic purple pigments such as manganese violet and cobalt violet, inorganic green pigments such as chromium hydroxide, chromium oxide, cobalt oxide and cobalt titanate, inorganic blue pigments such as dark blue and ultramarine, and tar pigments. Examples thereof include pigments made from natural pigments, pigments made from natural pigments, and composite powders obtained by combining these powders. Examples of the pearl pigment include titanium oxide-coated mica, titanium oxide-coated mica, bismuth oxychloride, titanium oxide-coated bismuth oxychloride, titanium oxide-coated talc, fish scale foil, and titanium oxide-coated colored mica. Examples of the metal powder pigment include aluminum powder, copper powder, stainless powder and the like.

As tar pigments, Red No. 3, Red No. 104, Red No. 106, Red No. 201, Red No. 202, Red No. 204, Red No. 205, Red No. 220, Red No. 226, Red No. 227, Red No. 228, Red No. No. 230, No. 401, No. Red No. 505, No. 4, Yellow No. 5, Yellow No. 5, Yellow No. 202, Yellow No. 203, Yellow No. 204, Yellow No. 401, Blue No. 1, Blue No. 2, Blue No. 201, Blue No. 404 , Green No. 3, Green No. 201, Green No. 204, Green No. 205, Orange No. 201, Orange No. 203, Orange No. 204, Orange No. 206, Orange No. 207 and the like. Examples of natural pigments include carminic acid, racaic acid, carsamine, brazilin, crocin and the like. The above-mentioned powders such as inorganic powders, organic powders, pigments, and tar pigments may be compounded or surface-treated with an oil agent, silicone, or a fluorine compound.

UV protection agents include -2-ethylhexyl paramethoxycinnamic acid, isopropyl paramethoxycinnamic acid, diethanolamine paramethoxyhydrocinnamic acid, glyceryl diparamethoxycinnamic acid-mono-2-ethylhexanoate, and methoxycinnamate. Cinnamic acid-based UV absorbers such as octyl dermatate and methyl diisopropylsilicate; 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfate, 2-hydroxy-4-methoxybenzophenone- Sodium 5-sulfate, 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2', 4,4'-tetra Benzopenone-based ultraviolet absorbers such as hydroxybenzophenone and 2-hydroxy-4-n-octoxybenzophenone; paraaminobenzoic acid, ethyl paraaminobenzoate, butyl paraaminobenzoate, -2-ethylhexyl paradimethylaminobenzoate, glyceryl paraaminobenzoate , Cinnamic acid-based ultraviolet absorbers such as amyl paraaminobenzoate.

In addition, as an ultraviolet protective agent, -2-ethylhexyl salicylate, triethanolamine salicylate, homomentyl salicylate, dipropylene glycol salicylate, methyl salicylate, ethylene glycol salicylate, phenyl salicylate, amyl salicylate, benzyl salicylate, isopropylbenzyl salicylate, potassium salicylate and the like Salicylic acid-based ultraviolet absorber; didibenzoylmethane such as 4-t-butyl-4'-methoxydibenzoylmethane, 4-isopropyldibenzoylmethane, 4-methoxydibenzoylmethane, 4-t-butyl-4'-hydroxydibenzoylmethane, etc. Benoxylmethane-based UV absorber; Menthyl-O-aminobenzoate, 2-phenyl-benzimidazol-5-sulfate, 2-phenyl-5-methylbenzoxazole, 3- (4-methylbenzylidene) camphor, 2-ethylhexyl- Anthranilic acids such as 2-cyano-3,3-diphenylacrylate, 2-ethyl-2-cyano-3,3'-diphenylacrylate, 2- (2'-hydroxy-5-methylphenyl) benzotriazole, and menthyl anthranylate Ultraviolet absorbers; urocanic acid-based ultraviolet absorbers such as ethyl urocanate; titanium oxide, zirconium oxide, cerium oxide and the like can be mentioned.

Examples of alcohols include lower alcohols such as ethanol and isopropanol, polyhydric alcohols such as glycerin, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol and polyethylene glycol. Can be mentioned.

Water-soluble polymers include plant-based polymers such as Arabic rubber, tragacant, galactan, carob gum, guar gum, karaya gum, carrageenan, pectin, agar, algae colloid, tranth gum, locust bean gum, and galactomannan; xanthan gum, dextran, and succino. Micromolecular polymers such as glucan and purulan; Animal polymers such as casein, albumin and gelatin; Starch polymers such as starch, carboxymethyl starch and methyl hydroxypropyl starch; Methyl cellulose, ethyl cellulose, methyl hydroxypropyl cellulose and carboxymethyl cellulose , Hydroxymethyl cellulose, hydroxypropyl cellulose, nitrocellulose, sodium cellulose sulfate, sodium carboxymethyl cellulose, crystalline cellulose, cellulose-based polymer of cellulose powder; alginic acid-based polymer such as sodium alginate, propylene glycol ester alginate; polyvinyl methyl ether, carboxy Vinyl-based polymers such as vinyl polymers and alkyl-modified carboxyvinyl polymers; Polyoxyethylene-based polymers; Polyoxyethylene polyoxypropylene copolymer-based polymers; Acrylic-based polymers such as sodium polyacrylate, polyethyl acrylate, and polyacrylamide. Molecules: Inorganic water-soluble polymers such as polyethyleneimine, cationic polymer, bentonite, laponite, and hectrite. In addition, a film-forming agent such as polyvinyl alcohol or polyvinylpyrrolidone is also included in this.

Antibacterial agents include benzoic acid, sodium benzoate, phenolic acid, sorbic acid, potassium sorbate, paraoxybenzoic acid ester, parachlormethacresol, hexachlorophene, benzalkonium chloride, chlorhexidine chloride, trichlorocarbanilide, photosensitizer, Examples thereof include bis (2-pyridylthio-1-oxide) zinc, phenoxyethanol and thiantol, and isopropylmethylphenol. Examples of the PH adjuster include potassium carbonate, sodium hydrogen carbonate, ammonium hydrogen carbonate and the like. Examples of the refreshing agent include L-menthol and camphor.

Examples of the cell activator include deoxyribonucleic acid and its salt, adenylic acid derivatives such as adenosine triphosphate and adenosine monophosphate and their salts, ribonucleic acid and its salt, cyclic AMP, cyclic GMP, flavin adenine nucleotide, and guanine. , Adenine, cytosine, timine, xanthine and their derivatives such as caffeine, theoferin and salts thereof, nucleic acid-related substances, calf blood extract, serum deproteinized extract, spleen extract, egg components such as birds, Chicken crown extract, shell extract, shellfish extract, royal jelly, silk protein and its degradation products or derivatives thereof, hemoglobin or its degradation products, lactoferrin or its degradation products, soft animal extracts such as squid, fish meat extracts, etc. , Mammalia, birds, shellfish, insects, fish, soft animals, shellfish and other animal-derived extracts, yeast extracts, lactic acid bacteria extracts, bifidus bacteria extracts and other fermentation metabolites. Things can be mentioned.

Further, as cell activators, vitamin A such as retinol and its derivatives (retinol palmitate, retinol acetate, etc.), retinal and its derivatives, carotinoids such as dehydroretinal, carotene, and thiamines (thiamine hydrochloride, thiamine sulfate), Riboflavins (riboflavin, riboflavin acetate, etc.), pyridoxines (pyridoxine hydrochloride, pyridoxine dioctanoate, etc.), flavin adenine nucleotides, cyanocobalamine, folic acids, nicotinic acids (nicotinic acid amide, benzyl nicotinate, etc.), choliners, etc. Vitamin B, apricot extract, ginkgo extract, otane carrot extract, corn extract, orange extract, cucumber extract, kiwi extract, shiitake extract, sugina extract, assembly extract, taiso extract, pepper extract Products, garlic extract, carrot extract, bukuryo extract, peach extract, lettuce extract, lemon extract, pyridoxine extract, rosemary extract, hinokithiol, cepharanthin and other plant-derived extracts, α- and Examples thereof include γ-linolenic acid, eicosapentaenoic acid and its derivatives, estradiol and its derivatives, and salts thereof, glycolic acid, succinic acid, lactic acid, organic acids such as salicylic acid, derivatives thereof, and salts thereof. As the cell activators listed above, one type or two or more types can be appropriately selected and blended.

Active oxygen removers include mannitol, riboflavin, cholesterol, tryptophan, histidine, quercetin, quercitrin, catechin, catechin derivative, rutin, rutin derivative, taurine, thiotaurine, eggshell membrane extract, gallic acid, gallic acid derivative, yeast extract. Substances, Reishi extract, Yashajitsu extract, Gennoshoco extract, Buttonpi extract, Melissa extract, Parsley extract and Dicoppi extract, Retinol and its derivatives (retinol palmitate, retinol acetate, etc.), Retinal and its derivatives, Vitamin A such as dehydroretinal; thiamines (thiamin hydrochloride, thiamine sulfate, etc.), riboflavins (riboflavin, riboflavin acetate, etc.), pyridoxins (pyridoxin hydrochloride, pyridoxin dioctanoate, etc.), flavin adenine nucleotide, cyanocobalamine , Folic acids, nicotinic acids (nicotinic acid amide, benzyl nicotinate, etc.), vitamin Bs such as choline; vitamin Ds such as ergocalciferol, cholecalciferol, dihydroxystanal; tocopherol and its derivatives (dl-α) (Β, γ) -tocopherol, dl-α-tocopherol acetate, nicotinic acid-dl-α-tocopherol, linoleic acid-dl-α-tocopherol, dl-α-tocopherol succinate, etc.), vitamin Es such as ubiquinones Examples include dibutylhydroxytoluene and butylhydroxyanisole.

Moisturizers include alkaline simple hot spring water, deep water, hyaluronic acid, chondroitin sulphate, dermatan sulphate, heparan sulphate, heparin and keratane sulphate and other mucopolysaccharides or salts thereof, collagen, elastin, keratin and other proteins or theirs. Derivatives and their salts, soybean and egg-derived phospholipids, glycolipids, ceramides, mutin, honey, erythritol, maltose, martitol, xylitol, xylose, pentaerythritol, fructose, dextrin and its derivatives, mannitol, sorbitol, inositol, Sugars such as trehalose and glucose, urea, asparagine, aspartic acid, alanine, arginine, isoleucine, ortinin, glutamine, glycine, glutamic acid and their derivatives and their salts, cysteine, cystine, citrulin, threonine, serine, tyrosine, tryptophan, theanine. , Valine, histidine, hydroxylysine, hydroxyproline, pyrrolidone carboxylic acid and salts thereof, amino acids such as proline, phenylalanine, methionine, lysine and derivatives thereof or salts thereof.

Other moisturizers include D-pantenol, avocado extract, almond oil, locust bean extract, rice extract, strawberry extract, uikyo extract, cheeses extract, auren extract, olive oil, odorikosou extract, cacao. Fat, crow wheat extract, scratch extract, kumazasa extract, sardine extract, grapefruit extract, gennoshoco extract, gentiana extract, gobo extract, kobotanzuru extract, sesame extract, cactus extract, sabonsou extract, Ginger extract, Jio extract, Shea butter, Shimotsuke extract, Senkyu extract, Zeniaoi extract, Tachijakousou extract, Tsubaki extract, Corn extract, Tochukasou extract, Tormentilla extract, Dokudami extract, Bakumondou extract Thing, Hauchimame extract, Hamamelis extract, Hakka extract, Midorihakka extract, Seiyohakka extract, Parsley extract, Rose extract, Sunflower extract, Hinoki extract, Hechima extract, Prun extract, Butcher's bloom extract Thing, Borage oil, Button extract, Johoba oil, Bodaiju extract, Hop extract, Pine extract, Maronnier extract, Macademia nut oil, Marumero extract, Murasaki extract, Meadow home oil, Melissa extract, Yagurumasou extract , Yuri extract, Yuzu extract, Lime extract, Lavender extract, Lindou extract, Waremokou extract, Apple extract and the like. The moisturizers listed above can be blended by appropriately selecting one type or two or more types.

Examples of vitamins include vitamin Ks such as phytonadione, menadione, menadione and menadiol, vitamin Ps such as eriocitrin and hesperidin, biotin, carcinine and ferulic acid.

Examples of the blood circulation promoter include valenylamide nonylate, capsaicin, zingerone, cantalis tincture, ictamol, α-borneol, inositol hexanicotinate, cyclanderate, cinnaridine, trazoline, acetylcholine, verapamil, γ-oryzanol and the like.

Examples of the skin astringent include tannic acid, examples of the antiseborrheic agent include thianthol, and examples of the enzyme include lipase and papain.

Examples of the whitening agent include ascorbic acid derivatives other than ascorbic acid as the component (B) of the present invention and salts thereof, cysteines such as N, N'-diacetylcystinedimethyl and derivatives thereof, and salts thereof, glabridin, glutathione, liquiritin, isoliquilitin, and the like. Examples thereof include placenta extract, hydroquinone such as arbutin and its derivatives, resorcin and its derivatives, ferulic acid and caffeic acid and their derivatives, salts thereof, glutathione and the like, and one or more of these may be used in combination. .. Among these, specific examples of the ascorbic acid derivative include L-ascorbic acid alkyl ester, L-ascorbic acid sulfate ester, and the like, and specific examples of the salts include alkali metal salts such as sodium salt and potassium salt, and calcium. Examples thereof include alkaline earth metal salts such as salts and magnesium salts.

More specifically, L-ascorbyl palmitate, L-ascorbyl dipalmitate, L-ascorbyl isopalmitate, L-ascorbyl diisopalmitate, L-ascorbyl tetraisopalmitate, L-ascorbyl stearate, distearate. L-ascorbyl, L-ascorbyl isostearate, L-ascorbyl diisostearate, L-ascorbyl myristate, L-ascorbyl dimyristate, L-ascorbyl isomylistate, L-ascorbyl diisomyristate, L-ascorbyl oleate, L-ascorbyl dioleate, L-ascorbyl 2-ethylhexanoate, sodium L-ascorbic acid sulfate, potassium L-ascorbic acid sulfate, magnesium L-ascorbic acid sulfate, calcium L-ascorbic acid sulfate, L-ascorbin Among the extracts such as acid sulfate aluminum, the extract, placenta extract, citrus extract, chamomile extract, animal and plant extract containing carotinoids, asparagus extract, pea extract, agetsu extract, etc. Ogon extract, Ononis extract, Seaweed extract, Kistrawberry extract, Kujin extract, Keiketto extract, Gokahi extract, Coffee extract, Rice bran extract, Wheat germ extract, Saishin extract, Palmitic acid extract, Sampens Extract, Shirayuri extract, Shakyaku extract, Sempukuka extract, Soybean extract, Tea extract, Sugar honey extract, Tomato extract, Byakuren extract, Beech sprout extract, Grape extract, Frodemanita extract , Hop extract, Maikaika extract, Mokka extract, Yukinoshita extract, Eucalyptus extract, Yokuinin extract, Rakan extract and the like.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. The blending amount of each component represents "mass%" unless otherwise specified.

<Tyrosinase activity inhibition evaluation test>
To the evaluation sample, 0.1 mL of tyrosinase (derived from mushrooms, 100 unit / mL manufactured by Sigma) is added, and then 0.1 M phosphate buffer (pH 6.5) is added to prepare a 2.0 mL test solution. Incubate this test solution in a constant temperature bath at 37 ° C. for 10 minutes, then add 1 mL of DOPA (3,4-Dihydroxy-L-phenylalanine 0.03% solution), and measure the absorbance at 475 nm after 2 minutes. Let the obtained value be D1. As a control, the same measurement is performed on the test solution in which each sample is replaced with purified water, and the obtained absorbance value is defined as D2. The tyrosinase activity inhibition rate is calculated by the following formula.
Tyrosinase activity inhibition rate (%) = (D2-D1) / D2 × 100

Reference example 1
Histidine dithiooctanamide (Na / zinc) tyrosinase activity inhibition evaluation test As an α-lipoyl amino acid derivative for evaluation, commercially available histidine dithiooctanamide (Na / zinc) (molecular weight = 430.84, manufactured by Oga Research Co., Ltd. DM-His.Zn ") was used. The contents of histidine dithiooctanamide (Na / zinc) are 1.08 μg / mL (2.5 μM), 2.15 μg / mL (5 μM), 3.23 μg / mL (7.5 μM), 4.31 μg /, respectively. A test solution added so as to be mL (10 μM) was prepared, and the tyrosinase activity inhibition rate was examined by the above test method. The results were as follows.

Histidine dithiooctanamide (Na / zinc) concentration Tyrosinase activity inhibition rate (%)
1.08 μg / mL 13.2
2.15 μg / mL 25.3
3.23 μg / mL 53.6
4.31 μg / mL 68.9

From this result, it was found that the tyrosinase activity inhibitory rate increased as the concentration of histidine dithiooctanamide (Na / zinc) increased, and that histidine dithiooctanamide (Na / zinc) had a tyrosinase activity inhibitory effect. confirmed. However, the ability to inhibit tyrosinase activity has not yet been sufficient.

Reference example 2
Evaluation test of inhibition of tyrosinase activity of ascorbic acid glucoside As ascorbic acids for evaluation, commercially available ascorbic acid glucoside (“AS-G” manufactured by Hayashibara Co., Ltd.) was used. Test solutions added so that the content of ascorbic acid glucoside was 5 mg / mL, 10 mg / mL, and 20 mg / mL, respectively, were prepared, and the tyrosinase activity inhibition rate was examined by the above test method. The results were as follows.

Ascorbic acid glucoside concentration Tyrosinase activity inhibition rate (%)
5 mg / mL 8.4
10 mg / mL 15.4
20 mg / mL 26.8

From this result, it was confirmed that when ascorbic acid glucoside was used alone, the tyrosinase activity inhibitory rate increased as the concentration increased, but the tyrosinase activity inhibitory effect was higher than that of histidine dithiooctanamide (Na / zinc). Turned out to be inadequate.

Example 1
Histidine dithiooctanamide (Na / zinc) and ascorbic acid glucoside combination tyrosinase activity inhibition evaluation test Histidine dithiooctanamide (Na / zinc) used in Reference Example 1 [abbreviated as component (A) in Table 1] and reference The test solution was prepared according to Reference Example 1 and Reference Example 2 except that the ascorbic acid glucoside used in Example 2 [abbreviated as component (B) in Table 1] was used in combination so as to have the ratios shown in Table 1. It was prepared and the tyrosinase activity inhibition rate was examined by the above test method. Table 1 shows the inhibition rate of tyrosinase activity of each sample and the degree of improvement from the case of each component alone. The results of Reference Example 1 and Reference Example 2 are also shown in Table 1.

From this result, it can be seen that the combined use of histidine dithiooctanamide (Na / zinc) and ascorbic acid glucoside significantly improves the tyrosinase activity inhibitory ability as compared with the case where both are used alone. For example, when histidine dithiooctanamide (Na / zinc) is used at 2.15 μg / mL and ascorbic acid glucoside is used at 20.0 mg / mL, the tyrosinase activity inhibitory ability is 25.3% and 26.8, respectively. However, when both are used in combination, the ability to inhibit tyrosinase activity is 100%. This value corresponds to 1.92 times the sum of the tyrosinase activity inhibition rates of 52.1% when both are used alone.

Real施例3-4 and Comparative Examples 1 and 2
Histidine dithio octa cyanamide (Na / zinc) and in place of ascorbic acid glucoside as tyrosinase activity inhibition evaluation test component (B) of the combination of ascorbic acid derivatives, ascorbic acid phosphate Na (5 mg / mL) or ascorbic acid (0 A test solution was prepared in the same manner as in Example 1 except that 0.01 mg / mL) was used, and the inhibition rate of each tyrosinase activity was examined. The concentration of histidine dithiooctanamide (Na / zinc) used in combination was 2.15 μg / mL. For comparison, a system using 3-O-ethylascorbic acid (2.5 mg / mL) or ascorbic acid sulfate 2Na (2.5 mg / mL) was also tested in the same manner. Table 2 shows the inhibition rate of tyrosinase activity of each sample and the degree of improvement from the case of each component alone. The results of Reference Example 1 are also shown in Table 2.

From this result, histidine dithio octa cyanamide (Na / zinc) and the ascorbic saury others a combination of ascorbic acid phosphoric acid Na, tyrosinase inhibitory potency as compared to when each is used singly is significantly improved You can see that. On the other hand, when 3-O-ethylascorbic acid or 2Na ascorbic acid sulfate was used, a sufficient ability to inhibit tyrosinase activity could not be obtained even if histidine dithiooctanamide (Na / zinc) was used in combination.

Comparative Example 3
The ability to inhibit tyrosinase activity was evaluated in the same manner as in Example 1 except that a 5 mg / mL aqueous solution of pyridoxine hydrochloride (vitamin B6) was used instead of ascorbic acid glucoside. The histidine dithiooctanamide (Na / zinc) concentration was 2.15 μg / mL. The results are as follows.

From this result, it can be seen that the combined use of histidine dithiooctanamide (Na / zinc) and pyridoxine hydrochloride has almost no effect of improving the tyrosinase activity inhibitory ability as compared with the case of using each of them alone. ..

Comparative Example 4
The ability to inhibit tyrosinase activity was evaluated in the same manner as in Example 1 except that an aqueous solution of 4.31 μg / mL of α-lipoic acid (manufactured by Tateyama Kasei Co., Ltd.) was used instead of histidine dithiooctanamide (Na / zinc). did. The concentration of ascorbic acid glucoside was 5 mg / mL. The results are as follows.

From this result, it can be seen that when α-lipoic acid is used, sufficient tyrosinase activity inhibitory ability cannot be obtained even if ascorbic acid glucoside is used in combination.

Example 5 Preparation of lotion A lotion was prepared according to the formulation and procedure shown below.
Procedure: Add a moisturizer, anti-fading agent, buffer, histidine dithiooctanamide, ascorbic acid glucoside, and pH adjuster to purified water and dissolve at room temperature to obtain an aqueous phase. On the other hand, an emollient, a surfactant, a preservative and a fragrance are added to ethanol and dissolved at room temperature to obtain an alcohol phase. The alcohol phase is then added to the aqueous phase.

Formulation (% by mass):
Moisturizer: 1,3-butylene glycol 6.0
Glycerin 5.0
PEG4000 3.0
Emollient: Olive oil 0.5
Surfactant: POE (20) sorbitan monostearic acid ester 1.5
POE (5) Oleyl alcohol ether 0.3
Ethanol: 10.0
Fragrance: Appropriate amount of colorant: Appropriate amount of preservative: Appropriate amount of buffering agent: Appropriate amount of anti-fading agent: Appropriate amount of histidine dithiooctanamide (Na / zinc) * 1 0.5
Ascorbic acid glucoside: 2.0
pH adjuster: Appropriate amount of purified water: Remaining amount * 1: "DM-His.Zn" (manufactured by Oga Research)

Example 6 Preparation of oil-in-water cream A cream was prepared according to the formulation and procedure shown below.
Procedure: Add a moisturizer and alkali to purified water and heat and mix at 70 ° C to obtain an aqueous phase. After the oil is dissolved by heating, a surfactant, a preservative, and an antioxidant are added to bring the oil phase to 70 ° C., and the oil phase is added to the aqueous phase and homogenized with a homomixer, and then cooled. Finally, a fragrance and a small amount of purified water in which histidine dithiooctanamide, a pH adjuster, and ascorbic acid glucoside are dissolved are added, mixed, and degassed.

Formulation (% by mass):
Oil: Stearic acid 8.0
Stearyl alcohol 4.0
Butyl stearate 6.0
Moisturizer: Propylene glycol 5.0
Surfactant: Glycerin monostearate 2.0
Alkali: Potassium hydroxide 0.4
Preservative: Appropriate amount Antioxidant: Appropriate amount Fragrance: Appropriate amount Histidine dithiooctanamide (Na / zinc) * 1 0.1
Ascorbic acid glucoside 0.1
Acidity regulator: Appropriate amount Purified water: Remaining amount

Example 7 Preparation of W / O / W (water-in-water oil-in-water type) cream A cream was prepared according to the formulation and procedure shown below.
procedure:
(1) Step of preparing an aqueous emulsion in intermediate oil A moisturizer, sodium chloride, and histidine dithiooctanamide (Na / zinc) are added to purified water and heated to 50 ° C. to obtain an aqueous phase. After the oil is dissolved by heating, a surfactant is added to adjust the temperature to 50 ° C. The above aqueous phase is added to this, homogenized with a disper mixer, and then cooled to obtain a water-in-intermediate emulsion.
(2) Step of preparing a water-in-water emulsion using a water-in-water emulsion in an intermediate oil The water-in-water cream is obtained by adding a moisturizer to purified water and heating and mixing at 75 ° C. to obtain an aqueous phase. After the oil is dissolved by heating, the water-in-water emulsion prepared in step (1), a surfactant, a preservative, and an antioxidant are added to adjust the temperature to 75 ° C. After adding this to the above aqueous phase and homogenizing it with a disperser mixer, cooling is performed. Finally, a fragrance and a small amount of purified water in which ascorbic acid glucoside and a pH adjuster are dissolved are added, mixed, and degassed.

Formulation (% by mass):
(1) Water emulsion in intermediate oil Oil content: Squalene 0.8
Ethylhexyl palmitate 0.5
Surfactant: Hexaglyceryl polyricinoleate 0.15
Diglyceryl monoisostearate 0.05
Moisturizer: Glycerin 5.0
Sorbitol 0.05
Purified water: 6.0
Sodium chloride: 0.2
Histidine dithiooctanamide (Na / zinc) * 1 0.1
(2) Water-in-water oil Medium-water cream Oil content: Squalene 5.0
Ethylhexyl palmitate 2.0
Microcrystalline wax 2.0
Vaseline 2.0
Behenyl alcohol 3.0
(1) Water emulsion in intermediate oil 12.85
Surfactant: Glycerin monostearate 2.0
Stearoyl glutamate Na 0.5
Moisturizer: 1,3-butylene glycol 10.0
Preservative: Appropriate amount Antioxidant: Appropriate amount Fragrance: Appropriate amount Ascorbic acid glucoside 0.5
Purified water: remaining amount

Example 8 Preparation of face-wash foam A face-wash foam was prepared according to the formulation and procedure shown below.
Procedure: Fatty acids, emollients and moisturizers are heated and dissolved and kept at 70 ° C to form an oil phase. The alkali is dissolved in purified water, and the oil phase is added with stirring. After the neutralization reaction is sufficiently carried out, a surfactant is added and mixed, and then cooling is started. A chelating agent, a fragrance, and a small amount of purified water in which histidine dithiooctanamide, a pH adjuster, and an ascorbic acid glucoside are dissolved are added to homogenize, cool, and defoam.

Formulation (% by mass):
Fatty acid: stearic acid 12.0
Myristic acid 14.0
Lauric acid 5.0
Emollient: Jojoba oil 3.0
Alkali: Potassium hydroxide 5.0
Moisturizer: Sorbitol (70% sorbitol solution) 15.0
Glycerin 10.0
1,3-butylene glycol 10.0
Surfactant: POE (20) glycerol monostearic acid ester 2.0
Acylmethyl taurine 4.0
Chelating agent: Appropriate amount Fragrance: Appropriate amount Histidine dithiooctanamide (Na / zinc) * 1 0.5
Ascorbic acid glucoside 0.5
Acidity regulator: Appropriate amount Purified water: Remaining amount

Example 9 Preparation of Liquid Foundation A liquid foundation was prepared according to the formulation and procedure shown below.
Procedure: After stirring the oil phase, a well-mixed and pulverized powder portion is added and homomixed. After dissolving the aqueous phase, it is added to this and treated with a homomixer. Histidine dithiooctanamide, a pH adjuster and sodium ascorbate dissolved in a small amount of purified water are added to homogenize and defoam.

Formulation (% by mass):
Powder: Hydrophobized talc 7.0
Hydrophobicized titanium dioxide 12.0
Hydrophobicized silicic anhydride 2.0
Nylon powder 4.0
Hydrophobicized color pigment 2.0
Oil phase: Decamethylcyclopentasiloxane 30.0
Rosin Pentaerythritol 1.5
Polyoxyethylene modified dimethylpolysiloxane 1.5
Aqueous phase: Remaining amount of purified water
1,3 Butylene glycol 4.0
Ethanol 7.0
Histidine dithiooctanamide (Na / zinc) * 1: 0.1
Na ascorbate: 1.0
Acidity regulator: Appropriate amount

The tyrosinase activity inhibitor of the present invention has a tyrosinase activity inhibitory ability that is significantly improved as compared with the case where the α-lipoic acid derivative is used alone, and is a material to be blended in cosmetics and quasi-drugs. It is useful as. In addition, the external preparation for skin containing the tyrosinase activity inhibitor can effectively suppress the tyrosinase activity and is useful as a cosmetic or quasi-drug having an excellent whitening effect.

Claims (4)

Of histidine dithiooctanamide (Na / zinc) (A) and one or more ascorbic acids (B) selected from ascorbic acid, ascorbic acid glucoside, ascorbic acid phosphoric acid monoester and alkali metal salts thereof. A tyrosinase activity inhibitor composed of a combination (however, the usage ratio (R) of the component (A) and the component (B) is 0.001 to 300).
R = [Concentration of component (A) (μg / mL)] / [Concentration of component (B) (mg / mL) ] The component (B), tyrosinase activity inhibitor according to claim 1 Symbol placement ascorbic acid glucoside. An external preparation for skin containing the tyrosinase activity inhibitor according to claim 1 or 2 . The skin external preparation according to claim 3 , wherein the skin external preparation is a cosmetic.