JP5403877B2 - Topical skin preparation - Google Patents

Description

  The present invention relates to a skin external preparation containing hydroquinone and tocopherol.

Hydroquinone is used as a whitening external preparation because of its strong melanin production inhibitory effect, but has the problem of causing cytotoxicity and skin irritation. In order to reduce this, methods such as ascorbic acid and other substances that have a catalase-like action have also been reported, but there are problems such as poor sustainability and poor stability in the formulation, and further improvements Is desired. Arbutin (hydroquinone-β-D-glucose) is colored under severe conditions and long-term storage, but it has been reported that vitamin E exhibits an excellent effect in its stable formulation (Patent Document 1: Japanese Patent Publication No. 03-58326).
On the other hand, tocopherol is contained in biological membranes and fats and oils and exhibits an antioxidant effect by erasing and inactivating radicals and active oxygen, but a catalase-like effect is not known. Also,
The physiological activity ratio of α-, β-, γ- and δ-tocopherol is 100: 40: 10: 1 (Non-patent document 1: Table of Japanese food standard ingredients, Chapter 1, 2-2, (6) Vitamin (3) Vitamin E) and α form are the highest and delta form is the lowest, but the antioxidant activity of fats and oils is highest in delta form and lowest in alpha form (Non-patent Document 2) : J. Act. Oxyg. Free Rad. 3: 531-54
1,1992) is known.

An object of the present invention is to find a component that reduces the cytotoxicity of hydroquinone. Another object of the present invention is to provide a highly safe skin external preparation containing hydroquinone.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that tocopherol reduces the cytotoxicity of hydroquinone and completed the present invention.

That is, this invention is a skin external preparation shown to the following (1)-(4).
(1) A skin external preparation containing hydroquinone and tocopherol.
(2) The skin external preparation according to (1), wherein the tocopherol is γ-tocopherol or δ-tocopherol.
(3) The external preparation for skin according to (1) or (2), further containing one or more selected from glycol, glycol ether, glycerin and diglycerin.
(4) Further, it contains one or more selected from the group consisting of an anti-aging component, a moisturizing component, a whitening component, an anti-inflammatory component, an antibacterial component, a cell activation component, an astringent component, and an antioxidant component (
The skin external preparation in any one of 1)-(3).
(5) Hydroquinone cytotoxicity-reducing agent containing tocopherol.
The present invention also includes a method for reducing cytotoxicity.
(6) A method for reducing the cytotoxicity of hydroquinone with tocopherol.
In the present specification, “%” means “% by weight” unless otherwise specified.

In the present invention, it has been found that tocopherol has a cytotoxic effect of hydroquinone and that γ-tocopherol or δ-tocopherol is higher than α-tocopherol, which is said to have the highest physiological activity.
Moreover, since the outstanding effect of hydroquinone, such as melanin production suppression, can be anticipated by mix | blending hydroquinone and tocopherol, a useful and safe skin external preparation can be provided.

BEST MODE FOR CARRYING OUT THE INVENTION

As the hydroquinone used in the present invention, hydroquinone commercially available as a component of a skin external preparation in the pharmaceutical, quasi-drug or cosmetic field can be used.
The amount of hydroquinone used in the present invention is not particularly limited as long as the effect of the present invention is achieved,
Although it can be appropriately selected and used in consideration of the feeling of use and effects on the skin, it is usually 0.0005 to 10% by weight, preferably 0.0008 to 8% by weight, particularly preferably 0.001%, based on the whole external preparation for skin. ~ 6
It is sufficient if it is weight%.

The tocopherol used by this invention can be obtained by a conventional method, and a commercial item can also be used. Tocopherols are known to have four types of structures, α-, β-, γ-, and δ-, but any structure may be used in the present invention, preferably α-, γ-, and δ-. And γ- and δ- are particularly preferable.
The blending amount of the tocopherol used in the present invention into the external preparation for skin is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. 0.01 to 10% by weight, preferably 0.1 to 8% by weight, particularly preferably based on the total amount of the external preparation
It may be 1 to 6% by weight. Moreover, you may use a tocopherol individually or in combination of 4 types of structures.

In the external preparation for skin of the present invention, the mixing ratio of hydroquinone and tocopherol is not particularly limited as long as the effects of the present invention can be obtained. For example, tocopherol is 0.01 to 12 parts by weight, preferably 0.05 to 1 part by weight of hydroquinone. -6 parts by weight, particularly preferably 0.1-4 parts by weight.

In the external preparation for skin of the present invention, glycol, glycol ether, glycerin or diglycerin can be blended in one kind or a combination of two or more kinds in order to stabilize hydroquinone.

In the present invention, the glycol is a diol that is liquid at 25 ° C. and is used as a component of a skin external preparation in the pharmaceutical, quasi-drug, or cosmetic field. For example, the general formula C _n H _2n (
A diol represented by (OH) ₂ or a condensate of one or two or more of the diols. Specifically, ethylene glycol, propylene glycol, trimethylene glycol, 1,
Examples of condensates such as 2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, isoprene glycol, 1,2-pentylene glycol, 1,2-hexylene glycol, and octylene glycol include diethylene glycol, Examples include triethylene glycol, tetraethylene glycol, dipropylene glycol, and tripropylene glycol. Preferred are propylene glycol, 1,3-butylene glycol and dipropylene glycol.
In addition, glycerin and diglycerin used in the present invention are known compounds that are frequently used in skin external preparations and the like.

In the present invention, the glycol ether is a compound in which one or both of the hydroxyl groups of glycol are etherified, and is not particularly limited as long as it is used as a component of a skin external preparation in the pharmaceutical, quasi-drug or cosmetic field. Glycol is a diol that is liquid at 25 ° C., and may be, for example, a diol represented by the general formula C _n H _2n (OH) ₂ or a condensate of one or more of the diols.

Specific examples of glycol ethers include ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene Glycol monopropyl ether, dipropylene glycol monoethyl ether, and dipropylene glycol monopropyl ether are preferred, with diethylene glycol monoethyl ether and diethylene glycol monobutyl ether being particularly preferred.

These glycols, glycol ethers, glycerin and diglycerin can be used alone or in combination of two or more, and the total amount of glycol, glycol ether, glycerin and diglycerin is 5 to 90 wt. %, Preferably 10-8
It may be 0% by weight, particularly preferably 20 to 70% by weight, but is not particularly limited as long as the effects of the present invention are exhibited.

Among these, specific examples of preferred combinations include (i) one or two selected from propylene glycol, 1,3-butylene glycol, dipropylene glycol, diethylene glycol monoethyl ether, glycerin and diglycerin. The above is mentioned. Another preferred combination includes (ii) only glycol, specifically, (ii) one or more selected from propylene glycol, 1,3-butylene glycol, and dipropylene glycol. is there.

In order to enhance or supplement the effects of the present invention, the external preparation for skin of the present invention has an anti-aging component, a moisturizing component, and a whitening component, an anti-inflammatory component for adding other useful effects to the external preparation for skin, One or two or more antibacterial components, cell activation components, astringent components, and antioxidant components can be blended. Each of these components is not particularly limited as long as it is conventionally used as a component of a skin external preparation in the pharmaceutical, quasi-drug, or cosmetic field, and used in the future. Can be used. Particularly preferred combinations of these components include each combination of a glutathione production promoter (tocopherol) and a moisturizing component, each combination of a glutathione production promoter and a whitening component, a glutathione production promoter, a moisturizing component and an antioxidant component. Each combination of glutathione production promoter and anti-aging component, each combination of glutathione production promoter, anti-aging component and antioxidant component, glutathionic acid production promoter, cell activation component and anti-aging component Each combination can be mentioned. Each of these components is not particularly limited as long as it is conventionally used as a component of a skin external preparation in the pharmaceutical, quasi-drug, or cosmetic field, and used in the future. Can be used.

Anti-aging components include retinoids (retinol, retinoic acid, retinal, etc.), pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon,
Silicic acid, N-methyl-L-serine, mevalonolactone and the like can be mentioned. Preferred are retinoid (retinol, retinoic acid, retinal, etc.) and kinetin.

When using the anti-aging component, it is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. Usually, it is 0.0003-10 weight%, More preferably, it is 0.01-5 weight%.

As moisturizing ingredients, amino acids such as alanine, serine, leucine, isoleucine, threonine, glycine, proline, hydroxyproline, glucosamine, theanine and derivatives thereof; peptides such as gelatin; glycerin, diglycerin, 1,3-butylene glycol, propylene Polyhydric alcohols such as glycol and polyethylene glycol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether , Propylene glycol monopropyl ether, dipro Glycol ethers such as pyrene glycol monoethyl ether and dipropylene glycol monopropyl ether; sugar alcohols such as sorbitol; phospholipids such as lecithin (including soybean phospholipid) and hydrogenated lecithin; mucopolysaccharides such as heparin and chondroitin; lactic acid and pyrrolidone In addition to NMF-derived components such as sodium carboxylate and urea, polyglutamic acid and the like can be mentioned. Preferred are alanine, serine, glycine, proline, hydroxyproline, glucosamine, theanine, glycerin, diglycerin, 1,3-butylene glycol, hydrogenated lecithin, heparin, chondroitin,
Lactic acid, sodium pyrrolidonecarboxylate, and polyglutamic acid.

When a moisturizing component is used, it is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. ~ 3
0% by weight, preferably 0.5 to 10% by weight, more preferably 0.5 to 5% by weight.

As whitening ingredients, ellagic acid; phytic acid; lucinol; chamomile ET; vitamin A or its derivative, vitamin C or its derivative (such as magnesium ascorbate phosphate),
Vitamins such as pantothenic acid or its derivatives are listed. Of these, preferred are pantothenic acid or derivatives thereof, ellagic acid, phytic acid, vitamin A or derivatives thereof, vitamin C or derivatives thereof, and particularly preferred is vitamin C or derivatives thereof (magnesium ascorbate phosphate). ). These whitening components may be used alone or in combination of two or more.

A plant component having a whitening effect may be used as a whitening component.
Iris (Iris), Almond, Aloe, Ginkgo, Oolong Tea, Ages, Ogon, Oren, Hypericum, Oyster, Seaweed, Cuckoo, Gardenia, Kujin, Chlorella, Gobaishi, Wheat, Rice, Rice Haiga, Oryzanol, Rice Plant, Saisin, Salamander, Perilla, Peonies, Senkyu, Sakuhakuhi, Soybean, Natto, Tea, Touki, Toki-Senka, Garlic, Hamelis, Safflower, Boppi, Yokuinin, Toki, Amethyst, Asenyaku, Acebi, Bracken, Inaki, Enoki, Oyster (Diospyros kaki) , Black Bean, Gentian, Genzin, Salsa, Sweet Bean, Shouma, Juju, Sage, Zenko, Daikon, Azalea, Tsukuhashigi, Toshishi, Nigaki, Parsley, Holly, Hop, Marubahagi, Choji, Kang Examples include components derived from plants such as elephants. Preferably, Iris (Iris), Aloe, Ginkgo, Oolong tea, Ages, Ogon, Oulen, Hypericum, Olysam, Seaweed, Cuckoo, Gardenia, Kujin, Gobaishi, Wheat, Rice, Rice bran, Saishin, Salamander, Perilla, Peonies, Senkyu , Sakuhakuhi, Tea, Toki, Toki-Senka, Hamelis, Safflower, Buttonpi, Yokuinin, Amethyst, Acalysia, Enoki, Oyster (Diospyros kaki), Cattle, Black Bean, Gentian, Salsa, Soyagen, Juju, Sage, Zenko, Daikon, Tsuji It is a plant-derived component of tsukushihagi, toshishi, nigaki, parsley, holly, hops, clove, licorice and pearl millet, more preferably Iris (iris), aloe, ginkgo, age, ogon, lauren, otogi Riso, gardenia, cucumber, rice, rice bran, saishin, peony, senkyu, sakuhakuhi, tea, touki, eucalyptus, hamamelis, safflower, buttonpi, amethyst, asenyaku, enoki, oyster (Diospyros kaki), sage, radish, azalea, azalea It is a plant-derived component of hops, licorice and yokuinin.
When these plant components are used in the external preparation for skin of the present invention, the form of the plant component is not particularly limited, but can usually be used in the form of a plant extract (plant extract), an essential oil or the like. In addition, the inside of () described in the said plant component is the kind of plant, an alias, or a crude drug name.

When using the above-mentioned whitening component, the ratio to be blended with the external preparation for skin of the present invention is preferably 0.0003.
-10% by weight, more preferably 0.01-5% by weight.
When using a plant component having a whitening effect as a whitening component, one or two are used depending on the purpose.
Species or more can be used in any combination. When the plant component is used as a whitening component, the blending ratio in the external preparation for skin of the present invention is usually 0, in terms of an extract such as extract or essential oil.
It is 00001 to 20% by weight, preferably 0.0001 to 15% by weight, more preferably 0.001 to 10% by weight.

Anti-inflammatory components include allantoin, calamine, glycyrrhizic acid or derivatives thereof, glycyrrhetinic acid or derivatives thereof, zinc oxide, guaiazulene, tocopherol acetate, pyridoxine hydrochloride, menthol, camphor, turpentine oil, indomethacin, salicylic acid or derivatives thereof. . Preferably allantoin, glycyrrhizic acid or a derivative thereof,
Glycyrrhetinic acid or its derivatives, guaiazulene and menthol.

When using the anti-inflammatory component, the proportion to be blended with the external preparation for skin of the present invention is preferably 0.00.
It is 03-10 weight%, More preferably, it is 0.01-5 weight%.

Antibacterial components include chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and its derivatives, popidone iodine, potassium iodide, iodine, isopropylmethylphenol, triclocarban, triclosan, photosensitizer No. 101 Photosensitive element 201, parabens (such as methylparaben, propylparaben, and butylparaben), phenoxyethanol, 1,2-pentanediol, and alkyldiaminoglycine hydrochloride. Preferably, benzalkonium chloride, benzethonium chloride, gluconic acid and derivatives thereof, isopropylmethylphenol, triclocarban, triclosan, photosensitizer 101, photosensitizer 201, paraben (methylparaben, propylparaben, butylparaben), phenoxyethanol, 1 , 2-pentanediol,
Examples thereof include alkyldiaminoglycine hydrochloride. More preferred are benzalkonium chloride, gluconic acid and its derivatives, benzethonium chloride, and isopropylmethylphenol.

When the antibacterial component is used, the proportion to be blended with the external preparation for skin of the present invention is preferably 0.0003.
-10% by weight, more preferably 0.01-5% by weight.

Cell activation components include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid: vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride and pantothenic acids: α-hydroxy acids such as glycolic acid and lactic acid: tannin, Examples include flavonoids, saponins, allantoin, and photosensitizer 301. Preferred are amino acids such as γ-aminobutyric acid and ε-aminocaproic acid: vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride and pantothenic acids.

When using the above-mentioned cell activation component, the ratio to be blended with the external preparation for skin of the present invention is preferably
It is 0.0003-10 weight%, More preferably, it is 0.01-5 weight%.

Convergent ingredients include alum, chlorohydroxyaluminum, aluminum chloride,
Examples include metal salts such as allantoin aluminum salt, zinc sulfate, and aluminum potassium sulfate; organic acids such as tannic acid, citric acid, lactic acid, and succinic acid. Alum, chlorohydroxyaluminum, aluminum chloride, allantoin aluminum salt, aluminum potassium sulfate, and tannic acid are preferred.

When the astringent component is used, the proportion to be blended in the external preparation for skin of the present invention is usually 0.0003 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.01 to 5% by weight.

Antioxidant components include ascorbic acid and its derivatives (magnesium ascorbyl phosphate, ascorbyl tetraisopalmitate), butylhydroxyanisole, dibutylhydroxytoluene, sodium bisulfite, erythorbic acid and its salts, flavonoids, catalase, superoxide dismutase Thioredoxin, taurine, thiotaurine, hypotaurine, thioredoxin, flavonoids, catechin, astaxanthin and the like. Preferred are ascorbic acid and its derivatives, thiotaurine, hypotaurine, thioredoxin, flavonoids, and astaxanthin.

When the antioxidant component is used, the proportion to be blended with the external preparation for skin of the present invention is usually 0.00001 to 10% by weight, preferably 0.0001 to 5% by weight, more preferably 0.001 to 2% by weight.

In addition to the above components, the external preparation for skin of the present invention further comprises a surfactant, a gelling agent, fats and oils,
Chelating agents, sugars, and UV protection agents can also be added.

Examples of the surfactant include polyoxyethylene (hereinafter also referred to as POE) -octyldodecyl alcohol and POE-2-decyltetradecyl alcohol; POE-branched alkyl ether; POE-oleyl ether and POE-cetyl ether POE-alkyl ethers; sorbitan esters such as sorbitan monooleate, sorbitan monoisostearate and sorbitan monolaurate; POE-sorbitan monooleate, POE-sorbitan monoisostearate, and POE-sorbitan monolaurate, POE- POE-sorbitan esters such as sorbitan tetraoleate; glycerol fatty acid esters such as glycerol monooleate, glycerol monostearate (glycerol monostearate), and glycerol monomyristate; POE-glycerol monooleate POE-glycerin monostearate and POE-glycerin fatty acid esters such as POE-glycerin monomyristate; POE-cured castor oil such as POE-dihydrocholesterol ester, POE-cured castor oil, and POE-cured castor oil isostearate Fatty acid esters; POE-alkyl aryl ethers such as POE-octylphenyl ether; glycerin alkyl ethers such as monoisostearyl glyceryl ether and monomyristyl glyceryl ether; POE-glycerins such as POE-monostearyl glyceryl ether and POE-monomyristyl glyceryl ether Alkyl ethers;
Polyglycerin fatty acid esters such as diglyceryl monostearate, decaglyceryl decastate, decaglyceryl decaisostearate, and diglyceryl diisostearate; various nonionic surfactants such as sorbitan sesquioleate: or lecithin, hydrogen Examples include naturally occurring surfactants such as added lecithin, saponin, surfactin sodium, cholesterol, bile acids, and amino acid surfactants. These surfactants may be used alone or in any combination of two or more.

When a surfactant is used, the blending ratio in the external preparation for skin of the present invention is not particularly limited as long as it does not affect the skin and mucous membranes and does not interfere with the effects of the present invention. It can be appropriately selected and used in such a range that it is contained in the agent at a ratio of 0.01 to 30% by weight. From the viewpoint of the stability of the active ingredient in the external preparation for skin of the present invention and the feeling of use on the skin, the range is preferably 0.1 to 20% by weight, more preferably 0.1 to 10% by weight.

Examples of the gelling agent include carboxyvinyl polymer, polyoxyethylene / polyoxypropylene block copolymer, polyvinyl alcohol, sodium polyacrylate, sodium alginate, acrylic acid / alkyl methacrylate copolymer, and the like. These gelling agents may be used alone or in any combination of two or more.

When a gelling agent is used, the blending ratio in the external preparation for skin of the present invention is not particularly limited as long as it does not affect the skin and mucous membranes and does not interfere with the effects of the present invention. Although it can be appropriately selected and used within the range of 0.01 to 20% by weight in the external preparation, from the viewpoint of the stability of the active ingredient in the external preparation of the present invention and the feeling of skin use, etc. , Preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight.

The fats and oils are not particularly limited as long as they are used as components of external preparations in the field of pharmaceuticals, quasi drugs and cosmetics. For example, synthetic fats and oils such as medium-chain fatty acid triglycerides; soybean oil, rice oil, rapeseed oil, cottonseed oil, sesame oil, safflower oil, castor oil, olive oil, macadamia nut oil, cacao oil, coconut oil, sunflower oil, palm oil, flax oil, perilla Oil, shea oil,
Vegetable oils such as coconut oil, tree wax, jojoba oil, grape seed oil, and avocado oil; egg yolk oil,
Animal fats such as beef tallow, milk fat, and pork fat; waxes such as beeswax, whale wax, lanolin, carnauba wax, candelilla wax; carbonization of liquid paraffin, squalene, squalane, microcrystalline wax, ceresin wax, paraffin wax, petrolatum, etc. Hydrogen; natural and synthetic fatty acids such as lauric acid, myristic acid, stearic acid, oleic acid, isostearic acid, behenic acid; natural and synthetic higher alcohols such as cetanol, stearyl alcohol, hexyldecanol, octyldecanol, lauryl alcohol, behenyl alcohol; Isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, octyldodecyl oleate, glyceryl tri-2-ethylhexanoate, octyl isononanoate, cholesterol Esters and ethers such as Ruoreto; silicone oils such as methyl phenyl polysiloxanes. These fats and oils may be used alone or in any combination of two or more.

When these oils and fats are used, the blending ratio in the external preparation for skin of the present invention is not particularly limited as long as it does not affect the skin and mucous membranes and does not interfere with the effects of the present invention. Although it can be appropriately selected and used within the range of 0.01 to 70% by weight contained in the external preparation for skin, it is possible to use the active ingredient in the external preparation for skin according to the present invention in terms of stability and feeling of use on the skin. Therefore, the range of 0.1 to 60% by weight, more preferably 0.1 to 50% by weight can be mentioned.

The chelating agent is not particularly limited as long as it is used as a component of an external preparation in the pharmaceutical, quasi-drug or cosmetic field. Examples thereof include ethylenediaminetetraacetic acid, ascorbic acid, citric acid, phytic acid, polyphosphoric acid, metaphosphoric acid, succinic acid, and salts thereof. Among these, ethylenediaminetetraacetic acid, citric acid or a salt thereof is preferable, and ethylenediaminetetraacetic acid or a salt thereof is particularly preferable.
The salt of ethylenediaminetetraacetic acid is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable. For example, ethylenediaminetetraacetic acid sodium, ethylenediaminetetraacetic acid trisodium (edetate trisodium), Mention may be made of alkali metal salts such as disodium ethylenediaminetetraacetate and tetrasodium ethylenediaminetetraacetate.
Ethylenediaminetetraacetic acid or a salt thereof can also be used in the form of a hydrate. Specific examples of the hydrate form include disodium ethylenediaminetetraacetate (hereinafter also referred to as sodium edetate).
These chelating agents may be used alone or in any combination of two or more.

When these chelating agents are used, the blending ratio in the external preparation for skin of the present invention is not particularly limited as long as it does not affect the skin and mucous membranes and does not interfere with the effects of the present invention. Although it can be appropriately selected and used within the range of 0.0005 to 0.5% by weight contained in the external preparation for skin, it is possible to use the active ingredient in the external preparation for skin according to the present invention in terms of stability and feeling of use on the skin. Therefore, the range of 0.001 to 0.2% by weight, more preferably 0.01 to 0.1% by weight can be mentioned.

The saccharide is not particularly limited as long as it is used as a component of an external preparation in the pharmaceutical, quasi-drug or cosmetic field. For example, monosaccharides (for example, glucose, galactose, mannose, ribose, arabinose, xylose, deoxyribose, fructose, ribulose, lyxose, etc.), disaccharides (for example, sucrose, trehalose, lactose, maltose, cellobiose, etc.), oligosaccharides ( For example, lactulose, raffinose, pullulan, etc.), cellulose or derivatives thereof (for example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose,
Nitrocellulose, cationized cellulose, etc.), high molecular sugars [for example, chondroitin sulfate, dermatan, heparan, heparin, keratan or salts thereof (for example, chondroitin sulfate sodium, dermatan sulfate, heparan sulfate, keratan sulfate, etc.) And the like, and sugar alcohols (eg, mannitol, xylitol, erythritol, pentaerythritol, maltitol, sorbitol, polydextrose, etc.), xylose, inositol, dextrin and derivatives thereof (
Dextrin palmitate, etc.), honey, brown sugar extract and the like. These saccharides may be used alone or in any combination of two or more.

The UV protection agent is not particularly limited as long as it is used as a component of an external preparation in the pharmaceutical, quasi-drug or cosmetic field. For example, inorganic such as zinc oxide, titanium oxide (crystal system: anatase, rutile or brookite), kaolin, calcium carbonate, iron oxide, cerium oxide, zirconium oxide, titanium silicate, zinc silicate, anhydrous silicic acid and cerium silicate Compounds, those inorganic compounds coated with inorganic powders such as mica and talc, compounded with resin powders such as polyamide, polyethylene, polyester, polystyrene, nylon, and silicon oil and fatty acid aluminum salts Treated, methyl diisopropylcinnamate, sinoxate, glyceryl mono-2-ethylhexanoate diparamethoxycinnamate, isopropyl dimethoxycinnamate diisopropylcinnamate ester, 2-ethylhexyl paramethoxycinnamate, Cinnamic acid such as benzyl cinnamate UV absorbers; benzophenone UV absorbers such as oxybenzone, hydroxymethoxybenzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenone disulfonate, dihydroxybenzophenone, tetrahydroxybenzophenone; paraaminobenzoic acid, paraaminobenzoic acid Benzoate-based ultraviolet rays such as ethyl acetate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, 2-ethylhexyl paradimethylaminobenzoate, ethyl 4- [N, N-di (2-hydroxypropyl) amino] benzoate Absorbent: ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, salicylic acid Salicylic acid UV absorbers such as phenyl, homomenthyl salicylate, methyl salicylate, guaiazulene, dimethoxybenzylidenedioxoimidazolidinepropionate 2-ethylhexyl, 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] 1, 3,5-triazine, parahydroxyanisole, 2- (2
-Hydroxy-5-methylphenyl) benzotriazole, 4-tert-butyl-4'-methoxydibenzoylmethane and the like. These UV protection agents may be used alone or in any combination of two or more.

The external preparation for skin of the present invention includes pharmaceuticals, quasi-drugs or cosmetics as necessary within a quantitative and qualitative range that does not impair quality such as appearance stability and viscosity and does not impair the effects of the present invention. Various components that are generally used as components of external preparations in the field, such as irritation reducers, thickeners, preservatives, colorants, dispersants, pH adjusters, and fragrances can be blended. These components may be used alone or in combination of two or more.

The skin external preparation of the present invention comprises hydroquinone and tocopherol, and if necessary, the above-mentioned optional components are mixed and mixed with other solvents and bases of commonly used external preparations as necessary. It can be prepared in various desired forms such as paste, mousse, gel, liquid, emulsion, cream, sheet (supported substrate), aerosol, and spray. These can be produced by conventional methods in the art.

The external preparation for skin of the present invention usually only has to have a liquidity of pH 1 to 8, but the stability of the preparation,
From the viewpoint of low irritation to skin and mucous membranes and good skin feeling, preferably pH 2
It is desirable to be in an acidic region of ˜7, more preferably pH 2-6.

The skin external preparation of the present invention includes, for example, basic cosmetics such as emulsions, creams, lotions, oils and packs; cleansing agents such as facial cleansers, cleansings and body cleansing agents; UV protection agents; cosmetics and external medicines such as whitening agents Various external compositions belonging to the field of external medicines such as quasi-drugs, stains, acne scars and buckwheat therapeutic agents can be obtained.

  The external preparation for skin of the present invention can effectively exhibit a melanin production-suppressing effect based on hydroquinone, that is, a whitening effect, and also realizes reduction of cytotoxicity and relaxation of skin irritation. It is safe. Because of the effects of the invention, the external preparation for skin of the present invention is preferably a cosmetic among the above, and whitening cosmetic is particularly preferable.

Furthermore, since the present invention can reduce the cytotoxicity of hydroquinone by containing tocopherol, it can also be a “hydroquinone cytotoxicity-reducing agent containing tocopherol”.
In the hydroquinone cytotoxicity-reducing agent of the present invention, tocopherol and the content thereof are the same as those used in the above-mentioned external preparation for skin. Furthermore, the product obtained by this method can be used in known or commonly used dosages and dosages by dividing it once to several times per day according to the application.

The present invention also includes a method for reducing the cytotoxicity of hydroquinone with tocopherol. In the method of the present invention, the reduction in cytotoxicity of hydroquinone can be achieved by applying tocopherol to the skin in combination with hydroquinone.
In the method of the present invention, tocopherol and the content thereof are the same as those used in the external preparation for skin. Furthermore, the product obtained by this method can be used in known or commonly used dosages and dosages by dividing it once to several times per day according to the application.

Hereinafter, the present invention will be described in more detail based on examples and test examples, but the present invention is not limited to these examples. In the following formulations,% means weight (W / W)% unless otherwise specified. The test was performed using fibroblasts and epidermal keratinocytes.

Test Example 1 Cytotoxicity evaluation test
Normal human fibroblasts (NHDF · AD: Kurashiki Boseki Co., Ltd.) were seeded in a 24-well plate at 1.0 × 10 ⁴ cells / well and cultured in 1 ml of DMEM (10% FBS) medium for 4 days. Next, the medium is replaced with 1 ml, and 5 μl of ethanol solution or 5 μl of ethanol containing each tocopherol at a predetermined concentration is added so that the sample concentrations shown in Tables 1 and 2 are added. Incubate for hours. Thereafter, the test drug was removed by exchanging with 1 ml of the medium, and the cell viability was measured by the WST-1 method. From these results, the cell viability was determined with the cell survival number of Control Example 1 being 100.
The results are shown in Tables 1 and 2.

From Table 1, it was confirmed that α-tocopherol had a cell viability of 1.3 times or more and γ-tocopherol was 2.3 times or more, and the cytotoxicity was reduced. The δ-tocopherol in Table 2 was 3.4 times even at a considerably low concentration of Example 7, indicating that the cytotoxicity was significantly reduced.
Therefore, it was clarified that all the examples had a cytotoxic effect of hydroquinone.

Test Example 2 Cytotoxicity evaluation test
Cytotoxicity was evaluated in the same manner as in Test Example 1 using normal human epidermal keratinocytes (NHEK · F: Kurashiki Boseki Co., Ltd.). The culture medium is EpiLife / HKGS (manufactured by Kurashiki Boseki Co., Ltd.)
The number of seeded cells was 2.0 × 10 ⁴ cells / well. From these results, the cell viability was determined with the number of viable cells in Control Example 2 as 100.
The results are shown in Table 3.

In Examples 10, 11, and 12, the cell viability after addition of hydroquinone was increased as compared with Control Example 2. Furthermore, the p values were 0.001%, 0.02%, and 0.001%, respectively, and statistically significant differences were observed.
Therefore, it was clarified that all the examples had a cytotoxic effect of hydroquinone.

It is known that α has the highest physiological activity of tocopherol. From the above, however, regarding the action of hydroquinone to reduce cytotoxicity, δ is observed in both fibroblasts and epidermal keratinocytes present in the skin. It was the most surprising result, the highest and then the higher γ. In particular, in the case of epidermal keratinocytes, the evaluation was conducted at a higher concentration than that of fibroblasts, and the effect was observed in the main constituent cells of the epidermis. Therefore, when applying the skin external preparation of the present invention to the skin, Safety improvement can be expected.
Furthermore, the skin external preparation of the present invention was a preparation that also reduced primary skin irritation by hydroquinone.

The formulation examples are given below. In addition, the compounding quantity in the following Examples represents weight% about all the things which have no description of a unit especially.

Example 13 (Cosmetic liquid)
Hydroquinone 4
δ-tocopherol 2
Sodium ascorbate 0.5
Sage extract 0.1
1,3-butylene glycol 15
Diglycerin 55
Purified water
100%

Example 14 (Cosmetic liquid)
Hydroquinone 1
γ-tocopherol 2
Ascorbyl magnesium phosphate 3
Dipropylene glycol 40
Propylene glycol 20
Purified water
100%

Example 15 (lotion)
Hydroquinone 2
γ-Tocopherol 1
Pyridoxine hydrochloride 0.1
Dipotassium glycyrrhizinate 0.2
Glycerin 15
Ethanol 10
1,3-butylene glycol 5
Polyoxyethylene hydrogenated castor oil 1
Lactic acid 1
Sodium alginate 0.1
Purified water
100%

Example 16 (pack)
Hydroquinone 1
γ-tocopherol 2
SOHAKUHI EXTRACT 0.1
Diglycerin 20
1,3-butylene glycol 10
Polyvinyl alcohol 10
Ethanol 8
Ethylene glycol 0.4
Methylparaben 0.1
Fragrance 0.2
Purified water
100%

Example 17 (milky lotion)
Hydroquinone 8
δ-Tocopherol 6
Squalane 2
Aloe extract 0.5
Glycerin 15
Diglycerin 10
Polyoxyethylene oleyl ether 2.8
Sorbitan sesquioleate ester 2.2
Octyl isononanoate 1
Carboxyvinyl polymer 0.1
Potassium hydroxide 0.1
Edetate trisodium 0.1
Phenoxyethanol 0.1
Methylparaben 0.15
Butylparaben 0.05
Purified water
100%

Example 18 (cream)
Hydroquinone 4
δ-Tocopherol 4
Arbutin 1
Parsley extract 0.5
Pyridoxine hydrochloride 0.1
Retinol 0.01
White petrolatum 20
Diglycerin 15
Stearyl alcohol 10
Propylene glycol 5
Behenyl alcohol 5
Polyoxyethylene (60) hydrogenated castor oil 4
Glycerol monostearate 1
Methylparaben 0.1
Propylparaben 0.1
Dibutylhydroxytoluene 0.01
Purified water
100%

Example 19 (Cosmetic liquid)
Hydroquinone 1
Arbutin 1
γ-tocopherol 2
Sodium ascorbate 3
Dipropylene glycol 40
Propylene glycol 20
Purified water
100%

Example 20 (sunscreen cream)
Hydroquinone 1
γ-Tocopherol 4
Hydroxyproline 0.5
Zinc oxide 10
Glyceryl tri-2-ethylhexanoate 10
Liquid paraffin 8
Dipropylene glycol 5
Octyl paramethoxycinnamate 5
Olive oil 5
Oxybenzone 4
Triethanolamine 0.5
Acrylic acid / alkyl methacrylate copolymer 0.4
Carboxyvinyl polymer 0.2
Phenoxyethanol 0.2
Purified water
100%

Example 21 (Gel)
Hydroquinone 0.5
δ-tocopherol 1.0
Hamelis Extract 1.5
Allantoin 0.1
Propylene glycol 15
1,3-butylene glycol 5
Polyoxyethylene (60) hydrogenated castor oil 2
Carboxyvinyl polymer 0.5
Potassium hydroxide 0.35
Hydroxypropyl methylcellulose 0.2
Methylparaben 0.2
Hydrogenated soybean phospholipid 0.05
Sodium edetate 0.02
Sodium polyacrylate 0.01
Purified water
100%

Example 22 (Cosmetic liquid)
Hydroquinone 2
α-Tocopherol 2
Sodium ascorbate 0.5
Diglycerin 55
1,3-butylene glycol 15
Purified water
100%

Claims (2)

(A) Hydroquinone and (B) δ-tocopherol, and the formulation ratio of hydroquinone and δ-tocopherol is 0.01-12 parts by weight of δ-tocopherol with respect to 1 part by weight of hydroquinone . The skin external preparation of Claim 1 whose compounding quantity of (delta) -tocopherol is 0.01 to 8 weight% with respect to the whole skin external preparation.