JP2016506925A - Skin-whitening application of resveratrol derivatives - Google Patents

Abstract

The present invention relates to a skin whitening use of a resveratrol derivative, and more specifically, an acetylated derivative of resveratrol or a hydroxy derivative thereof, or a cosmetically acceptable salt thereof as an active ingredient. Cosmetic composition; cosmetic comprising the cosmetic composition; pharmaceutical composition for skin whitening comprising resveratrol or an acetylated derivative of a hydroxy derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient; A topical skin preparation comprising the pharmaceutical composition for whitening the skin; a method for whitening the skin comprising administering resveratrol or an acetylated derivative of a hydroxy derivative thereof, or a pharmaceutically acceptable salt thereof to an individual; and skin whitening The present invention relates to a novel resveratrol derivative compound having an effect.

Description

  The present invention relates to a skin whitening application of a resveratrol derivative, and more specifically, a cosmetic comprising an acetylated derivative or a cosmetically acceptable salt of resveratrol or a hydroxy derivative thereof as an active ingredient. A cosmetic composition containing the cosmetic composition; a pharmaceutical composition for skin whitening comprising an acetylated derivative of resveratrol or a hydroxy derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient; A topical skin preparation comprising a pharmaceutical composition for skin whitening; a skin whitening method comprising administering an acetylated derivative of resveratrol or a hydroxy derivative thereof or a pharmaceutically acceptable salt thereof to an individual; and a skin whitening effect It has a novel resveratrol derivative compound.

  Melanin has been found in many organisms as a pigment that exists everywhere in nature, and is a generic term for black or brown pigments that exist mainly in tissues such as animal skin and eyes. These exist primarily as melanin proteins that bind strongly to globulins and do not dissolve in water, but dissolve in basic or concentrated acidic solutions. Melanin has a function of blocking a certain amount or more of ultraviolet rays, so that the temperature of the skin is maintained and the skin is protected from the ultraviolet rays. In short, it absorbs ultraviolet rays that can induce malignant melanoma and skin cancer, and converts it into harmless heat. In addition, the amount of melanin determines the color of the skin, and these are present not only in the skin but also in the hair, eyes, ears, and even the brain as important factors that determine the color of human skin. Skin melanin is produced by melanocytes, but the gene that expresses melanin differs depending on the race, which regulates the amount of melanocytes and determines the color of the skin. Some animals and humans may have albino, which has few or no melanocytes. Melanin is an assembly of small molecules, and there are various types. For example, pheomelanin and eumelanin are found in human skin and hair, and eumelanin accounts for the majority, and the lack of eumelanin is the most common cause of whiteness It has become.

  The appropriate amount of melanin present in the skin may show positive effects such as absorbing UV rays and making it look healthy and attractive, but excess melanin causes the skin to appear dull. This is not preferable in terms of beauty. In addition, excessive production of melanin may induce skin darkening or pigmented skin diseases such as spots and freckles. In general, hyperpigmentation of the skin results from internal factors such as hormonal abnormalities, genetic disorders and / or external factors such as excessive UV radiation.

  It is known that the process of pigment deposition on the skin is caused by the action of an enzyme called tyrosinase, followed by excessive production of melanin polymer through a series of oxidation processes and accumulation in the skin. Tyrosinase is a process of producing melanin that converts tyrosine, a kind of amino acid, into dopa (3,4-dihydroxyphenylalanine, DOPA) and dopaquinone (DOPA-quinone), which are intermediates for the production of melanin polymer. It is the most important enzyme. Therefore, melanin can be regulated by suppressing the expression of the tyrosinase or suppressing the activity of the expressed enzyme.

  For the purpose of cosmetics or treating skin diseases, research on ingredients having a skin whitening effect has been ongoing, and one of the methods is tyrosinase, which is the main enzyme involved in melanin production. Efforts have been made to continuously discover substances that suppress the expression of tyrosinase or the activity of expressed tyrosinase. In such a situation, resveratrol and oxyresveratrol are components extracted from natural products, are less harmful to the human body, and have an excellent effect of suppressing melanin production. It is considered as a candidate. However, these compounds have a problem that their chemical stability is not guaranteed and it is difficult to formulate them into cosmetics or pharmaceutical compositions that must be stored for several months or longer. Efforts such as developing new dosage forms have been attempted to overcome these problems, but no reliable countermeasure has been found at present.

  The present inventors are harmless to the human body like resveratrol or oxyresveratrol, and increase chemical stability while maintaining an excellent whitening effect. As a result of diligent efforts to discover materials, it was confirmed that the compounds obtained by acetylating these compounds exhibited the above-mentioned effects, and the present invention was completed.

  One object of the present invention is to provide a cosmetic composition comprising an acetylated derivative of resveratrol or a hydroxy derivative thereof or a cosmetically acceptable salt thereof as an active ingredient.

  Another object of the present invention is to provide a cosmetic containing the cosmetic composition.

  Still another object of the present invention is to provide a pharmaceutical composition for skin whitening comprising, as an active ingredient, an acetylated derivative of resveratrol or a hydroxy derivative thereof or a pharmaceutically acceptable salt thereof. .

  Still another object of the present invention is to provide an external preparation for skin comprising the pharmaceutical composition for whitening the skin.

  Yet another object of the present invention is a skin whitening method comprising the step of administering an acetylated derivative of resveratrol or a hydroxy derivative thereof or a pharmaceutically acceptable salt thereof to an individual in need thereof. Is to provide.

  Still another object of the present invention is to provide a tetraacetyloxyresveratrol compound having a skin whitening effect.

  The triacetyl resveratrol and tetraacetyloxy resveratrol according to the present invention maintain the whitening effect at the same level as the resveratrol and tetraacetyloxy resveratrol, which are the compounds before acetylation, while maintaining the whitening effect at the same level. In terms of stability, it provides a far superior composition and can be effectively used as a cosmetic and pharmaceutical composition for whitening.

It is the figure which showed the reaction formula which manufactures triacetyl resveratrol (III) and tetraacetyloxy resveratrol (IV) from the resveratrol (I) or oxyresveratrol (II) by this invention, respectively. It is the figure which showed the HPLC chromatogram of resveratrol (I), oxyresveratrol (II), triacetyl resveratrol (III), and tetraacetyloxy resveratrol (IV). It is a figure which shows the UV absorption spectrum of resveratrol (I), oxyresveratrol (II), triacetyl resveratrol (III), and tetraacetyloxy resveratrol (IV). FIG. 4 a is a diagram showing a ¹ H NMR spectrum of (a) resveratrol (I). FIG. 4 b shows a ¹ H NMR spectrum of (b) oxyresveratrol (II). FIG. 4 c is a diagram showing a ¹ H NMR spectrum of (c) triacetylresveratrol (III). FIG. 4d is a diagram showing a ¹ H NMR spectrum of (d) tetraacetyloxyresveratrol (IV). FIG. 5a is a diagram showing a ¹³ C NMR spectrum of (a) resveratrol (I). FIG. 5 b is a diagram showing a ¹³ C NMR spectrum of (b) oxyresveratrol (II). FIG. 5 c is a diagram showing a ¹³ C NMR spectrum of (c) triacetylresveratrol (III). FIG. 5d is a diagram showing a ¹³ C NMR spectrum of (d) tetraacetyloxyresveratrol (IV). FIG. 6 a is a diagram showing the results of mass spectrometry of (a) resveratrol (I). FIG. 6 b is a diagram showing the results of mass spectrometry of (b) oxyresveratrol (II). FIG. 6c is a diagram showing the results of mass spectrometry of (c) triacetylresveratrol. FIG. 6d is a diagram showing the results of mass spectrometry of (d) tetraacetyloxyresveratrol (IV). It is the result of measuring cell viability by treatment according to the concentration of resveratrol, oxyresveratrol, triacetylresveratrol, and tetraacetyloxyresveratrol in B16 / F10 cells (A) and HEMs cells (B). . It is the result of having measured the amount of melanins by the treatment according to the density | concentration of resveratrol, an oxyresveratrol, a triacetyl resveratrol, and the tetraacetyloxy resveratrol in a B16 / F10 cell (A) and a HEMs cell (B).

  As one aspect for achieving the above object, the present invention provides a cosmetic composition comprising an acetylated derivative of resveratrol or a hydroxy derivative thereof or a cosmetically acceptable salt thereof as an active ingredient.

  The cosmetic composition may have a skin whitening effect. The term “whitening” in the present invention means that melanocytes increase due to continuous exposure of the skin to ultraviolet rays, thereby preventing excessive deposition of melanin on the skin, or melanin pigment that has already been deposited. Says the function of thinning. Therefore, it is possible to suppress the generation of stains and freckles caused by excessive melanin pigment deposition.

  The acetylated derivatives according to the present invention are characterized by increased chemical stability compared to the reactants before acetylation. Maintained.

  Resveratrol is called 5- [2- (4-hydroxyphenyl) ethenyl] benzene-1,3-diol (5- [2- (4-hydroxyphenyl) ethylene] benzene-1,3-diol) A compound having the IUPAC name, which can be expressed as the following alternative name: 3,5,4'-trihydroxy-trans-stilbene (3,5,4'-trihydroxy-trans-stilbene) Trans-3,5,4′-trihydroxystilbene; 3,4 ′, 5-stilbenetriol (3,4 ′, 5-stilbenetriol); trans-resvera Trans-resveratrol; (E) -5- (p-hydroxystyryl) resorcinol ((E) -5- (p-hydroxystyryl) resorcinol); (E) -5- (4-hydroxystyryl) benzene-1,3-diol ((E) -5- (4-hydroxystyryl) benzene-1,3-diol) .

  Resveratrol is a phytoalexin that some plants naturally produce to combat pathogens such as bacteria or fungi, and a stilbenoid that is a type of phenol that exists in nature. It is. In the chemical aspect, the stilbenoid is a hydroxylated derivative of stilbene, and in the biological aspect, is involved in most biosynthetic pathways utilizing chalcone. It belongs to phenylpropanoids. Since it is contained in a large amount in the red grape skin and other fruits, it can be extracted from them, or biochemically synthesized using a chemically or metabolically controlled microorganism.

  Currently, various effects of resveratrol on humans and animals are being studied. Although known to be involved in longevity, this is still controversial. Mouse and rat experiments have confirmed that they have anti-cancer, anti-inflammatory, hypoglycemic and other beneficial cardiovascular effects. However, the effects reported for humans, although largely judged to be favorable, fall short of these. For example, a significant effect of reducing blood glucose was confirmed by administering resveratrol in a form produced to improve biosynthesis in an extremely high volume (3 to 5 g). In addition, although it is known to have an anti-aging effect, the scientific basis is still not sufficient. Research on resveratrol has just begun and the long-term effects on humans are not yet known.

  The hydroxy derivative of resveratrol may preferably be oxyresveratrol. The oxyresveratrol is 4-[(E) -2- (3,5-hydroxyphenyl) ethenyl] benzene-1,3-diol (4-[(E) -2- (3,5-dihydroxyphenyl) ethene] benzene-1,3-diol), which can be expressed as the following alternative names: 2,3 ′, 4,5′-tetrahydroxy-trans-stilbene ( 2,3 ′, 4,5′-tetrahydroxy-trans-stilbene); 2,3 ′, 4,5′-tetrahydroxystilbene (2,3 ′, 4,5′-tetrahydroxystilbene); 4-[(E) -2- (3,5-dihydroxyphenyl) vinyl] resorcinol (4-[(E) -2- (3,5-dihydroxyphenyl) vinyl] resorcinol); tetrahydroxystilbene (tet ahydroxystilbene).

  The oxyresveratrol is a kind of stilbenoid present in the redwood of Artocarpus lakocha, and is a raw material of “Pug-Haad” which is a traditional drug. Moreover, it is an aglycone of mulberoside A (mulberoside A) which is a compound existing in mulberry (also known as white mulberry). Oxyresveratrol can also be extracted from natural products or chemically synthesized for use. It is considered a potential tyrosinase inhibitor.

  In the present invention, the resveratrol or a hydroxy derivative thereof can have a skin whitening effect, but it cannot be used as a composition for skin whitening due to its inherent chemical instability. As a result of studying to maintain and increase the skin whitening effect, and to provide further stability and actually be used as a composition for skin whitening, the form of acetylated derivative It has been found that the above conditions can be satisfied if possible. Therefore, when an acetylated derivative of resveratrol or an acetylated derivative of resveratrol hydroxy derivative is included as an active ingredient, the cosmetic composition or the pharmaceutical composition for skin whitening described below can be used in practice. It can be produced as a composition and used effectively.

The acetylated derivative of resveratrol may preferably be triacetylresveratrol. The triacetyl resveratrol is trans-triacetyl resveratrol; acetyl-resveratrol; acetyl-trans-resveratrol; trans-res Trans-resveratrol triacetate; 5-[(1E) -2- [4- (acetyloxy) phenyl] ethenyl] -1,3-benzenediol-1,3-diacetate (5-[(1E ) -2- [4- (acetyloxy) phenyl] ethyl] -1,3-benzendiol-1,3-diacetate); 4-[(E) -2- (3,5-diacetoxyphenyl) vinyl] phenyl acetate (4-[(E) -2- (3,5- iacetoxyphenyl) vinyl] phenyl acetate); resveratrol 3,5,4′-triacetate; 3,5,4′-tri-O-acetylresveratrol (3,5, 4'-tri-O-acetylresveratrol);3,5,4'-triacetoxy-trans-stilbene and trans-3,5,4'-triacetoxystilbene Different notations such as (trans-3,5,4′-triacetoxy stilbene) can be used, and can be expressed as a structural formula of the following chemical formula 1.
[Chemical 1]

The acetylated derivative of the hydroxy derivative of resveratrol may preferably be tetraacetyloxyresveratrol. Said tetraacetyloxyresveratrol is acetyl-oxyresveratrol; trans-tetraacetyloxyresveratrol; acetyl-trans-oxyresveratrol; acetyl-trans-oxyresveratrol Trans-oxyresveratrol tetraacetate; 4-[(E) -2- (3,5-diacetoxyphenyl) ethenyl] benzene-1,3-diacetate (4-[(E ) -2- (3,5-diacetoxyphenyl) ethyl] benzene-1,3-diacetate); 2,3 ′, 4,5′-tetraacetoxy-trans-still (2,3 ′, 4,5′-tetraacetoxy-trans-stilbene); 2,3 ′, 4,5′-tetraacetoxystilbene (2,3 ′, 4,5′-tetraacetoxystilbene); and tetraacetoxystilbene Different notations such as (tetraacetoxystilbene) can be used, and can be expressed as a structural formula of the following chemical formula 2.
[Chemical 2]

  According to a specific embodiment of the present invention, triacetyl resveratrol and tetraacetyloxyresveratrol are more chemically stable than resveratrol and oxyresveratrol, which are acetylated transfer compounds, on the dosage form. Because it is excellent, it does not change color even when stored at high temperature for a long time, maintains a constant content, and is decomposed by ester hydrolase (esterase) when applied to the human body, and resveratrol and oxyres, respectively Converted to veratrol and exhibits whitening activity. In addition, when it was first applied to the human body after confirming that the cytotoxicity was low by in-vitro cell tests, it showed an excellent whitening effect while being harmless to the human body. It is judged that it can be used as a preparation and a pharmaceutical composition.

  The resveratrol or an acetylated derivative of a hydroxy derivative thereof as an active ingredient of the composition in the present invention can be used in the form of a cosmetically acceptable salt thereof. As the salt, an acid addition salt formed by a cosmetically acceptable free acid is useful. Acid addition salts are prepared in the usual manner, for example, by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Can do. The same molar amount of the compound and the acid or alcohol in water (eg glycol monomethyl ether) can be heated and the mixture can then be evaporated to dryness or the precipitated salt can be filtered off with suction. At this time, organic acids and inorganic acids may be used as free acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as inorganic acids, and methanesulfone as organic acids. Acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid Acid (citric acid), lactic acid (lactic acid), glycolic acid (gluconic acid), gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid (glucuronic acid), aspartic acid, aspartic acid, Corbic acid, carbon acid, vanillic acid, hydroiodic acid and the like may be used, but are not limited thereto.

  Also, cosmetically acceptable metal salts can be made using a base. The alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving the compound in excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. And get. A silver salt corresponding to this can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (eg, silver nitrate).

  The cosmetically acceptable salt of the acetylated derivative of resveratrol or its hydroxy derivative is a salt of an acidic or basic group that can be present in the acetylated derivative of resveratrol or its hydroxy derivative unless otherwise specified. Including most. For example, cosmetically acceptable salts may include sodium, calcium and potassium salts of hydroxy, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate. Salt, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfone There are acid salts (tosylate) and the like, which can be produced by a salt production method known in the art.

  The cosmetic composition of the present invention may contain the active ingredient in an amount of 0.001 to 5% by weight, preferably 0.01 to 5% by weight, based on the entire composition.

  The cosmetic composition according to the present invention may further comprise an excipient for cosmetics. Known ingredients used in ordinary cosmetics as long as the effects of the present invention, i.e., skin whitening effects are not impaired, such as humectants, powder ingredients, ultraviolet absorbers, antioxidants, cosmetic ingredients, glycolipids, plants An extract, an antiseptic, a fragrance, a pH adjuster, a pigment, a viscosity adjuster, or a gelling agent may be included as an auxiliary component.

  Non-limiting examples of humectants include propylene glycol, isoprene glycol, 1,2-heptanediol, 1,3-butylene glycol, dipropylene glycol, hexanediol, polyethylene glycol glycerin, glycerin, diglycerin, triglycerin, Polyglycerin, neopentyl glycol, sorbitol, erythritol, pentaerythritol, glycols such as glucose, galactose, fructose, sucrose, maltose, xylose, xylobiose, reduced oligosaccharides, protein, mucopolysaccharide, collagen, elastin, keratin or tri Ethanolamine or the like may be used.

  Non-limiting examples of powder components include white inorganic pigments such as titanium oxide, silicon-treated titanium oxide, zinc oxide and barium sulfate, colored inorganics such as iron oxide, carbon black, titanium / titanium oxide sintered products and ultramarine blue Pigment, talc, siliconized talc, muscovite, kaolin, silicon carbide, bentonite, smectite, anhydrous silicic acid, aluminum oxide, magnesium oxide, zirconium oxide, diatomaceous earth, calcium silicate, barium silicate, magnesium silicate, calcium carbonate, White body powders such as magnesium carbonate, hydroxyapatite and boron nitride, titanium dioxide-coated mica, iron oxide mica titanium, silicon-treated mica titanium, fish scale foil, polyethylene resin, fluorine resin, cellulose resin and silicon resin Polymer resin powder, Organic low molecular weight powder such as zinc acid and N-acyl lysine, natural organic powder such as starch, silk powder and cellulose powder, red 201, red 202, orange 203, orange 204, blue 404 and yellow Organic pigment powder such as No. 401, red No. 3, red No. 104, red No. 106, orange No. 205, yellow No. 4, yellow No. 5, green No. 3 and blue No. 1 such as zirconium, barium or aluminum lake It may be a composite powder such as a gold foil powder such as organic powder pigment, mica and gold powder, and a fine particle titanium oxide-coated mica titanium.

  Non-limiting examples of ultraviolet absorbers may be benzophenone derivatives, paraaminobenzoic acid derivatives, methoxycinnamic acid derivatives, urocanic acid, and the like.

  Non-limiting examples of antioxidants may be BHT, BHA, vitamin Cs, vitamin Es, derivatives thereof and salts thereof.

  Non-limiting examples of cosmetic ingredients may include vitamins including the above-mentioned vitamins, derivatives thereof and salts thereof, anti-inflammatory agents and herbal medicines.

  A non-limiting example of a glycolipid may be a glycosphingolipid.

  Non-limiting examples of plant extracts may be extracts such as aloe vera, witch hazel, cucumber, lemon, lavender and rose.

  Non-limiting examples of preservatives may include methyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and ethanol.

  Non-limiting examples of fragrances may include camphor oil, tangerine oil, brackish oil, jasmine absolute, pine oil, lime oil, lavender oil, rose oil, and marsk oil.

  Non-limiting examples of pH adjusters may include edetic acid, sodium edetate, sodium chloride, citric acid, sodium citrate, sodium hydroxide, potassium hydroxide, and triethanolamine.

  Non-limiting examples of dyes may be Blue No. 1, Blue No. 204, Red No. 3 and Yellow No. 201.

  Non-limiting examples of viscosity modifiers include polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, other cellulose derivatives, polyvinyl pyrrolidone (PVP), carboxymethyl cellulose, xanthan gum (xanthan). gum), alginic acid or a salt thereof, carrageenan, quince seed, alkaline-genes-producing polysaccharide, carboxyvinyl polymer, acrylate, acrylic acid polymer (chain type, cross-linked type), and acrylic acid / alkyl methacrylate copolymer. May be.

  Non-limiting examples of gelling agents include (behenic acid / eicosanedioic acid) glyceryl and (behenic acid / eicosanedioic acid) polyglyceryl-10, fatty acid metal salts, hydroxystearic acid, textrin fatty acid ester, inulin fatty acid ester , Sucrose fatty acid ester, acylated cellobiose, dibenzylidene sorbitol, amino acid gelling agent, silicic anhydride, organically modified clay mineral, fumed silica, alumina, cross-linked organic polysiloxane, polyethylene wax, paraffin wax and other hydrocarbons It may be a vegetable wax such as wax, carnauba wax or candelilla wax, agar and gelatin.

  The cosmetic composition of the present invention can also be produced in any dosage form normally produced in the art, such as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, It can be formulated into soaps, surfactant-containing cleansings, oils, powder foundations, emulsion foundations, wax foundations, sprays, and the like, but is not limited thereto. More specifically, it can be manufactured into a dosage form of soft lotion, nourishing lotion, cream, nourishing cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder. it can.

  In addition, the cosmetic composition of the present invention may further include one or more cosmetically acceptable carriers that are blended in general skin cosmetics. For example, normal ingredients include milk, water, and an interface. An activator, a humectant, a lower alcohol, a thickener, a chelating agent, a pigment, a preservative, a fragrance, and the like may be appropriately blended, but are not limited thereto.

  The cosmetically acceptable carrier contained in the cosmetic composition of the present invention varies depending on the dosage form. When the dosage form of the present invention is a paste, cream or gel, the carrier component is animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicon, bentonite, silica In addition, talc or zinc oxide may be used.

  When the dosage form of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, especially when it is a spray. Further, a propellant such as chlorofluorohydrocarbons, propane / butane or dimethyl ether may be included.

  When the dosage form of the present invention is a solution or an emulsion, a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component. For example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, There are benzyl alcohol, benzyl benzoate, propylene glycol, and 1,3-butyl glycol oil, especially cottonseed oil, peanut oil, oil from corn kernels, olive oil, castor oil and sesame oil, glycerol aliphatic ester, polyethylene glycol Alternatively, sorbitan fatty acid ester or the like may be used.

  When the molding of the present invention is a suspension, the carrier component is water, a liquid diluent such as ethanol or propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester. Suspending agents such as, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth may be used.

  Further, when the dosage form of the present invention is cleansing containing a surfactant, the carrier component is aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionic acid, imidazolium derivative, methyl Taurate, sarcosinate, fatty acid amide ether sulfate, alkylamide betaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative or ethoxylated glycerol fatty acid ester may be used.

  As another aspect of the present invention, a cosmetic comprising the cosmetic composition is provided.

  The term “cosmetics” in the present invention is an article used on the human body to cleanse and beautify the human body, increase its appeal, change its appearance brightly, and maintain or improve the health of skin and hair. , Defined as a modest effect on the human body.

  Preferably, the cosmetic product according to the present invention may be a functional cosmetic product having a skin whitening effect. The above-mentioned “functional cosmetics” are cosmetics with specific effects emphasized, products that are useful for whitening the skin, products that are useful for improving skin wrinkles, and that are useful for baking the skin cleanly and protecting the skin from ultraviolet rays. Limited as a main product.

  The cosmetic product according to the present invention has been confirmed to exhibit a skin whitening effect when applied to the human body, and therefore it is obvious that it belongs to a functional cosmetic product.

  The cosmetics according to the present invention include skin lotion, skin softener, skin toner, astringent lotion, milk lotion, moisture lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, essence, nutrition essence, pack, soap, shampoo. , Cleansing foams, cleansing lotions, cleansing creams, body lotions, body cleansers, emulsions, pressed powders, loose powders or eye shadows.

  As another embodiment of the present invention, there is provided a pharmaceutical composition for skin whitening comprising resveratrol or an acetylated derivative of a hydroxy derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

  The active ingredient is as described above. Preferably, the hydroxy derivative of resveratrol may be oxyresveratrol, and the acetylated derivative of resveratrol is triacetylresveratrol. Alternatively, the acetylated derivative of the hydroxy derivative of resveratrol may be tetraacetyloxyresveratrol.

  The definition of the compound is as described above.

  As an active ingredient of the composition in the present invention, the acetylated derivative of resveratrol or a hydroxy derivative thereof can be used in the form of a pharmaceutically acceptable salt thereof. The form and manufacturing method of the pharmaceutically acceptable salt are as described for the cosmetically acceptable salt.

  The pharmaceutical composition of the present invention contains the active ingredient in an amount of 0.001 to 10% by weight, preferably 0.01 to 10% by weight, more preferably 0.1 to 10% by weight, based on the entire composition. it can.

  The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable excipient. The term “pharmaceutically acceptable” in the present invention means having a property that is not toxic to cells or humans exposed to the composition. The carrier is not limited as long as it is known in the art such as a buffer solution, preservative, soothing agent, solubilizer, tonicity agent, stabilizer, base, excipient, and lubricant. Can be used. In addition, the pharmaceutical composition of the present invention is prepared by oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterilizations according to the usual methods. It can be used in the form of a liquid for injection. Further, it may be used as a form of an ointment, lotion, spray, patch, cream, powder, suspension, gel, or gel external skin preparation. Carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, silicic acid. Calcium, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulating, it is prepared using a diluent or excipient such as a filler, a bulking agent, a binder, a wetting agent, a disintegrant, and a surfactant that are usually used. Examples of solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations contain at least one excipient, such as starch, in the composition. , Calcium carbonate, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquids for internal use, emulsions, syrups, etc., but various excipients in addition to commonly used simple diluents such as water and liquid paraffin For example, wetting agents, sweeteners, fragrances, preservatives and the like may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories. Nonaqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a suppository base, witepsol, macrogol, tween 61, cacao butter, lauric fat, glycerogelatin may be used.

  As another aspect of the present invention, an external preparation for skin comprising the pharmaceutical composition for whitening the skin is provided.

  The term “external preparation for skin” of the present invention is a comprehensive concept that includes all substances generally used for external application to the skin, and includes, as a non-limiting example of the preparation containing the pharmaceutical composition, Plaster (PLASTERS), lotion (LPTINS), liniment (LINIMENTS), liquid (LIQUIDS AND SOLUTIONS), aerosol (AEROSOLS), extract (EXTRACTS), ointment (OINTENTS), fluid extract (ACLUIDTR) There are emulsions (EMULSIONS), suspensions (SUSPESIONS), capsules (CAPSULES), creams (CREAMS), soft or light gelatin capsules, patches, and gradual preparations.

  The external preparation for skin according to the present invention may be a parenteral administration agent formulated into a solid, semi-solid or liquid form by adding usual inorganic or organic carriers, excipients and diluents. The preparation for parenteral administration may be a transdermal dosage form selected from the group consisting of drops, ointments, lotions, creams, patches, sprays, suspensions and emulsions. It is not limited to.

  Carriers, excipients and diluents that can be included in the external preparation include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, silica Calcium acid, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

  In the external preparation composition for skin according to each dosage form, other ingredients other than the composition of the present invention described above can be appropriately selected and blended by those skilled in the art depending on the dosage form of other external preparation for external use or intended purpose. In this case, when applied simultaneously with other raw materials, a synergistic effect is obtained.

  In addition, when the composition according to the present invention is used as a pharmaceutical composition, a pharmaceutical adjuvant such as a preservative, stabilizer, wettable powder or emulsifier, salt or buffer for adjusting osmotic pressure, etc. And other therapeutically useful substances, and can be formed into parenteral dosage forms by conventional methods.

  The actual dosage of the active ingredient is understood as having to be determined taking into account various relevant factors such as the severity of the symptoms, the chosen route of administration, the age, sex, weight and health status of the subject Should.

  Generally, the dosage of active ingredient ranges from 0.001 ug / kg / day to about 2000 ug / kg / day. A more preferred dosage is from 0.5 ug / kg / day to about 2.5 ug / kg / day. The topical administration may be administered once a day or may be divided into several times.

  In another aspect of the present invention, there is provided a skin whitening method comprising the step of administering resveratrol or an acetylated derivative of a hydroxy derivative thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof. To do.

  Since the acetylated derivative or pharmaceutically acceptable salt of resveratrol or a hydroxy derivative thereof according to the present invention exhibits a skin whitening effect, a skin whitening method using the composition containing the compound is provided. be able to.

  In addition, the skin whitening effect of the present invention can prevent or improve pigmentation on the skin, and correct or recover symptoms caused by pigmentation. Symptoms due to pigmentation can include spots, freckles, seborrheic keratosis (senile moles, black spots) and hyperpigmentation after inflammation or stimulation.

  The term “individual” in the present invention means all animals including humans that require skin whitening as described above, and more specifically, pigmentation occurs or may occur in the skin, or It can mean all animals including humans who may or may develop symptoms due to the pigmentation. Therefore, by administering the compound of the present invention or a composition containing the same to an individual, a skin whitening effect can be effectively achieved, and skin pigmentation can be prevented or improved, or symptoms caused by pigmentation can be achieved. It can be corrected or recovered. The pharmaceutical composition of the present invention can be used in parallel with existing pharmaceutical compositions for skin whitening.

  The term “administration” in the present invention is a general term for providing a predetermined substance to an individual by any appropriate method, and the administration route is arbitrary as long as it can reach the target skin. It may be administered through any route. The administration may be oral or parenteral administration, preferably parenteral administration, and more preferably in the form of being applied to the skin.

  The term “application” in the present invention means any method by which the composition according to the present invention is brought into contact with the skin of an individual by any appropriate method, whereby the composition is absorbed into the skin. And

As another aspect of the present invention, a compound having a skin whitening effect represented by the following chemical formula 2 is provided.
[Chemical formula 2]

  The compound having the skin whitening effect represented by Chemical Formula 2 is tetraacetyloxyresveratrol, and can be produced by acetylation reaction or esterification reaction of oxyresveratrol.

  The term “acetylation” in the present invention is a reaction called an ethanolylation reaction according to the IUPAC nomenclature, which is a reaction for introducing an acetyl functional group into a compound. As a result, an active hydrogen atom is substituted with an acetyl group, thereby providing a compound in which an acetoxy group is substituted. A typical example is a reaction of synthesizing asparin from salicylic acid. In particular, in the case of a reaction in which an acetyl group replaces a hydrogen atom of a hydroxy group, an acetate that is a special form of ester is produced as a result. Acetic anhydride may be used as the acetylating agent that reacts with hydroxy, but is not limited thereto. The acetylation reaction can be performed using a method known in the art without limitation.

The term “esterification reaction” in the present invention refers to, for example, a reaction of carboxylic acid (RCOOH) with alcohol (R′OH) under heating in the presence of an acid catalyst, ester (RCOOR ′) and water (H ₂ O). As the acid catalyst, concentrated sulfuric acid, hydrochloric acid, p-toluenesulfuric acid or the like may be used, and dry hydrogen chloride gas may be used, but is not limited thereto. Since the esterification reaction is usually slow and reversible, the yield can be increased by reacting while continuously removing another product, water, to suppress the reverse reaction. In addition, when the boiling point of the product ester is lower than that of the reaction product alcohol or carboxylic acid, a method of maintaining the reaction while recovering the product by distillation can be used. The esterification reaction can be performed using a method known in the art without limitation.

  According to specific embodiments of the invention, resveratrol and oxyresveratrol, each containing 3 or 4 reactive hydroxy groups, are reacted with acetic anhydride in the presence of pyridine to produce 3 or 4 Triacetyl resveratrol and tetraacetyloxy resveratrol in which all hydrogen atoms of the hydroxy group were substituted with acetyl groups were produced (FIG. 1, Examples 1 and 2).

  Hereinafter, the present invention will be described in more detail with reference to examples. These examples are for explaining the present invention more specifically, and the scope of the present invention is not limited by these examples.

Example 1: Preparation of triacetyl resveratrol (III)
20 g of resveratrol (I) was dissolved in a mixture of 100 g of pyridine and 200 g of acetic anhydride, and then stirred at room temperature for 24 hours. 700 g of water was gradually added to the mixture and mixed to precipitate the reaction product. The precipitate was collected by filtration, washed with water, dissolved in 2000 g of ethanol while heating, and allowed to stand at room temperature to induce crystallization. This was filtered again to recover the crystals and dried to obtain 22 g of triacetylresveratrol (III).

Example 2: Preparation of tetraacetyloxyresveratrol (IV)
20 g of oxyresveratrol (II) was dissolved in a mixture of 200 g of pyridine and 50 g of acetic anhydride, and then stirred at 50 ° C. for 3 hours. The mixture was mixed while gradually adding 750 g of water to precipitate the reaction product. The precipitate was collected by filtration, washed with water, dissolved in 200 g of ethanol, 100 g of water was gradually added and left at room temperature to induce crystallization. This was filtered again to recover the crystals and dried to obtain 24 g of tetraacetyloxyresveratrol (IV).

Analysis Example 1: Analysis of produced triacetylresveratrol and tetraacetyloxyresveratrol To confirm the triacetylresveratrol and tetraacetyloxyresveratrol produced in Examples 1 and 2, HPLC, UV, And analyzed using NMR.

1-1: HPLC analysis For analysis by HPLC, a Gilson HPLC system (Gilson Inc., Middleton, WI, USA) equipped with a UV / VIS 151 detector was used. As the stationary phase, a 5 μm hectare MC18 column (Hector-MC18 column; 4.6 mm × 250 mm; RS tech co., Daejeon, Korea) was used. As a mobile phase, using a mixed solution of 0.5% formic acid (A) and acetonitrile (acetonitryl; B), increasing the content of B with a constant gradient of 30% to 100% over 50 minutes. went. The flow rate was 0.8 mL per minute, and the detection wavelength of the UV detector was set at 280 nm. A 20 μL sample adjusted to a concentration of 1 mM was used.

  The analysis result of HPLC is shown in FIG. Each compound was identified by a specific retention time peak.

1-2: Absorbance analysis The produced sample was dissolved in ethanol, and a UV absorption spectrum was recorded using a Shimadzu UV-1650PC spectrophotometer system (Shimadzu Corporation, Kyoto, Japan).

  The measurement results are shown in FIG. Each chemical showed a specific absorption spectrum, and it was confirmed that the absorption spectrum of the acetylated derivative moved at a slightly shorter wavelength than the reaction product before acetylation.

1-3: NMR analysis The produced sample was dissolved in acetone-d6, and ¹ H- and ¹³ C-NMR spectra were obtained using 500 Mhz Varian Unity INOVA 500 FT-NMR (Varian Inc., Palo Alto, CA, USA). It was. The chemical shift (δ ppm) was recorded based on tetramethylsilane. The results are shown in FIGS. 4 and 5, respectively.

1-4: MS analysis A DIP / MS spectrum was measured using an Agilent 5975C GC / MSD mass spectrophotometer system, and the results are shown in FIG.

Example 3: Evaluation of whitening effect of triacetylresveratrol and tetraacetyloxyresveratrol in vitro at the cellular level Skin of triacetylresveratrol and tetraacetyloxyresveratrol produced in Examples 1 and 2 above In order to elucidate the whitening effect, the effect on tyrosinase inhibitory activity and cell viability and the inhibitory effect on cell melanin production were confirmed.

In order to confirm the effect of the compound at the cellular level, mouse melanoma B16F10 cells were purchased from American Type Culture Collection (ATCC) and used. Cells were cultured at 37 ° C., 5% CO ₂ in using DMEM medium containing 10% fetal bovine serum (FBS), penicillin 100 U / mL and streptomycin 0.1 mg / mL. Cultivation was carried out in a cuvette.

3-1: Tyrosinase activity inhibition efficiency in a test tube Cultured cells were collected and cell lysate (10 mM Tris-Cl, pH 7.4, 120 mM NaCl, 25 mM KCl, 2 mM EGTA, 1 mM EDTA, 0.5% Triton X-) 100, a protein differentiation enzyme inhibitor mixture) was added and allowed to stand on ice for 45 minutes to disrupt the cells. After centrifugation at 14,000 g for 15 minutes at 4 ° C., the supernatant was collected and used for enzyme activity measurement.

In a 96-well microplate, 0.1M phosphate buffer solution (pH 6.8), cell lysate 20 μg / mL, 0.5 mM L-tyrosine (tyrosin), 1 μM L-topa (DOPA) and various concentrations of tyrosinase The reaction was carried out at 37 ° C. for 60 minutes so that the test solution was contained and the volume of the reaction solution was 200 μL. Using a microplate reader, OD (optical density) was measured at 490 nm, which is the absorption wavelength of the reaction product, DOPA Chrome, and the enzyme activity was evaluated. The tyrosinase activity inhibition rate was calculated by the following formula.
Tyrosinase activity inhibition rate (%)
= [((OD _{control / tyrosinase-} OD _{experiment / tyrosinase} ) / (OD _{control / tyrosinase-} OD _control )] × 100
OD _control ; measured value when containing only vehicle OD _{control /} tyrosinase; measured value when containing vehicle and tyrosinase OD _{experiment /} tyrosinase: measured value when containing sample and tyrosinase

  The calculation results are shown in Table 1 below. As shown in Table 1, the triacetylresveratrol and tetraacetyloxyresveratrol produced in Examples 1 and 2 can more effectively inhibit the activity of tyrosinase than resveratrol and oxyresveratrol. confirmed. Specifically, triacetylresveratrol and tetraacetyloxyresveratrol are converted to resveratrol and oxyresveratrol, respectively, by ester hydrolase (esterase) contained in the cell lysate, thereby inhibiting tyrosinase. It was presumed to show activity, and it was confirmed that the tyrosinase inhibitory activity further increased after acetylation.

  On the other hand, tyrosinase inhibitory activity in vitro of oxyresveratrol and tetraacetyloxyresveratrol was confirmed to be higher than resveratrol and triacetylresveratrol.

3-2: Influence on cell viability Cell viability was measured by a trypan blue dye exclusion assay (trypan blue exclusion assay). Specifically, mouse B16 / F10 melanoma cells and human epidermal melanocytes (HEMs) are used, and each cell is treated with trypsin after 3 to 100 μM of each test substance. And centrifuged at 1200 rpm for 3 minutes. Cells were suspended from the culture medium and mixed with 0.1% trypan blue solution (Sigma-Aldrich) at a 1: 1 ratio. The number of stained dead cells and unstained live cells were counted under a microscope with a hemocytometer.

  As a result, as shown in FIG. 7, it was confirmed that no cytotoxicity was observed at a generally low concentration. First, as a result of experiments on B16 / F10 cells, oxyresveratrol is superior to resveratrol in terms of cell viability, and triacetylresveratrol is tetraacetyloxyresveratrol compared to resveratrol. It was confirmed that trol was less cytotoxic than oxyresveratrol (FIG. 7a). In addition, as a result of experiments on HEMs cells, triacetyloxyresveratrol is less cytotoxic than resveratrol at a concentration of 30 μM or less, and tetraacetyloxyresveratrol has similar cell viability to oxyresveratrol. It was confirmed that this level was shown (FIG. 7b). From these results, it was found that the acetylated derivatives were superior in terms of cell viability and stable compared to the respective pre-acetylated compounds.

3-3: Inhibitory effect on melanin production in cells Intracellular melanin production was measured using mouse B16 / F10 melanoma cells and human epidermal melanocytes (HEMs). B16 / F10 cells were stimulated with 100 nM α-MSH for 48 hours after treating the test substances according to the concentration for 60 minutes. HEMs cells were pretreated with test substances for 60 minutes according to concentration, and then stimulated with 1.0 mM L-tyrosine for 48 hours. The above procedure was repeated three times while changing the medium. Melanin produced in the cells was extracted with 0.1 M NaOH at 60 ° C. for 60 minutes, and the absorbance at 490 nm, which is the absorption wavelength of melanin, was measured and quantified to standardize the protein amount. Protein was measured using Bio-Rad DC analysis.

  The results are shown in FIG. 8, and the melanin production inhibitory effect of triacetylresveratrol and tetraacetyloxyresveratrol is generally similar to that of resveratrol and oxyresveratrol, which are compounds before acetylation. Maintained the level. Specifically, as a result of experiments on B16 / F10 cells, resveratrol, oxyresveratrol, triacetylresveratrol and tetraacetyloxyresveratrol are effective in increasing the amount of intracellular melanin increased by α-MSH. (Fig. 8a). Similarly, in the experimental results for HEMs cells, resveratrol, oxyresveratrol, triacetylresveratrol and tetraacetyloxyresveratrol effectively inhibit the amount of melanin increased by L-tyrosine, respectively. It was found (Fig. 8b). From these facts, triacetyl resveratrol and triacetyloxy resveratrol according to the present invention are converted into resveratrol and oxyresveratrol, respectively, by ester hydrolase (esterase) introduced into the cell and existing in the cell. It can be assumed that melanin production is suppressed.

  Moreover, as shown in the said Table 1, in the tyrosinase activity inhibitory effect, it was confirmed that oxyresveratrol and tetraacetyloxy resveratrol have a stronger inhibitory effect than resveratrol and triacetyl resveratrol. However, as shown in FIG. 8, in the melanin production inhibitory effect, resveratrol and triacetylresveratrol showed a better effect than oxyresveratrol and tetraacetyloxyresveratrol. Such a difference is good for the process of suppressing cellular melanogenesis and suggests that other factors other than tyrosinase are involved. Therefore, the whitening effect of these substances needs to be finally evaluated by human experiments.

Production Example 1 Production of Cosmetic Composition for Skin Whitening A cosmetic composition containing triacetyl resveratrol and / or tetraacetyloxyresveratrol according to the present invention as an active ingredient was produced. As a comparative group, a cosmetic composition containing resveratrol or oxyresveratrol as an active ingredient or not containing the ingredient was produced and used. The content ratio of each component of the cosmetic composition produced in Table 2 below is shown. Experimental groups 1 and 2 were each prepared to contain 0.5% triacetylresveratrol or tetraacetyloxyresveratrol, and experimental groups 3 and 4 were each 2.0% triacetylresveratrol. Alternatively, Experimental Example 5 was prepared so as to contain 2.0% each of triacetylresveratrol and tetraacetyloxyresveratrol so as to contain tetraacetyloxyresveratrol. Comparative groups were prepared so that each resveratrol or oxyresveratrol contained 2.0% or no active ingredient. The other components were used at a constant content, and the difference in the content of the active components used was adjusted to a total of 100% by adjusting the content of purified water in the composition.

Experimental Example 4: Analysis of Dosage Form Stability In order to test the dosage form stability of the cosmetic compositions of Experimental Groups 1 to 5 and Comparative Groups 1 to 3 manufactured according to the above Preparation Examples, the respective compositions were tested. Was placed in a cosmetic container and stored in an oven at 60 ° C., and the active ingredient was quantitatively analyzed at intervals of 30 days to confirm the content of the remaining active ingredient, and the presence or absence of discoloration was confirmed with the naked eye.

  The quantitative analysis of the active ingredient was performed using the same equipment and method as the method described in Analysis Example 1. As the sample, each cosmetic sample produced in Production Example 1 was diluted to 1/100 with methanol, and 20 μL was taken for use.

  The results are shown in Table 3 below. In Comparative Groups 1 and 2, which are cosmetic compositions containing resveratrol or oxyresveratrol as an active ingredient, discoloration progressed after one month, the content of the active ingredient also decreased, and the remaining amount after five months Was significantly reduced to less than 50%. On the other hand, in the experimental groups 1 to 5 which are cosmetic compositions containing triacetylresveratrol and / or tetraacetylresveratrol as active ingredients, no discoloration is observed until 6 months have passed, and the content of active ingredients is also constant. Was confirmed to be maintained. The triacetylresveratrol or tetraacetyloxyresveratrol of the present invention in combination with the results of the above-described analysis of dosage form stability in combination with the results of evaluating the whitening effect in the test tube at the cell level performed in Example 3 above, Compared to resveratrol or oxyresveratrol, it has the same whitening effect at the cellular level. When it is manufactured as a cosmetic composition and stored at a high temperature, it may be discolored due to long-term storage, Since it did not decrease, it is expected that a better whitening effect can be exhibited when applied to the skin.

Experimental Example 5: Stability test when applied to human skin 5-1: Skin irritation test In order to confirm the human body irritation in the cosmetic composition of the experimental group and the comparative group produced according to Production Example 1, The primary irritation test was performed on the skin. The cosmetic compositions of Comparative Groups 1 and 2 are stable because they may be harmful due to discoloration and are excluded from human body application experiments and do not contain resveratrol and / or oxyresveratrol at all. The experiment was performed including only Comparative Group 3.

  The human body application experiment was conducted on 30 healthy adult males and females. Each cosmetic composition was dropped in an appropriate amount (20 μL) of an IQ chamber for patch test, and removed after 48 hours of patch test on the back part. did. At 30 minutes and 24 hours after removal, changes in skin condition were judged with the naked eye. The evaluation criteria and the corresponding store of skin reaction are shown in Table 4 below.

The patch was removed, the primary determination was made 30 minutes later, the secondary determination was made after 24 hours had passed again, and the reactivity was calculated by the following formula. The degree of irritation to human skin was expressed as the average reactivity of primary and secondary determinations, and this is summarized in Table 5 below.
Degree of stimulation
= [(Number of reaction points × number of respondents) / {maximum number of response points (4) × total number of examiners (n)}] × 100 × 1/2

  As shown in Table 5, the average reactivity of the cosmetic compositions of Experimental Groups 1 to 5 and Comparative Group 3 belongs to the category of low irritation in the primary irritation of human skin, It was confirmed that no stimulation was given.

5-2: Test of whitening effect on human skin The cosmetic composition of the experimental group and the comparative group 3 that were confirmed not to induce skin irritation when applied to the human body by the roll of the skin irritation test (Testol) The whitening effect on human skin was examined using the product, and the results are shown in Table 6 below.

  The skin whitening effect test was performed on 20 healthy adult males and females by attaching an opaque tape with four holes of 1.5 cm x 1.5 cm inside the forearm on both sides of each subject. The artificial pigmentation of the skin was induced by irradiating ultraviolet rays (UVB) twice as much as the amount (MED). The cosmetic compositions of Experimental Groups 1 to 5 and Comparative Group 3 manufactured in Preparation Example 1 were applied to the pigmented site, respectively, twice a day for 8 weeks in the morning / night. The evaluation regarding the result evaluated the melanin index and the color of the skin using the mexometer and the spectrophotometer before use of the cosmetic composition and after 8 weeks of use. The melanin index measured using a megger meter is shown in Table 6 below. When the melanin index measured after use is lower than the melanin index measured before use, it can be determined that there is a whitening effect, and as the difference is larger, it can be determined that the effect is superior. Therefore, the cosmetic compositions of Experimental Groups 1 to 5 according to the present invention showed an excellent skin whitening effect as compared with Comparative Group 3, and it was confirmed that the higher the content of the active ingredient, the higher the effect.

The effect on the change in skin color is determined by calculating an ITA ° (Individual Typical Angle) value reflecting the degree of skin whiteness from the values of L ^* , a ^* and b ^* measured using a spectrophotometer using the following formula. Calculated and evaluated. The calculated values are shown in Table 7 below, and it can be evaluated that the whitening effect is better as the ITA ° value is larger.
ITA ° = arctg [(L ^* -50) / b ^* ] × (180 / π)
L ^* : Lightness factor: Brightness b ^* : Color factor: Blue-yellow

  As shown in Table 7, it was confirmed that the cosmetic compositions of Experimental Groups 1 to 5 had a skin whitening effect superior to the cosmetic composition of Comparative Group 3 even in changes in skin color. In particular, it was confirmed that the experimental groups 3 and 4 having a high content of active ingredients and the experimental group 5 containing two active ingredients in high contents each showed an excellent whitening effect.

Production Example 2: Production of a pharmaceutical skin external preparation composition for skin whitening Skin containing triacetylresveratrol and / or tetraacetyloxyresveratrol produced according to Example 1 or 2 of the present invention as an active ingredient A pharmaceutical composition for whitening was prepared. The contents of the active ingredient and other ingredients are shown in Table 8 below. The molding thus produced was stable and suitable for use on the human body.

Claims (20)

  A cosmetic composition comprising, as an active ingredient, an acetylated derivative of resveratrol or a hydroxy derivative thereof or a cosmetically acceptable salt thereof.   The cosmetic composition according to claim 1, wherein the composition has a skin whitening effect.   The cosmetic composition according to claim 1, wherein the acetylated derivative has increased chemical stability compared to a reactant before acetylation.   The cosmetic composition according to claim 1, wherein the hydroxy derivative of resveratrol is oxyresveratrol.   The cosmetic composition according to claim 1, wherein the acetylated derivative of resveratrol is triacetyl resveratrol.   The cosmetic composition according to claim 1, wherein the acetylated derivative of the hydroxy derivative of resveratrol is tetraacetyloxyresveratrol.   The cosmetic composition according to claim 1, comprising the active ingredient in an amount of 0.01 to 5% by weight.   The cosmetic composition according to claim 1, further comprising an excipient for cosmetics.   Cosmetics containing the cosmetic composition according to any one of claims 1 to 8.   A pharmaceutical composition for skin whitening comprising, as an active ingredient, an acetylated derivative of resveratrol or a hydroxy derivative thereof or a pharmaceutically acceptable salt thereof.   The pharmaceutical composition according to claim 10, wherein the hydroxy derivative of resveratrol is oxyresveratrol.   The pharmaceutical composition according to claim 10, wherein the acetylated derivative of resveratrol is triacetyl resveratrol.   The pharmaceutical composition according to claim 10, wherein the acetylated derivative of the hydroxy derivative of resveratrol is tetraacetyloxyresveratrol.   The pharmaceutical composition according to claim 10, comprising 0.1 to 10% by weight of the active ingredient.   The pharmaceutical composition according to claim 10, further comprising a pharmaceutically acceptable excipient.   The skin external preparation containing the pharmaceutical composition for skin whitening as described in any one of Claims 10-15.   A method of whitening the skin comprising the step of administering an acetylated derivative of resveratrol or a hydroxy derivative thereof or a pharmaceutically acceptable salt thereof to an individual in need thereof.   The method according to claim 17, wherein the administration is applied to the skin. A compound having a skin whitening effect represented by the following chemical formula 2.
[Chemical formula 2]
The compound according to claim 19, wherein the compound is produced by an acetylation reaction or an esterification reaction of oxyresveratrol.