JP2009221179A - Skin whitening agent containing maleic acid as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a demelanizing agent, skin whitening agent, and external preparation for skin which make a compound with high melanogenesis inhibition activity as an active ingredient. <P>SOLUTION: The confirmation has been provided on the fact that maleic acid has an effect of melanogenesis inhibition, but fumaric acid, glutaconic acid, and chelidonic acid which are a dicarboxylic acid similarly as maleic acid do not have the effect of melanogenesis inhibition. The demelanizing agent which makes maleic acid or its salt an active ingredient, the skin whitening agent which makes maleic acid or its salt an active ingredient, and the external preparation for skin for bleaching containing maleic acid or its salt are prepared. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a melanin production inhibitor containing maleic acid or a salt thereof as an active ingredient, a whitening agent containing maleic acid or a salt thereof as an active ingredient, and a skin whitening external preparation containing maleic acid or a salt thereof.

  Melanin (melanin) is a brown to black pigment commonly found in the flora and fauna and fungus kingdom. In humans, it is one of the factors that determine skin color and plays an important role in protecting the body from the harmful effects of ultraviolet rays. Although it is said to be responsible, excessive production of melanin is considered to be dark black, and phenomena such as spots and freckles that are unevenly distributed can be regarded as cosmetic defects and skin aging. is there. In recent research, melanin is produced by activation of tyrosinase in the melanocytes existing in the basal part of the skin under the stimulation of active oxygen generated in the skin by ultraviolet rays and stress. After being synthesized through the pathway and stored in vesicles called melanosomes, it is becoming clear that they are transported to keratinocytes and hair matrix cells in the skin, causing changes in body color.

  Therefore, the development of an external preparation for the purpose of preventing darkening of the skin caused by melanin production and whitening is an important issue in the cosmetics industry and the like, and inhibits and suppresses various actions in the melanin production pathway. Products using ingredients for this purpose have been developed. For example, cysteine (see, for example, Patent Document 1 and Patent Document 2) and glutathione (see, for example, Patent Document 2) as a component exhibiting a reducing action, and hydroquinone (for example, as a component having inhibitory / inhibitory activity on tyrosinase) , Patent document 3), kojic acid (for example, see patent document 4), substituted phenoxypropanolamines or salts thereof (for example, see patent document 5), etc., cosmetics, whitening agents, skin external preparations, and the like have been proposed. ing.

On the other hand, in addition to these compounds, specific organic acids have been reported as compounds that inhibit or suppress melanin production. For example, it has been reported that lactic acid has an ability to inhibit melanin production (for example, see Patent Document 6), and that L-ascorbic acid exhibits a reducing action on the produced melanin (for example, see Patent Document 7). Also, the fumaric acid is a component of the citric acid cycle, vitamin B _6, the use of the synergistic skin lightening composition comprising a vitamin B ₃ has been proposed (e.g., see Patent Document 8).

  On the other hand, maleic acid, a geometric isomer of fumaric acid, is used as a raw material for organic acids such as malic acid and succinic acid, and as a dyeing finish for textiles, but is also included with ceramides or pseudoceramides. It has been proposed to be used for skin cosmetics (for example, see Patent Document 9) as a dicarboxylic acid and cosmetics (for example, see Patent Document 10) as an organic acid contained together with a hinokitiol compound. However, there has been no report on the whitening effect and melanin production inhibitory effect of maleic acid.

JP 2006-315962 A Japanese Patent Laid-Open No. 11-269051 JP 2007-314528 A Japanese Patent Laid-Open No. 2-200622 JP 2006-282645 A JP 2005-325105 A JP 2007-277119 A JP 2007-509899 A Japanese Patent No. 3299054 JP 2002-47123 A

  Reducing agents such as glutathione do not have a sufficient whitening effect, tyrosinase inhibitors such as hydroquinone may cause safety problems such as cytotoxicity, and kojic acid tends to be colored by exposure to light due to physical properties. -Ascorbic acid is easily oxidized and stability may be a problem, and even with the above-mentioned organic acid, a sufficient whitening effect may not be obtained. An object of the present invention is to provide a highly safe melanin production inhibitor, a whitening agent, and a skin external preparation, which contains a compound having a high melanin production inhibitory activity as an active ingredient.

  In order to solve the above problems, the present inventors have conducted intensive research to identify compounds having a melanin production inhibitory action different from conventional ones, such as tyrosinase inhibitors such as kojic acid and reducing agents such as L-ascorbic acid. As a result, it was discovered that maleic acid, a kind of dicarboxylic acid, has a melanin production inhibitory effect, and the present invention has been completed. In addition, as with maleic acid, dicarboxylic acids such as fumaric acid, glutaconic acid and chelidonic acid do not have a melanin production-inhibiting effect and are said to have a whitening effect due to a reducing action. Ascorbic acid was confirmed to have no melanin production inhibitory effect at the same concentration as maleic acid. In addition, it is thought that the melanin production inhibitory effect of maleic acid is exhibited by a unique mechanism other than a reaction involving tyrosinase or a reducing agent.

  That is, the present invention relates to a melanin production inhibitor containing one or more compounds selected from maleic acid and salts thereof as an active ingredient, and one or more compounds selected from maleic acid and salts thereof. The present invention relates to a skin whitening agent containing a whitening agent, and one or more compounds selected from maleic acid and salts thereof. In addition, the present invention provides a method of using one or more compounds selected from maleic acid and salts thereof as a melanin production inhibitor, a whitening agent, or a whitening skin external preparation, a melanin production inhibitor, or a whitening agent. Or a method of using one or more compounds selected from maleic acid and salts thereof in the manufacture of skin external preparations for skin whitening, and one or more compounds selected from maleic acid and salts thereof are whitened. Includes skin preparations for external use.

  The melanin production inhibitor of the present invention comprising one or more compounds selected from maleic acid and salts thereof as an active ingredient is an agent for improving / preventing stains, buckwheat, etc. caused by melanin production, and a whitening agent. Useful.

  The melanin production inhibitor or whitening agent of the present invention is not particularly limited as long as it contains one or more compounds selected from maleic acid and salts thereof as an active ingredient, and the skin for whitening of the present invention. The external preparation is not particularly limited as long as it contains one or more compounds selected from maleic acid and salts thereof, and the type of skin external preparation for whitening of the present invention includes sunscreen, Examples include cosmetics such as skin lotions, milky lotions, creams, cosmetics, packs and other basic cosmetics for face, limbs and body, makeup cosmetics such as foundation, concealer, white powder, blusher, lipstick and eye shadow. Examples of the dosage form of the skin whitening external preparation for whitening include liquid, powder, solid, rod, oil-in-water / water-in-oil emulsion, cream, gel and the like. In addition, as a composition of the said skin external preparation for whitening of the said invention, when not containing 1 type, or 2 or more types of compounds selected from maleic acid and its salt as a whitening agent, for example, a hinokitiol compound is mix | blended In addition, it is excluded when blended with specific ceramides or pseudo-ceramides.

  The maleic acid is a kind of chain unsaturated dicarboxylic acid represented by the formula (I), and the IUPAC name is represented by cis-butenedioic acid.

  The maleic acid salt of the present invention is not particularly limited as long as the melanin production inhibitory activity is a maleic acid salt having the same effect as maleic acid. For example, sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, etc. Cation salts, triethanolamine salts, and salts with basic amino acids such as arginine, histidine, and lysine, and sodium salts are preferred. Furthermore, chelate complexes with iron, copper, and the like can be appropriately prepared and used. In addition, you may use maleic acid, its salt, and a chelate complex individually or in combination of 2 or more types.

  A method for producing a maleic acid-containing composition such as one or more compounds selected from the maleic acid represented by the above formula (I) and salts thereof used in the present invention, or a crude product purified in the process of refining maleic acid There are no particular limitations on the method of obtaining it as long as it is a known chemical synthesis method. For example, a reaction product obtained by a gas phase oxidation reaction of benzene in the presence of a catalyst such as vanadium pentoxide in water. When absorbed, maleic acid can be obtained, and a commercially available product can also be purchased.

  In addition, the melanin production inhibitor and whitening agent of the present invention containing one or two or more compounds selected from maleic acid and salts thereof as an active ingredient are used in the purification process in the above-described chemical synthesis method. In addition to including purified products, as long as melanin production inhibitory activity is not impaired, excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, A composition containing a dispersant, a stabilizer, a solubilizing agent and the like is included.

  The melanin production inhibitory activity in the melanin production inhibitor of the present invention is not particularly limited as long as it is an activity that suppresses the action of causing darkening of the body color of the skin and the like accompanying the production and accumulation of melanin. The whitening effect of the whitening agent and the skin external preparation for whitening includes not only an active whitening effect to whiten the skin but also a passive whitening effect to suppress the blackening of the skin, such as stains, buckwheat etc. This includes not only a whitening effect that improves pigmentation of the skin, but also a whitening effect that suppresses pigmentation.

  As a method for determining the presence or absence of inhibitory activity in the melanin production inhibitor of the present invention, for example, an appropriate amount of 10% FBS-containing MEM medium is taken in a 6-well plate, B16 melanoma cells are seeded, and the carbon dioxide concentration is 5 v / v%. The sample is allowed to stand at 37 ° C. for one day, and the following day, the sample is dissolved in a soluble solvent and appropriately prepared as a final concentration sample test solution. The sample test solution is added to the medium inoculated with the B16 melanoma cells and mixed. Then, on the fifth day of culture, the medium is changed and the sample test solution is added again. The next day, the medium is removed, and the cultured B16 melanoma cells are washed and collected with phosphate buffer, and then the sample is added. A method for visually evaluating and judging the degree of whitening of the cells compared to the control that was not performed can be mentioned.

  The melanin production inhibitor of the present invention is a means for improving the state caused by the melanin production action, for example, a whitening agent or a skin whitening agent for whitening or whitening for improving / preventing spots, freckles, sunburn, etc. You may use as medicines, such as a quasi-drug.

  In preparing the melanin production inhibitor of the present invention as a pharmaceutical product, quasi-drug, etc., excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives , Wetting agents, emulsifiers, dispersants, stabilizers, solubilizing agents, and other pharmaceutical additives may be mixed, diluted or dissolved as appropriate, and such dosage forms include ointments, liquids for external use, patches, Examples include emulsions, lotions, solutions, gels and the like, packs, powders, sticks, and the like, and they can be used parenterally or orally depending on the purpose of treatment.

  Furthermore, the skin whitening preparation for whitening of the present invention includes the following oily components, powder components, surfactants, aqueous components as components that are usually added to the skin whitening external preparation for whitening in addition to maleic acid as the essential component. One or two or more selected from ingredients, antioxidants, antiseptics, compounds that are said to be effective in preventing skin aging, UV protection agents, and anti-inflammatory ingredients, as long as the effects of the present invention are not impaired. It can mix | blend suitably.

  An oily component can be mix | blended with the skin external preparation for whitening of this invention. The oily component is not particularly limited as long as it is an oily component generally used for a skin whitening external preparation, for example, hydrocarbons, fats and oils, waxes, hydrogenated oils originating from animal oils, vegetable oils, synthetic oils, etc. Ester oils, fatty acids, higher alcohols, silicone oils, fluorinated oils, lanolin derivatives, oily gelling agents, etc., specifically, liquid paraffin, squalane, petrolatum, polyethylene Hydrocarbons such as wax, ethylene / propylene copolymer, paraffin wax, montan wax, Fischer-Tropsch wax, polyisobutylene, polybutene, ceresin wax, ozokerite wax, owl, olive oil, castor oil, mink oil, macadamian nut oil, etc. Oils and fats, beeswax, gallows, carnaubawack Waxes such as candelilla wax, jojoba oil, cetyl 2-ethylhexanoate, isostearyl lactate, octyldodecyl lactate, oleyl lactate, stearyl lactate, glyceryl diisostearate, diglyceryl triisostearate, diisostearyl malate, myristic Isopropyl, isopropyl palmitate, octyldodecyl myristate, pentaerythritol ester of rosin acid, neopentyl glycol dioctanoate, neopentyl glycol dioctanoate, esters of cholesterol fatty acid ester, phytosterol fatty acid ester, triglyceride, stearic acid, lauric acid , Fatty acids such as myristic acid, behenic acid, isostearic acid, oleic acid, stearyl alcohol, cetyl alcohol, lauryl alcohol Alcohol, oleyl alcohol, isostearyl alcohol, higher alcohols such as behenyl alcohol, dimethylpolysiloxane, methylphenylpolysiloxane, decamethylcyclopentasiloxane, octamethylcyclotetrasiloxane, trimethylsiloxysilicic acid, high degree of polymerization methylphenylpolysiloxane , Cross-linked methylpolysiloxane, polyoxyalkylene-modified organopolysiloxane, cross-linked polyether-modified methylpolysiloxane, methacryl-modified polysiloxane, stearyl-modified methylpolysiloxane, oleyl-modified methylpolysiloxane, behenyl-modified methylpolysiloxane, polyvinylpyrrolidone-modified Methyl polysiloxane, high degree of polymerization dimethyl polysiloxane, polyoxyalkylene alkylmethyl polysiloxane Silicone such as chilled polysiloxane copolymer, alkoxy-modified polysiloxane, cross-linked organopolysiloxane, fluorine-modified polysiloxane, fluorine oils such as perfluorodecane, perfluorooctane, perfluoropolyether, lanolin, lanolin acetate Lanolin derivatives such as lanolin fatty acid isopropyl, lanolin alcohol, dextrin octoate, dextrin laurate, dextrin palmitate, dextrin myristate, dextrin stearate, dextrin behenate, coconut oil fatty acid dextrin, (palmitic acid / octanoic acid) dextrin, Oily gelling agents such as sucrose fatty acid ester, starch fatty acid ester, aluminum isostearate, potassium stearate, 12-hydroxystearic acid Etc. can be mentioned.

  A powder component can be mix | blended with the skin external preparation for whitening of this invention. As such a powder, if it is a powder generally used in a skin whitening external preparation, a spherical shape, a plate shape, a needle-like shape, a fumed shape, a fine particle, a particle size such as a pigment grade, a porous material, a non-porous material, etc. There are no particular restrictions on the particle structure such as, for example, inorganic powders, glitter powders, organic powders, pigment powders, metal powders, composite powders, and the like, Specifically, white inorganic pigments such as titanium oxide, zinc oxide, cerium oxide and barium sulfate, colored inorganics such as iron oxide, carbon black, titanium / titanium oxide sintered product, chromium oxide, chromium hydroxide, bitumen and ultramarine blue Pigment, talc, muscovite, phlogopite, saucite, biotite, synthetic mica, sericite, sericite, kaolin, silicon carbide, bentonite, smectite, silicic anhydride, aluminum oxide, magnesium oxide, oxidation zirconium, Soil, aluminum silicate, magnesium aluminum silicate, calcium silicate, barium silicate, magnesium silicate, calcium carbonate, magnesium carbonate, hydroxyapatite, boron nitride, etc. white powder, titanium dioxide coated mica, titanium dioxide coated Bismuth oxychloride, titanium oxide mica titanium, bituminized mica titanium, carmine-treated mica titanium, bismuth oxychloride, fish scale foil, polyethylene terephthalate / aluminum / epoxy laminated powder, polyethylene terephthalate / polyolefin laminated film powder, polyethylene terephthalate / polymethyl methacrylate laminated Bright powder such as film powder, polyamide resin, polyethylene resin, polyacrylic resin, polyester resin, fluorine resin, cellulose resin, police Copolymer resin such as len resin, styrene-acrylic copolymer resin, organic polymer resin powder such as polypropylene resin, silicone resin and urethane resin, organic low molecular weight powder such as zinc stearate and N-acyl lysine, silk Natural organic powder such as powder, cellulose powder, organic pigments such as red 201, red 202, red 205, red 226, red 228, orange 203, orange 204, blue 404, yellow 401 Powder, organic pigment powder such as zirconium, barium or aluminum lake such as red No. 3, red No. 104, red No. 106, orange No. 205, yellow No. 4, yellow No. 5, green No. 3, blue No. 1, etc. Metal powder such as aluminum powder, gold powder, silver powder, fine titanium oxide coated mica titanium, fine zinc oxide coated mica titanium, barium sulfate coated mica Examples thereof include composite powders such as tan, titanium oxide-containing silicon dioxide, and zinc oxide-containing silicon dioxide.

  A surfactant can be added to the whitening skin external preparation of the present invention. Such a surfactant is not particularly limited as long as it is a surfactant generally used for a skin whitening external preparation, and examples thereof include a nonionic surfactant, an anionic surfactant, a cationic surfactant, and an amphoteric interface. Activating agents, etc., specifically, glycerin fatty acid ester and its alkylene glycol adduct, polyglycerin fatty acid ester and its alkylene glycol adduct, sorbitan fatty acid ester and its alkylene glycol adduct, sucrose fatty acid ester, poly Examples thereof include oxyethylene hydrogenated castor oil, polyoxyalkylene alkyl co-modified organopolysiloxane, polyether-modified organopolysiloxane, and lecithin.

  An aqueous component can be mix | blended with the skin external preparation for whitening of this invention. Such an aqueous component is not particularly limited as long as it is water and a component that is soluble in water, which is generally used for whitening skin external preparations. For example, lower alcohols, glycols, glycerols, plant extracts, water-soluble polymers Specifically, water, ethyl alcohol, butyl alcohol, propylene glycol, 1,3-butylene glycol, dipropylene glycol, polyethylene glycol, glycerin, diglycerin, polyglycerin, aloe vera, witch hazel, Hamamelis, cucumber, lemon, lavender, rose, guar gum, sodium chondroitin sulfate, sodium hyaluronate, gum arabic, sodium alginate, carrageenan, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, Bo carboxyvinyl polymers, alkyl addition carboxyvinyl polymer, polyvinyl alcohol, polyvinyl pyrrolidone, and sodium polyacrylate.

  Antioxidants and preservatives can be added to the skin whitening external preparation of the present invention. Examples of such antioxidants include α-tocopherol and ascorbic acid. Examples of preservatives include paraoxybenzoic acid esters and phenoxyethanol, and are generally used as skin whitening external preparations. There is no particular limitation as long as it is an antioxidant or preservative used.

  In addition, the compound which is said to be effective in skin aging prevention can be mix | blended with the skin external preparation for whitening of this invention. Such a skin antiaging agent is not particularly limited as long as it is a skin antiaging agent generally used in a skin whitening external preparation, and examples thereof include retinol, retinoic acid, coenzyme Q10, superoxide dismutase, mannitol, quercetin, catechin and the like. Derivatives, Rutin and its derivatives, Butterpi extract, Yashajitsu extract, Melissa extract, Luohan fruit extract, carotenoids and other vitamin A, thiamine and its derivatives, riboflavin and its derivatives, pyridoxine and its derivatives, nicotinic acid and its derivatives And vitamin Bs such as tocopherol and derivatives thereof, dibutylhydroxytoluene and butylhydroxyanisole.

  Moreover, it is preferable to mix | blend a ultraviolet protective agent with the skin external preparation for whitening of this invention from the point which prevents the melanin production | generation by an ultraviolet-ray. The UV protection agent is not particularly limited as long as it is a UV protection agent generally used for skin whitening external preparations. For example, benzophenone compounds, PABA compounds, cinnamic acid compounds, salicylic acid compounds, 4-tert-butyl -4'-methoxydibenzoylmethane, p-methoxycinnamic acid-2-ethylhexyl, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5 sodium sulfate, 2-phenyl-benzimidazole Examples include -5-sulfuric acid, titanium oxide, and zinc oxide.

  In addition, it is desirable to add an anti-inflammatory agent to the skin whitening external preparation of the present invention in order to suppress skin inflammation and reduce the activity of tyrosinase and the like. Such an anti-inflammatory agent is not particularly limited as long as it is an anti-inflammatory agent generally used in a skin whitening external preparation, and examples thereof include allantoin, sulfur and derivatives thereof, glycyrrhizic acid and derivatives thereof, glycyrrhetinic acid and derivatives thereof, and Altea extraction. , Ashitaba extract, Arnica extract, Ginseng extract, nettle extract, Duckweed extract, Hypericum extract, Chamomile extract, Snapdragon extract, Watercress extract, Comfrey extract, Salvia extract, Bamboo extract , Perilla extract, birch extract, gentian extract and the like.

  The blending ratio of the maleic acid of the present invention in the whitening skin external preparation is not particularly limited as long as the effects of the present invention are exerted, but is usually preferably 0.0001 to 10% by mass, preferably 0.01 to 3%. The mass% is more preferable.

  Hereinafter, the present invention will be described more specifically by way of examples. However, the technical scope of the present invention is not limited to these examples.

(Inhibition of melanin production and cell viability test using cultured B16 melanoma cells)
B16 melanoma cultured cells derived from mice were used, and maleic acid was used as a specimen to examine the melanin production inhibitory effect and cell survival rate.

[Melanin production inhibitory effect test]
Appropriate amount of 10v / v% FBS-containing MEM medium (manufactured by Nissui Pharmaceutical Co., Ltd.) is taken in two 6-well plates, seeded with B16 melanoma cells, and left at 37 ° C for one day at a carbon dioxide concentration of 5v / v%. did. The next day, maleic acid (manufactured by Wako Pure Chemical Industries, Ltd.) is dissolved in purified water and prepared as a sample preparation solution so that the final concentration is 0 (control), 10, 30, 100 μg / mL. The B16 melanoma cells were added to the medium inoculated and mixed, the medium was changed on the fifth day of culture, the sample preparation solution was added again, and the medium was removed the next day. B16 melanoma cells cultured on one of the two plates were washed with a phosphate buffer and collected, and then the degree of whitening was evaluated visually.

[Cell viability test]
For the remaining one plate, the B16 melanoma cells were fixed with formalin and added to a 0.1 w / v% crystal violet solution for staining. The number of viable cells at the concentration of each sample preparation solution was measured with a monocerator (manufactured by Olympus), and the viable cell ratio (%) was calculated from the ratio to the number of viable cells at the control concentration. The results are shown below.

（判定基準）
◎：対照に対して極めて白色である。
○：対照に対してあきらかに白色である。
△：対照に対してやや白色である。
−：対照と同じ黒色である。

(Criteria)
(Double-circle): It is very white with respect to a control | contrast.
○: Clearly white compared to the control.
Δ: Slightly white compared to the control.
-: The same black color as the control.

[Comparative example]
Like maleic acid, dicarboxylic acids such as glutaconic acid and kelidonic acid, maleic acid as well as carboxylic acid groups but tricarboxylic acid, cis-aconitic acid, and maleic acid, are organic acids. In the same manner as in Example 1, L-ascorbic acid, which has been reported for whitening effect, and kojic acid, which has a tyrosinase inhibitory action and is widely blended in whitening agents as a component having a melanin production inhibitory effect, are purified in the same manner as in Example 1. It melt | dissolved in water and tested about the melanin production inhibitory effect (whitening degree) and cell viability. Moreover, about the fumaric acid which is a geometric isomer of maleic acid, it tested about the melanin production inhibitory effect (whitening degree) and cell viability similarly to Example 1 except having melt | dissolved in ethanol. The results are shown in Table 2 for glutaconic acid, kelidonic acid, cis-aconitic acid, L-ascorbic acid, and fumaric acid, and in Table 3 for kojic acid.

[result]
Maleic acid showed a significant inhibitory effect on melanin production at 100 μg / mL, but fumaric acid, which is a geometric isomer of maleic acid, and ketolinic acid and glutaconic acid, which are dicarboxylic acids as well as maleic acid, produce melanin. The inhibitory effect was not confirmed, and cis-aconitic acid having a structure similar to maleic acid in its structure was found to have a slight inhibitory effect on melanin production, but did not reach the effect of maleic acid. Moreover, about L-ascorbic acid currently reported about the whitening effect, sufficient melanin inhibitory effect was not confirmed by the same density | concentration as a maleic acid show | plays the melanin inhibitory effect. Furthermore, kojic acid used as a positive control showed a melanin production inhibitory effect, but maleic acid showed a more remarkable melanin inhibitory effect than kojic acid.

(Tyrosinase inhibitory effect test)
Maleic acid was dissolved in purified water and prepared as sample solutions with respective concentrations of 0.1, 0.3, 1.0, and 3.0 mM. 10 mg of tyrosinase (manufactured by Sigma, 28,000 units) was dissolved in 20 mL of 0.1 mol / L phosphate buffer (pH 6.8) to prepare an enzyme solution. In addition, 198.0 mg of L-DOPA (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in 100 mL of 0.1 mol / L phosphate buffer (pH 6.8) to prepare a substrate solution. 0.1 mL of the above enzyme solution is added to each concentration of the sample solution, and 0.1 mol / L phosphate buffer (pH 6.8) is further added to 4.0 mL, which is incubated at 25 ° C. for 10 minutes. did. Thereafter, 1.0 mL of the substrate solution previously kept at 25 ° C. was added and allowed to react for 10 minutes. After the reaction, the absorbance at 475 nm (OD _S ) was measured. Similarly, except that the heat-inactivated tyrosinase was added, the absorbance in the case of performing the same tyrosinase inhibitory effect test as above was set to OD _HE , and the enzyme solution was added, but the sample solution was not added. Except for this, the absorbance (OD _B) when the same tyrosinase inhibitory effect test as described above was performed, the absorbance when the sample solution and heat-inactivated tyrosinase were added (OD _SHE ), and heat-inactivated The absorbance (OD _HE ) when the reaction was performed using an enzyme was measured, and the inhibition rate of tyrosinase activity was calculated from the following formula (1). The result is shown in FIG.

(Wherein: OD _S: absorbance at sample and enzyme addition, OD _B: Absorbance at the time of the enzyme addition in the sample without addition, _{OD HE:} absorbance when reacted with the enzyme was heated to _{inactivate, OD SHE:} Absorbance with sample and inactivated enzyme added)

[Comparative example]
A tyrosinase inhibitory effect test was also conducted on cis-aconitic acid, which is fumaric acid, glutaconic acid, and tricarboxylic acid, as described above.

[result]
No inhibitory effect on tyrosinase activity was observed for any of maleic acid, fumaric acid, glutaconic acid, and cis-aconitic acid (see FIG. 1). As a mechanism for directly inhibiting tyrosinase, a drug that deprives copper ions contained in tyrosinase by a chelate is known. Since maleic acid did not directly inhibit tyrosinase, maleic acid's melanin production-suppressing activity was not due to chelating action that deprives copper ion of tyrosinase, but suppressed melanin production by some mechanism in the cell. It was confirmed that it has the effect to do.

  The following cosmetics were prepared using maleic acid and its salts.

[Example 1: Lotion 1]
(Manufacturing method)
A. The following components (3) to (5) and (12) and (13) were mixed and dissolved.
B. The following components (1), (2), (6) to (11) and (14) were mixed and dissolved.
C. A and B were mixed to obtain a skin lotion.
(Ingredient) (mass%)
(1) Glycerin 5.0
(2) 1,3-butylene glycol 6.5
(3) Polyoxyethylene (20E.O.) sorbitan monolaurate ester 1.2
(4) Ethyl alcohol 12.0
(5) Ascorbyl palmitate 0.1
(6) Sodium ascorbate 0.5
(7) Ascorbic acid glucoside 2.0
(8) Lactic acid 0.05
(9) Sodium lactate 0.1
(10) Sodium maleate 0.1
(11) Collagen 1.0
(12) Preservative appropriate amount (13) perfume appropriate amount (14) remaining amount of purified water

[Example 2: Oil-in-water emulsion 1]
A. The following components (7) and (8) were added to the following component (12) and swollen, then the following components (9) and (11) were added and mixed, and heated to 70 ° C. to prepare an aqueous phase.
B. The following components (1) to (6) were heated to 70 ° C.
C. B was added to A and emulsified.
D. C was cooled to room temperature, the following components (10) and (13) were added, and mixed uniformly to obtain an emulsion.
(Ingredient) (mass%)
(1) Polyoxyethylene (10E.O.) sorbitan monostearate 1.0
(2) Polyoxyethylene (60E.O.) sorbit tetraoleate 0.5
(3) Glyceryl monostearate 1.0
(4) Stearic acid 0.5
(5) Behenyl alcohol 0.5
(6) Squalane 8.0
(7) Preservative 0.1
(8) Carboxyvinyl polymer 0.1
(9) Sodium hydroxide 0.05
(10) Ethyl alcohol 5.0
(11) Sodium maleate 0.1
(12) Purified water remaining amount (13) Perfume appropriate amount

[Example 3: Face wash]
(Manufacturing method)
A. The following components (1) to (5) were dissolved by heating.
B. The following components (6) to (7) were dissolved by heating.
C. B was added to A and mixed.
D. Furthermore, the following components (8) to (11) were dissolved by heating and added to C and mixed.
E. After cooling D, the following components (12) to (14) were added and mixed to obtain a face wash.
(Ingredient) (mass%)
(1) Lauric acid 5.0
(2) Myristic acid 18.5
(3) Stearic acid 6.0
(4) Glycerin 12.0
(5) Polyethylene glycol 1500 5.0
(6) Potassium hydroxide 6.5
(7) Purified water remaining amount (8) Palm oil fatty acid diethanolamide 5.0
(9) Palm oil fatty acid methyl taurine sodium 1.8
(10) Polyoxyethylene (7.5E.O.) lauryl ether 2.0
(11) Ethylene glycol distearate 1.0
(12) Hydroxypropyl methylcellulose 1% aqueous solution 5.0
(13) Maleic acid 1.0
(14) Perfume appropriate amount

[Example 4: Lotion 2]
(Manufacturing method)
A. The following components (1) to (8) were mixed and dissolved.
B. The following components (9) to (12) were mixed and dissolved.
C. B was added to A and mixed to obtain a skin lotion.
(Ingredient) (mass%)
(1) Citric acid 0.05
(2) Sodium citrate 0.2
(3) Sodium pyrrolidonecarboxylate (50%) solution 0.5
(4) Dipotassium glycyrrhizinate 0.1
(5) Glycerin 3.0
(6) 1,3-butylene glycol 8.0
(7) Potassium maleate 0.01
(8) Purified water remaining amount (9) Ethyl alcohol 10.0
(10) Perfume Appropriate amount (11) Preservative Appropriate amount (12) Polyoxyethylene monooleate (20E.O.)
Sorbitan 0.5

[Example 5: Oil-in-water emulsion 2]
(Manufacturing method)
A. The following components (1) to (13) were dissolved by heating and kept at 70 ° C.
B. The following components (14) to (18) were dissolved by heating and kept at 70 ° C.
C. B was added to A to emulsify, and the following components (19) and (20) were further added and mixed.
D. After cooling C, the following component (21) was added and mixed to obtain an emulsion.
(Ingredient) (mass%)
(1) Stearic acid 1.0
(2) Cetanol 0.5
(3) Lipophilic glyceryl monostearate 0.5
(4) Liquid paraffin 2.0
(5) Squalane 3.0
(6) Jojoba oil 3.0
(7) Cetyl palmitate 0.2
(8) Retinol palmitate 0.2
(9) Tocopherol acetate 0.05
(10) Preservative appropriate amount (11) Sorbitan monostearate 0.3
(12) Polyoxyethylene monooleate (20E.O.)
Sorbitan 0.5
(13) Dibutylhydroxytoluene 0.1
(14) Polyethylene glycol 6000 0.5
(15) Triethanolamine 0.5
(16) 1,3-butylene glycol 15.0
(17) Glycerin 3.0
(18) Purified water remaining amount (19) Maleic acid 2.0
(20) Carboxyvinyl polymer 1% solution 8.0
(21) Perfume appropriate amount

[Example 6: Oil-in-water cream]
(Manufacturing method)
A. The following components (1) to (14) were dissolved by heating and kept at 70 ° C.
B. The following components (15) to (21) were dissolved by heating and kept at 70 ° C.
C. B was added to A and emulsified, and the following component (22) was further added and mixed.
D. After cooling C, the following component (23) was added and mixed to obtain a cream.
(Ingredient) (mass%)
(1) Stearic acid 2.5
(2) Cetanol 2.5
(3) Lipophilic glyceryl monostearate 2.0
(4) Vaseline 2.0
(5) Dipentaerythritol fatty acid ester 2.0
(6) Isotridecyl myristate 5.0
(7) Liquid paraffin 8.0
(8) Squalane 5.0
(9) Beeswax 1.0
(10) Cetyl palmitate 2.0
(11) Sorbitan sesquioleate 0.5
(12) Polyoxyethylene monooleate (20E.O.)
Sorbitan 1.5
(13) Coenzyme Q10 0.1
(14) Preservative appropriate amount (15) Maleic acid 1.0
(16) Triethanolamine 1.2
(17) 1,3-butylene glycol 8.0
(18) Glycerin 2.0
(19) Polyethylene glycol 20000 0.5
(20) Sodium 2,3-dihydroxybenzoate 2.0
(21) Purified water remaining amount (22) 1% aqueous solution of carboxyvinyl polymer 10.0
(23) Perfume appropriate amount

[Example 7: Water-in-oil sunscreen cream]
(Manufacturing method)
A. The following components (1) to (8) were heated and mixed at 70 ° C.
B. The following components (9) to (12) and (14) to (15) were heated and mixed at 50 ° C.
C. B was added to A and emulsified, and after cooling, the following component (13) was added and mixed to obtain a water-in-oil sunscreen cream.
(Ingredient) (mass%)
(1) Polyoxyalkylene-modified organopolysiloxane * 1 2.0
(2) Octyl palmitate 15.0
(3) Decamethylcyclopentasiloxane 20.0
(4) Glyceryl tribehenate 1.0
(5) Fine zinc oxide 12.0
(6) Fine particle titanium oxide 3.0
(7) 2-Ethylhexyl paramethoxycinnamate * 2 7.0
(8) 4-tertbutyl-4′-methoxydibenzoylmethane * 3 1.0
(9) Dipropylene glycol 5.0
(10) Ethanol 5.0
(11) Polyethylene powder 3.0
(12) Preservative appropriate amount (13) perfume appropriate amount (14) maleic acid 0.5
(15) Purified water remaining amount * 1: KF-6017 (manufactured by Shin-Etsu Chemical Co., Ltd.)
* 2: Yubinar MC80 (BASF)
* 3: PARSOL 1789 (manufactured by LC UNITED)

[Example 8: Pack cosmetic]
(Manufacturing method)
A. The following components (1) to (5) and (15) were heated and mixed at 70 ° C. and cooled to room temperature.
B. The following components (6) to (14) were added to A and mixed to obtain a pack cosmetic.
(Ingredient) (mass%)
(1) Polyvinyl alcohol 15.0
(2) Glycerin 10.0
(3) Polyoxyethylene (10) methyl glycol 3.0
(4) Glyceryl trioctanoate 5.0
(5) Sodium polyoxyethylene alkyl ether phosphate 1.0
(6) Ethanol 20.0
(7) Kaolin 2.0
(8) Titanium oxide 2.0
(9) Dipotassium glycyrrhizinate 0.1
(10) Lactic acid 0.25
(11) Sodium lactate 0.25
(12) Preservative appropriate amount (13) perfume appropriate amount (14) sodium maleate 0.1
(15) Purified water remaining

[Example 9: Liquid foundation]
(Manufacturing method)
A. The following components (1) to (7) were heated and mixed at 70 ° C., and the following components (14) to (18) were added to the mixture and mixed, and the mixture was kept at 70 ° C.
B. The following components (8) to (13) were heated and mixed at 70 ° C.
C. A was added to B and emulsified, and after cooling, the following components (19) to (20) were added and mixed to obtain a liquid foundation.
(Ingredient) (mass%)
(1) Dipentaerythritol fatty acid ester 2.0
(2) Liquid paraffin 5.0
(3) Stearic acid 2.0
(4) Cetanol 1.0
(5) Self-emulsifying glyceryl monostearate 1.0
(6) 2-Methylhexyl paramethoxycinnamate 8.0
(7) Preservative appropriate amount (8) Glycerin 5.0
(9) Triethanolamine 1.0
(10) Carboxymethylcellulose 0.2
(11) Bentonite 0.5
(12) Maleic acid 0.1
(13) Purified water remaining amount (14) Titanium oxide 6.0
(15) Fine particle titanium oxide 2.0
(16) Fine particle zinc oxide 4.0
(17) Mica 2.0
(18) Talc 4.0
(19) Coloring pigment appropriate amount (20) Fragrance appropriate amount

  The cosmetics prepared above are all excellent in stability over time, and can apply a whitening effect when applied to the skin.

It is a figure which shows the tyrosinase activity inhibitory effect of maleic acid, fumaric acid, cis-aconitic acid, and glutaconic acid.

Claims (3)

A melanin production inhibitor comprising as an active ingredient one or more compounds selected from maleic acid and salts thereof. A whitening agent comprising one or more compounds selected from maleic acid and salts thereof as an active ingredient. An external preparation for skin whitening comprising one or more compounds selected from maleic acid and salts thereof.

Images