JP2003137716A - Skin care preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine and a skin care preparation including the same, excellent in melanin production inhibitory action, i.e., bleaching action to the skin, with high safety/stability. SOLUTION: The medicine is a 1,4-quinone derivative expressed by formula (I) and/or a 1,4-hydroquinone derivative expressed by formula (II) as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a melanin production inhibitor and a skin external preparation containing the same. More specifically, it relates to a melanin production inhibitor having an excellent melanin production inhibitory effect and high stability and safety, and a skin and / or quasi drug external preparation for external use containing the melanin production inhibitor as an active ingredient.

[0002]

2. Description of the Related Art Pigmentation on the skin is the result of markedly enhanced melanin production due to the activation of pigment-producing cells (melanocytes) present in the skin, and is one of the serious skin problems. There is. In particular, in recent years, a substance useful for improving and / or suppressing the deposition of such pigments and keeping the skin white, that is, a substance having a whitening effect on the skin has been desired.

Examples of substances that suppress melanin production include ascorbic acid and its derivatives, sulfur-containing amino acid compounds such as glutathione and cysteine, kojic acid and its derivatives, azelaic acid and its derivatives, tranexamic acid and its derivatives, and alkylresorcinol derivatives. (JP 2000
-38334), ubiquinone derivatives (JP-A-61-61)
No. 289029, Japanese Patent Publication No. 9-510725) and the like are known, and it is possible to apply these substances as an active ingredient to creams, ointments, emulsions, etc., and apply and apply them locally on pigmented areas. Proposed. However, ascorbic acid and its derivatives not only have a problem in stability, but may cause discoloration and odor in a system containing water. Glutathione, cysteine, and the like have a problem that they have a strong offensive odor and are easily oxidized, which makes it difficult to mix them with an external preparation. Furthermore, since these compounds show a slow onset of action, a sufficient effect cannot be expected. Azelaic acid and its derivatives, and tranexamic acid and its derivatives are odorless white powders and are relatively compatible with various base materials used for external preparations for skin, but they all exhibit slow melanin production inhibitory effects. Further, the alkylresorcinol derivative may cause allergic contact dermatitis and the like as a side effect because it has skin irritation and / or sensitization, and thus it has been problematic to use it in a skin external preparation.

[0004]

DISCLOSURE OF THE INVENTION The present invention is excellent in the melanin production inhibitory action, that is, the skin whitening action, and the safety and
It is an object to provide a highly stable drug and an external preparation for skin containing the drug as an active ingredient.

[0005]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that 1,4-quinone derivatives and 1,4-hydroquinone derivatives have high solubility in cosmetic base materials. Found that it has good skin permeability, excellent whitening effect and high stability and safety,
The present invention has been completed. That is, the present invention provides the compound represented by the general formula (I);

[Chemical 4] And (II):

[Chemical 5]

[Chemical 6] [Wherein R is a methyl group or two R together represent a 1,4-butadienylidene group of the formula (III),
R'is a methyl group or a hydrogen group, and x and y are 4 to
An integer of 7, provided that x + y = 4 to 7], the melanin production inhibitor comprising a 1,4-quinone derivative and a 1,4-hydroquinone derivative represented by the following formula as an active ingredient.
When the value of x + y is less than 4, the toxicity to cells becomes strong, and when the value of x + y is 8 or more, the melanin production inhibitory effect is remarkably lowered, and the desired melanin production inhibitory effect cannot be expected.

In the present invention, 2-methyl-3- (3,7,11,15) is an example of a preferred 1,4-quinone derivative.
-Tetramethyl-2,6,10,14-hexadecatetraenyl) -1,4-naphthoquinone (hereinafter referred to as menaquinone 4), 2-methyl-3- (3,7,11,15-tetramethyl- 2-hexadecenyl) -1,4-naphthoquinone (hereinafter referred to as phytonadione), 2-methyl-3- (3,7,
11,15,19-pentamethyl-2,6,10,14,18
-Eicosapentaenyl) -1,4-naphthoquinone (hereinafter referred to as menaquinone 5), 2-methyl-3- (3,7,
11,15,19,23-hexamethyl-2,6,10,1
4,18,22-tetracosahexaenyl) -1,4-naphthoquinone (hereinafter referred to as menaquinone 6), 2-methyl-
3- (3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18,22,26-octacosaheptaenyl) -1,4-naphthoquinone (hereinafter referred to as menaquinone 7 Call it) 2,3,5-trimethyl-6- (3,7,11,15
-Tetramethyl-2,6,10,14-hexadecatetraenyl) -1,4-benzoquinone, 2,3,5-trimethyl-6- (3,7,11,15-tetramethyl-2-hexadecenyl) Mention may be made of -1,4-benzoquinone or 2,3-dimethyl-5- (3,7,11,15-tetramethyl-2-hexadecenyl) -1,4-benzoquinone.

As an example of a preferred 1,4-hydroquinone derivative, 2-methyl-3- (3,7,11,15-
Tetramethyl-2,6,10,14-hexadecatetraenyl) -1,4-naphthalenediol (hereinafter referred to as dihydromenaquinone 4), 2-methyl-3- (3,7,11,1)
5-tetramethyl-2-hexadecenyl) -1,4-naphthalenediol (hereinafter referred to as phytonadiol),
2-Methyl-3- (3,7,11,15,19-pentamethyl-2,6,10,14,18-eicosapentaenyl)-
1,4-naphthalenediol (hereinafter referred to as dihydromenaquinone 5), 2-methyl-3- (3,7,11,15,1)
9,23-Hexamethyl-2,6,10,14,18,22-
Tetracosahexaenyl) -1,4-naphthalenediol
(Hereinafter referred to as dihydromenaquinone 6), 2-methyl-3
-(3,7,11,15,19,23,27-heptamethyl-
2,6,10,14,18,22,26-octacosaheptaenyl) -1,4-naphthalenediol (hereinafter referred to as dihydromenaquinone 7), 2,3,5-trimethyl-6-
(3,7,11,15-tetramethyl-2,6,10,14-
Hexadecatetraenyl) -1,4-benzenediol, 2,3,5-trimethyl-6- (3,7,11,15-tetramethyl-2-hexadecenyl) -1,4-benzenediol, or 2, 3-dimethyl-5- (3,7,11,1
5-Tetramethyl-2-hexadecenyl) -1,4-benzenediol may be mentioned.

The above 1,4-quinone derivative and 1,4-quinone derivative
Hydroquinone derivatives show high solubility in cosmetic-based medium-chain fatty acid triglycerides. In addition, the above 1,
4-quinone derivative and 1,4-hydroquinone derivative,
In particular, phylloquinone, phytonadiol, menaquinone 4 and dihydromenaquinone 4 are melanin pigment-producing cells.
Direct contact with (B16 melanoma) shows a remarkable melanin production inhibitory effect at a low concentration of 3 to 10 ppm, and exhibits an extremely excellent whitening effect on the skin.

Therefore, the present invention is characterized by containing at least one melanin production inhibitor consisting of the 1,4-quinone derivative and the 1,4-hydroquinone derivative described above, which is excellent in skin whitening, and is used for external skin application. Provide medicine. The content of at least one melanin production inhibitor in the external preparation for skin is 0.0001% by weight or more. As described above, the melanin production inhibitor of the present invention exerts a remarkable effect at an extremely low concentration, so 0.0001% by weight or more is sufficient. Further, even if the melanin production inhibitor of the present invention is contained at a certain concentration or more, the effect exhibited is not increased, so it is not necessary to contain it at 5% by weight or more. Therefore, in a preferred embodiment of the present invention, the skin external preparation for whitening skin contains 0.0001 or more of one or more melanin production inhibitors comprising the 1,4-quinone derivative and the 1,4-hydroquinone derivative of the present invention.
.About.5% by weight, preferably 0.01 to 1% by weight.

Further, the dose of the external preparation for skin whitening according to the present invention depends on age, individual difference, racial difference, pigment deposition state, etc. The quinone derivative and the 1,4-hydroquinone derivative were added in 0.01-
15 mg / cm ^2, preferably 1-1 days 0.1 to 1 mg / cm ²
Apply 3 times directly to the affected skin.

Further, in the embodiment of the present invention, the external preparation for skin is combined with other pharmaceutically acceptable agents, additives and / or base materials. Additives include antioxidants, UV blockers, corneal exfoliants, surfactants, fragrances, dyes, preservatives, p
It is selected from H-adjusting agents, chelating agents, etc., but in order to further improve the stability of the 1,4-quinone derivative and the 1,4-hydroquinone derivative of the present invention, an antioxidant and / or an ultraviolet blocking agent It is preferable to combine with.
Further, it is also preferable to combine a keratin layer peeling agent which improves the effectiveness of the external preparation for skin and a natural surfactant which improves the transdermal absorbability.

The antioxidant used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, tocopherol or its derivative, low concentration of ascorbic acid or its derivative as water-soluble antioxidant, thiotaurine. , Sulfur-containing amino acids such as glutathione, antioxidant crude drug extract such as rosemary extract and sage extract, and synthetic antioxidants such as butylhydroxytoluene and butylhydroxyanisole. One or more of these may be used. They can be combined and appropriately blended.

The ultraviolet blocking agent used in the present invention includes:
UV absorbers and UV reflectors are included. Examples of UV absorbers include cinnamic acid ester derivatives such as octyl cinnamate, glyceryl mono-2-ethylhexanoyl-diparamethoxycinnamate, para-aminobenzoic acid octyl ester, N, N-dimethyl-benzoic acid octyl ester, etc. Benzoic acid ester derivatives of 2,4-hydroxybenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonate, etc. As benzophenone and other ultraviolet absorbers, 3- (4'-methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l-
Camphor, urocanic acid, urocanic acid ethyl ester, 4-methoxy-4′-t-butyl-dibenzoylmethane and the like can be mentioned. Examples of the ultraviolet reflecting agent include titanium oxide, zinc oxide, titanium mica and the like.

Examples of the stratum corneum release agent include α-hydroxy-carboxylic acids such as citric acid and glycolic acid, ethylenediaminetetracarboxylic acid mono-, di- and trisodium salts, and amino acids such as trimethylglycine and hydroxyproline.

Examples of natural surfactants include lysolecithins such as monoalkyloxyylphosphatidylcholine and lecithins such as dialkyloylphosphatidylcholine and dialkyloylphosphatidylethanolamine.

The external preparation for skin of the present invention may be blended with components usually used in cosmetics (for example, oily component, moisturizing component, thickener, emulsifier and various additives). Examples of the oily component include hydrocarbons, various synthetic esters, waxes, fats and oils, higher fatty acids, higher alcohols, silicones and the like. Examples of the moisturizing component include propylene glycol, 1,3-butylene glycol, isoprene glycol, glycerin, polyethylene glycol, sodium hyaluronate, sodium chondroitin sulfate, hydrolyzed collagen peptide, elastin peptide, keratin peptide, and sterol glycoside. . Examples of the thickener include water-soluble synthetic polymer compounds such as carboxyvinyl polymer, carboxymethyl cellulose and salts thereof, and water-soluble natural polymer compounds such as quince seed extract, guar gum, xanthan gum and sodium alginate. Emulsifiers that can be used include polyoxyethylene adducts of various higher alcohols as nonionic emulsifiers, various higher fatty acid polyoxyethylene glycol mono / diesters and mono / diesters of glycerin / sorbitan, and various higher fatty acid soaps as anionic emulsifiers. Examples of the phosphate ester emulsifier include α-phosphatidylcholine (lysolecithin), soybean lecithin and egg yolk lecithin. Further, as the additive, a fragrance, a dye, an antiseptic, a pH adjusting agent, a chelating agent and the like can be mentioned, and these can be appropriately combined and combined.

Further, in the embodiment of the present invention, the external skin preparation has a dosage form of W / O type lotion, O / W type lotion, W / O type cream, O / W type cream, viscous microemulsion essence or O type. It can be selected from / W type essence and the like.

Here, synthesis examples of the 1,4-quinone derivative and the 1,4-hydroquinone derivative of the present invention are shown below.

[Synthesis Example 1] Synthesis of phytonadiol 2.5 g of phytonadione is dissolved in 50 ml of acetic acid. The solution is warmed to 60 ° C. and powdered zinc (about 2 g) is slowly added with stirring. When the color of phytonadione has disappeared, the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The concentrated residue is dissolved in diisopropyl ether, and the solvent layer is washed with water and then saturated saline. Then, it was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 2.2 g of phytonadiol.
(Yield 88%).

[Synthesis Example 2] Synthesis of dihydromenaquinone 4 2.5 g of menaquinone 4 is dissolved in 50 mL of acetic acid. The solution is warmed to 60 ° C. and powdered zinc (about 2 g) is slowly added with stirring. When the color of menaquinone disappears, the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The concentrated residue is dissolved in diisopropyl ether, and the solvent layer is washed with water and then saturated saline. Then, it was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 2.3 g of dihydromenaquinone 4 (yield 92%).

[Synthesis Example 3] Synthesis of dihydromenaquinone 7 0.5 g of menaquinone 7 is dissolved in 10 mL of acetic acid. Warm the solution to 60 ° C and, with stirring, powder zinc (approx. 0.5 g)
Is gradually added. When the color of menaquinone disappears, the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The concentrated residue is dissolved in diisopropyl ether, and the solvent layer is washed with water and then saturated saline. Then dried over anhydrous magnesium sulfate,
The solvent was distilled off to obtain 0.5 g of dihydromenaquinone 7 (yield 100%).

[Synthesis Example 4] 2,3,5-trimethyl-6-
(3,7,11,15-tetramethyl-2,6,10,14-
Synthesis of hexadecatetraenyl) -1,4-benzenediol 2.5 g of 2,3,5-trimethylhydroquinone and 2.5 g of boron trifluoride ether complex are dissolved in 100 ml of ethyl acetate. The solution is heated to 40 ° C., and 5.0 g of all-trans-geranylgeraniol is added dropwise over 20 minutes while stirring. Add 2 mL of water to complete the reaction. The reaction solution is transferred to a separating funnel, and the ethyl acetate layer is washed with water and then with saturated saline. Then, it is dried over anhydrous magnesium sulfate and the solvent is distilled off. The concentrated residue was dissolved in a mixed solution of diisopropyl ether and hexane and purified by silica gel chromatography to obtain 2,3,5-trimethyl-6- (3,7,11,
1.5 g of 15-tetramethyl-2,6,10,14-hexadecatetraenyl) -1,4-benzenediol was obtained.
(Yield 21%).

Comparative Example 2-Methyl-3- (3,7,11)
-Trimethyl-2,6,10-dodecatrienyl) -1,4
-Synthesis of naphthalene diol 2.5 g of menadiol and boron trifluoride ether complex 2.
5 g are dissolved in 100 mL ethyl acetate. The solution is heated to 40 ° C., 4.0 g of all-trans-farnesol is added dropwise over 20 minutes while stirring, and 2 mL of water is added to terminate the reaction. The reaction is transferred to a separatory funnel and the ethyl acetate layer is washed with water then saturated aqueous solution. Then, it is dried over anhydrous magnesium sulfate and the solvent is distilled off. The concentrated residue was dissolved in a mixed solution of diisopropyl ether and hexane and purified by silica gel chromatography to give 2-methyl-3-
1.0 g of (3,7,11-trimethyl-2,6,10-dodecatrienyl) -1,4-naphthalenediol was obtained (yield 16%).

Next, the present invention will be described with reference to the following examples, which do not limit the present invention in any way.

[0025]

EXAMPLE The melanin production inhibition test and toxicity test of the 1,4-quinone derivative and the 1,4-hydroquinone derivative of the present invention are shown below.

[Melanin production inhibition test and toxicity test] As compounds of the present invention, phytonadiol (Synthesis Example 1), dihydromenaquinone 4 (Synthesis Example 2) and 2,3,5-trimethyl-6- (3,7, 11,15-tetramethyl-2,6,1
0,14-hexadecatetraenyl) -1,4-benzenediol (Synthesis Example 4) was used as a comparative example, and a similar compound 2-
Methyl-3- (3,7,11-trimethyl-2,6,10-
Dodecatrienyl) -1,4-naphthalenediol (Comparative Example) was used. Moreover, what added only ethanol was used as a control. (1) Melanin production inhibition test 1) Test with mouse-derived B16 melanoma (malignant melanoma cell) cultured cells B16 melanoma cultured cells were seeded on a 96-well microtiter plate at 2000 cells per well, 10% fetal bovine serum and theophylline (0.09 mg
/ ML) in Eagle MEM medium at 37 ° C., 5% CO ₂
Cultured in the presence. After 1 day of culturing, various concentrations of the sample compounds phytonadiol, dihydromenaquinone 4, 2, 3,
5-Trimethyl-6- (3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl) -1,4
-Benzenediol or 2-methyl-3- (3,7,1)
1-trimethyl-2,6,10-dodecatrienyl) -1,
20 μL of 4-naphthalenediol was added to a final concentration of 3.1
Each well was added to 0, 50, 100 or 200 μg / mL. After culturing for 72 hours, change the medium,
Also at that time, the sample compound was added. The cells were collected on the next day, and the inhibitory effect on nascent melanin synthesis was determined by the color tone of the cell pellet.

At the same time, the cytotoxicity was evaluated by fixing the cells with 10% formalin buffer, staining with 1% crystal violet, measuring the cell growth rate with respect to the control with a monoserator, and setting the cell number of the control as 100%. To determine the melanin production based on the color of the cell pellet, wash the wells with phosphate buffer (50 mM, pH 6.8), detach the cells with a microscraper, collect with phosphate buffer and centrifuge and precipitate. The color tone of the prepared cell pellet was evaluated in four levels according to the following criteria. The results obtained for the compounds of Synthesis Example 1, Synthesis Example 2, Synthesis Example 4 and Comparative Example are shown in Table 1 below.

[0028]

[Table 1]

The compounds of the comparative examples show a high melanin production inhibitory effect at 3 μg / mL, but at the same time, show a high concentration-dependent toxicity to B16 melanoma, and at a high concentration of 50 μg / mL, all cells are killed. did. From this, it is considered that the melanin production inhibitory effect of the compound of Comparative Example is due to its cytotoxicity. On the other hand, the compounds of Synthesis Example 1, Synthesis Example 2 and Synthesis Example 4 of the present invention show a melanin production inhibitory effect at 3 μg / mL and a remarkable effect at 10 μg / mL, but the cell growth rate is a control. No change and no cytotoxicity was observed. A control was prepared by adding only ethanol.

The 1,4-hydroquinone and 1,4-quinone derivatives of the invention were further tested for toxicological properties.

(2) Single-dose toxicity test Using Wister rats and ICR-JCL mice, acute toxicity in various administration routes was examined. For administration, the substance was given as a suspension in physiological saline under ultrasonic waves, adjusted to a predetermined amount. After the administration, observation of intoxication symptoms was continued, the mortality rate over time for 7 days was calculated, and the LD ₅₀ value was calculated. Findings were obtained by dissecting both surviving cases and dead cases. The LD ₅₀ was calculated by the Litchfield-Wilcoxon graphic algorithm.

Phytonadiol (Synthesis Example 1) and dihydromenaquinone 4 (Synthesis Example 2) were orally 4000 mg / kg, transdermally 4000 mg / kg, subcutaneously 500 mg / kg, and intramuscularly in male and female rat and male and female mice. 500 mg / kg, 150 intraperitoneally
0 mg / kg or 250 mg / kg was administered intravenously and the acute toxicity in each case was observed. As a result, there was no particular change in body weight or sample intake of both male and female rats and male and female mice, and no abnormality was observed in various organs in the autopsy findings. From these results, it was confirmed that the 1,4-quinone derivative and the 1,4-hydroquinone derivative of the present invention have high safety.

(3) Sensitization test Magnusson B. and Kligman
Sensitization test was performed according to the maximization test method developed by AM). (i) Twenty guinea pigs for induction of sensitization are prepared, 10 for induction of sensitization, and 10 for control. 4x above the scapula of the guinea pig
An area of 6 cm was shaved and shaved, and intradermal injection of the following 3 pairs of a, b, and c was simultaneously performed on the left and right sides symmetrically with respect to the midline. As a test sample, 10% of the compounds of Synthesis Example 1, Synthesis Example 2, and Synthesis Example 4 were used.
A suspension aqueous solution having a concentration of ultrasonic waves was used. a. Freund complete adjuvant (FCA Difco) of 0.05 mL (total 0.1 mL) each on two left and right sides.
(Manufactured by the company) was intradermally injected. b. Test sample of 0.05mL (10%
Ultrasonic suspension of concentration) was injected intradermally. c. Test sample of 0.05mL (10%
A concentration of FCA emulsion) was injected intradermally. After 7 days, the shoulder blades are shaved again and shaved, and vaseline containing 10% sodium lauryl sulfate is applied to cause slight inflammation. This treatment enhances induction of sensitization.
Then, a test sample is applied to this site and the block is attached.

(Ii) On the 21st day after induction of sensitization, 5 × 5 cm flanks of the guinea pigs in the sensitized group and the control group were shaved and shaved, and each test sample was cut to 80%.
It was diluted with the ethanol aqueous solution of and the block was stuck for 24 hours.
The same operation was performed on the control group.

(Iii) Score Abnormality is visually observed in both the sensitized treatment group and the control group, or the presence or absence of erythema / edema and its degree (mild, moderate or severe) only in the sensitized treatment group. Was evaluated comparatively.

(Iv) Results With the 1,4-quinone derivative and 1,4-hydroquinone derivative of the present invention, no sensitization reaction was observed in all guinea pigs. This result indicates that these compounds are safe for long-term transdermal administration.

(4) Pharmacological effect test 8-methoxypsoralen-treated phototoxic pigmentation Weiser Map
50μ on the shaved back with 5 le guinea pigs
L test sample was applied once a day in an area of about 4 cm ² for 8 weeks, and the decolorizing effect and the degree of pigmentation appearing as a side effect were evaluated according to the following evaluation criteria. The test sample was phytonadiol as the compound of the present invention.
(Synthesis example 1), dihydromenaquinone 4 (synthesis example 2) and menaquinone 4 were used. The compound of Comparative Example was used as a control. Each test sample was dissolved in dipropylene glycol to a concentration of 1% by weight and this solution was applied to guinea pigs as described above. The average evaluation points of five Weiser Maple guinea pigs are shown in Table 2 below.

[0038]

[Table 2]

1,4-quinone derivatives and 1,4 of the present invention
-The decolorization effect of each of the hydroquinone derivatives increased with time. On the other hand, with the 1,4-naphthalenediol derivative of the comparative control, the decolorizing effect was maximized at 3 weeks, but thereafter, pigmentation due to irritation occurred, and 6 to 8
On the contrary, in the week, a tendency of blackening was observed.

Next, production examples of the external preparation for skin according to the present invention will be shown. In addition, all the following compounding amounts are weight%.

[0041] [Example 1] W / O type emollient lotion     Micro Crystalline Wax 1.0     Beeswax 2.0     Macadamia nut oil 2.0     Squalane 10.0     Liquid paraffin 19.0     Phytonadiol (Synthesis example 1) 1.0     1,3-butylene glycol 4.0     Glycerin 3.0     Sorbitan sesquioleate 3.0     Lysolecithin 1.0     Polyoxyethylene (20 mol) sorbitan     Monooleate 1.0     α-tocopherol 0.02     Preservative Suitable amount     Deionized water 52.98

(Production method) 1,3 as a moisturizer in ion-exchanged water
-Butylene glycol, glycerin were added and heated to 70 ° C. Separately, microcrystalline wax, beeswax, macadamia nut oil, squalane and liquid paraffin are heated to 70 ° C to dissolve, and then 70 ° C.
Phytonadiol (Synthesis Example 1), an emulsifier sorbitan sesquioleate, lysolecithin and polyoxyethylene (20 mol) sorbitan monooleate, an antioxidant α-tocopherol, and a preservative are added. did. While stirring, the previously prepared aqueous phase was gradually added to this oil phase for preliminary emulsification, and the emulsified particles were homogenized with a homomixer, then deaerated and cooled.

[0043] [Example 2] W / O type emollient lotion     Cetyl alcohol 1.0     Beeswax 0.5     Vaseline 2.0     Squalane 6.0     Dimethyl polysiloxane 2.0     Ethanol 5.0     Dihydromenaquinone 4 (Synthesis example 2) 1.0     Glycerin 4.0     1,3-butylene glycol 4.0     Polyoxyethylene (10 mol) monooleate 1.0     Quinceseed mucus (1% aqueous solution) 20.0     α-tocopherol 0.02     Preservative Suitable amount     Fragrance suitable amount     Deionized water 52.48

(Production method) Ion-exchanged water with glycerin, 1,3
Add butylene glycol and quince seed mucus and heat to 70 ° C. Separately, cetyl alcohol, beeswax, petrolatum, squalane and dimethylpolysiloxane were heated to 70 ° C. to dissolve them, and then 70
Dihydromenaquinone 4, an emulsifier polyoxyethylene (10 mol) monooleate, an antioxidant α-tocopherol, and a preservative were added while maintaining the temperature at ℃. While stirring, the previously prepared aqueous phase was gradually added to this oil phase for preliminary emulsification, ethanol was added after the temperature reached 35 ° C or lower, and then the homogenized particles were homogenized with a homomixer. Degassed and cooled.

[0045] [Example 3] W / O type emollient cream     Liquid paraffin 30.0     Microcrystalline Wax 2.0     Vaseline 5.0     Phytonadion 1.0     Diglycerol dioleate 5.0     α-tocopherol 0.02     Preservative Suitable amount     Fragrance suitable amount   Water phase (1)       L-Glutamate sodium 1.2       L-serine 0.4       Trimethylglycine 0.4       Ion-exchanged water 13.0   Water phase (2)       Dipropylene glycol 3.0       Ascorbic acid-α-D-glucopyranoside 0.2       Sodium glycolate 0.1       Glycolic acid 0.1       Deionized water 38.58

(Manufacturing Method) The aqueous phase (1) heated and dissolved at 50 ° C. was gradually added to the emulsifier part dichrycerol dioleate ester which was also heated at 50 ° C. with stirring to prepare an emulsified composition. . The emulsified composition was uniformly dispersed in a solution obtained by heating and dissolving an oil phase containing phytonadione and α-tocopherol (liquid paraffin, microcrystalline wax and vaseline) at 70 ° C. Further water phase
The mixture obtained by heating (2) to 70 ° C. was added to the above dispersion with sufficient stirring, and the mixture was uniformly emulsified with a homomixer, degassed, filtered, and cooled to 30 ° C.

[0047] [Example 4] O / W type emollient cream     Cetyl alcohol 5.0     Stearic acid 3.0     Vaseline 5.0     Squalane 10.0     Glycerol tri-2-ethylhexanoate 7.0     Menaquinone 5 0.5     α-tocopherol 0.02     1,3-butylene glycol 5.0     Glycerin 5.0     Propylene glycol monostearate 3.0     Polyoxyethylene (20 mol) cetyl alcohol ether 3.0     Triethanolamine 0.8     Preservative Suitable amount     Fragrance suitable amount     Ion-exchanged water 52.68

(Production Method) Triethanolamine and 1,3-butylene glycol and glycerin which are moisturizers were added to ion-exchanged water and heated to 70 ° C. An oil phase containing menaquinone 5 and α-tocopherol (cetyl alcohol, stearic acid, petrolatum, squalane, and glycerol tri-2-ethylhexanoate) was dissolved by heating, and then propylene glycol monostearate and polyoxyethylene which were emulsifiers. (20 moles) cetyl alcohol ether, preservatives and flavors are added,
Heated to 70 ° C. This was added to the previously prepared aqueous phase to be pre-emulsified. Then, the emulsified particles were homogenized with a homomixer, deaerated, filtered, and cooled to 30 ° C.

[0049] [Example 5] Semi-transparent microemulsion lotion     1,3-butylene glycol 6.0     Glycerin 5.0     Polyethylene glycol 4000 3.0     Macadamia nut oil 0.5     Dihydromenaquinone 5 0.15     Menaquinone 5 0.15     α-tocopherol 0.02     Polyoxyethylene (20 mol) sorbitan monostearic acid     Esters 1.5     Polyoxyethylene (5 mol) oleoyl alcohol ether 0.3     Ethanol 10.0     Fragrance suitable amount     Coloring agent     Preservative Suitable amount     pH adjusting agent     Chelating agent     Ion-exchanged water 73.38

(Production method) 1,3-butylene glycol, glycerin and polyethylene glycol 4000 as a moisturizing agent, a coloring agent, a pH adjusting agent and a chelating agent were added to ion-exchanged water and dissolved at room temperature. Separately from this, dihydromenaquinone 5, menaquinone 5, α-tocopherol, macadamia nut oil, polyoxyethylene (20 mol) as an emulsifier
Sorbitan monostearate and polyoxyethylene (5 mol) oleoyl alcohol ether, preservative and perfume were added to ethanol and dissolved at room temperature. Add this alcohol phase to the previously prepared aqueous phase,
A microemulsion was prepared with a homomixer.

[0051] [Example 6] Viscous microemulsion essence     Dipropylene glycol 5.0     Polyethylene glycol 4000 5.0     Ethanol 10.0     Carboxy vinyl polymer 0.3     Sodium alginate 0.3     Potassium hydroxide 0.15     Polyoxyethylene (20 mol) sorbitan monostearic acid     Esters 1.0     Sorbitan monooleate 0.3     Lysolecithin 0.2     Dihydromenaquinone 7 0.3     Menaquinone 4 0.2     α-tocopherol 0.02     α-tocopherol acetate 0.02     Oleyl alcohol 0.5     Fragrance suitable amount     Preservative Suitable amount     Ion-exchanged water 73.38

(Production Method) After dissolving the carboxyvinyl polymer in ion-exchanged water, dipropylene glycol and polyethylene glycol 4000 were sequentially dissolved. Separately from this, sorbitan monooleate, polyoxyethylene (20 mol) sorbitan monostearate, lysolecithin, dihydromenaquinone 7, menaquinone 4, oleyl alcohol, α-tocopherol, α-tocopherol acetate, perfume and preservative are ethanol. Sequentially dissolved. Add this to the previously prepared aqueous phase,
It was made into a microemulsion with a homomixer. Next, potassium hydroxide dissolved in a part of ion-exchanged water was added, and the mixture was stirred, degassed, and filtered.

[0053] [Example 7] Essence containing O / W type ultraviolet shielding agent     Stearic acid 3.0     Ethanol 1.0     Cholesteryl-12-hydroxystearate 3.0     Liquid paraffin 5.0     2-Ethylhexyl palmitate 3.0     Menaquinone 6 0.1     Phytonadiol 0.5     α-tocopherol 0.02     1,3-butylene glycol 5.0     Polyoxyethylene (20 mol) cetyl alcohol ether 2.0     Glyceryl monostearate 2.0     Glyceryl mono-2-ethylhexanoyl-diparamethoxy     Cinnamate 4.0     4-Methoxy-4'-t-butyl-dibenzoylmethane 4.0     Silicone surface treated fine particles zinc oxide 2.0     Decamethylcyclomethicone 2.0     Triethanolamine 0.8     Fragrance suitable amount     Preservative Suitable amount     Ion-exchanged water 61.88

(Production method) 1,3-butylene glycol and triethanolamine were added to ion-exchanged water and heated to 70 ° C. Stearic acid, cholesteryl-12-hydroxystearate, liquid paraffin and 2-ethylhexyl palmitate are heated and dissolved at 70 to 80 ° C., and then an emulsifier (polyoxyethylene (20 mol) cetyl alcohol ether and glyceryl monostearate) and ultraviolet rays. Absorbent (cinnamate and 4-methoxy-4'-t-
(Butyl-dibenzoylmethane), menaquinone 6, phytonadiol, α-tocopherol, preservative and perfume were added in that order and heated to 70 ° C. The oil phase was added to the previously prepared aqueous phase with stirring to pre-emulsify. afterwards,
The temperature was cooled to 40 ° C. or lower, the emulsified particles were homogenized with a homomixer while adding silicone surface-treated fine particle zinc oxide and a decamethylcyclomethicone dispersion, and deaerated and cooled.

[Practical test in humans] 1) Administration sample and test method In order to confirm the effect of the external preparation for skin of the present invention on human skin, the following tests were conducted. Subject 105 who has a pigmented lesion on the face (has liver spots / spot egg spots, senile pigment spots, post-inflammatory pigmentation and other pigmentation)
The name was a panelist. The skin external preparation of the present invention was applied to about 55 of about half of the panelists, and the placebo was applied to the other 50 directly to the affected area where melanin pigment production is enhanced after washing the face every morning and evening. After two months of continuous use, the effect was judged by the visual judgment by a doctor, and a comparative examination was also carried out by photographs before the start of the test and two months after the test. As the test sample, the W / O type emollient lotion prepared in Example 1 was used, and for the placebo, the W / O type emollient lotion prepared by substituting 1% of phytonadiol with ion-exchanged water was used. In addition, when applying the external drug on the skin, the dosage of phytonadiol should be 0.05 to 0.5 mg / cm 3.
Lotion was applied to the affected skin to give ² .
The test results obtained are shown in Table 3 below.

[0056]

[Table 3]

2) Test Results As is clear from the above table, in the W / O type emollient lotion of the present invention, 98% (improved + slightly improved) symptom improvement was observed. In contrast, placebo showed no improvement in 78% and deterioration was observed in 2%. Further, an improvement was observed in 22% of the placebos, which is considered to be a so-called placebo effect. In addition, in this test, no significant difference in the effect due to the difference in the symptoms of pigmentation (chloasma / cockroach, senile pigmentation, pigmentation after inflammation and other pigmentation) was observed. From the above results, it was shown that the external preparation for skin according to the present invention is actually effective for improving pigmentation in the skin in humans.

[0058]

INDUSTRIAL APPLICABILITY According to the present invention, a melanin production inhibitor having an excellent melanin production inhibitory effect and high stability and safety, as well as cosmetic and / or quasi-drug external use for external use on the skin containing the same An agent is provided. The melanin production inhibitor of the present invention exerts a remarkable melanin production inhibitory effect at an extremely low concentration of 0.0001% by weight or more, and has no or extremely low toxicity to the skin and cells thereof. The external preparation for skin containing
Not only when it has an excellent skin whitening effect, it can be used continuously for a long period of time because of its high safety.

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 9/107 A61K 9/107 31/05 31/05 31/122 31/122 A61P 17/16 A61P 17/16 43 / 00 105 43/00 105 (72) Inventor Ikuo Yoshimura 1-25, Kandanishiki-cho, Chiyoda-ku, Tokyo Within Nisshin Pharma Co., Ltd. (72) Inventor Junhiro Yamamoto 7-3, Hongo, Bunkyo-ku, Tokyo University of Tokyo Graduate School of Engineering F-term (reference) 4C076 AA17 BB31 CC18 CC26 DD34 DD38 DD45 DD46 DD67 EE51 EE53 FF32 FF57 FF68 4C083 AA082 AA122 AB032 AB212 AC012 AC022 AC072 AC102 AC111 AC112 AC122 AC132 AC182 AC212 AC242 AC422 AC442 AC352 AC352 AC352 AC352 AC352 AC582 AD042 AD092 AD152 AD172 AD302 AD352 AD572 AD642 AD662 AD672 BB01 BB21 BB41 BB44 BB45 BB46 BB47 BB48 BB51 CC04 CC05 DD32 DD33 EE01 EE10 EE16 4C206 AA01 AA02 CA19 CB27 KA01 MA01 MA04 ZB21 MA14 MA48 NA83

Claims (6)

[Claims] 1. A compound represented by the general formula (I): [Wherein R is a methyl group, or two R together form a compound of formula (III) Of 1,4-butadienylidene group, R ′ is a methyl group or a hydrogen group, and x and y are integers of 4 to 7, provided that x + y = 4 to 7,] A quinone derivative or general formula (II): [Wherein R, R ′, x and y have the same definitions as above]
A melanin production inhibitor comprising a 1,4-hydroquinone derivative represented by 2. The 1,4-quinone derivative is 2-methyl-
3- (3,7,11,15-tetramethyl-2,6,10,1
4-hexadecatetraenyl) -1,4-naphthoquinone,
2-methyl-3- (3,7,11,15-tetramethyl-2
-Hexadecenyl) -1,4-naphthoquinone, 2-methyl-3- (3,7,11,15,19-pentamethyl-2,6,
10,14,18-Eicosapentaenyl) -1,4-naphthoquinone, 2-methyl-3- (3,7,11,15,19,2)
3-hexamethyl-2,6,10,14,18,22-tetracosahexaenyl) -1,4-naphthoquinone, 2-methyl-3- (3,7,11,15,19,23,27-heptamethyl -2,6,10,14,18,22,26-octacosaheptaenyl) -1,4-naphthoquinone, 2,3,5-trimethyl-6- (3,7,11,15-tetramethyl-2 , 6,1
0,14-hexadecatetraenyl) -1,4-benzoquinone, 2,3,5-trimethyl-6- (3,7,11,15-
Tetramethyl-2-hexadecenyl) -1,4-benzoquinone or 2,3-dimethyl-5- (3,7,11,15)
-Tetramethyl-2-hexadecenyl) -1,4-benzoquinone, and the 1,4-hydroquinone derivative is 2-methyl-3- (3,7,11,15-tetramethyl-2,6,1
0,14-hexadecatetraenyl) -1,4-naphthalenediol, 2-methyl-3- (3,7,11,15-tetramethyl-2-hexadecenyl) -1,4-naphthalenediol, 2-methyl -3- (3,7,11,15,19-pentamethyl-2,6,10,14,18-eicosapentaenyl) -1,4-naphthalenediol, 2-methyl-3-
(3,7,11,15,19,23-hexamethyl-2,6,1
0,14,18,22-tetracosahexaenyl) -1,4
-Naphthalene diol, 2-methyl-3- (3,7,11,
15,19,23,27-heptamethyl-2,6,10,1
4,18,22,26-octacosaheptaenyl) -1,4
-Naphthalenediol, 2,3,5-trimethyl-6-
(3,7,11,15-tetramethyl-2,6,10,14-
Hexadecatetraenyl) -1,4-benzenediol,
2,3,5-trimethyl-6- (3,7,11,15-tetramethyl-2-hexadecenyl) -1,4-benzenediol, or 2,3-dimethyl-5- (3,7,11, 15-
The melanin production inhibitor according to claim 1, which is tetramethyl-2-hexadecenyl) -1,4-benzenediol. 3. An external preparation for skin, comprising one or more of the melanin production inhibitor according to claim 1 or 2. 4. The content of the melanin production inhibitor is 0.0.
The external preparation for skin according to claim 3, which is 001 to 5% by weight. 5. An antioxidant, an ultraviolet blocking agent, a horny layer peeling agent,
The external preparation for skin according to claim 3 or 4, which contains an additive selected from a surfactant, a fragrance, a dye, a preservative, a pH adjusting agent, and a chelating agent. 6. The external skin preparation has a dosage form of W / O type lotion, O / W type lotion, W / O type cream, O / W type cream, viscous microemulsion essence, and O / W type essence. The external preparation for skin according to any one of claims 3 to 5, which is selected.