JPH0873336A - Melanogenesis inhibitor and skin external preparation - Google Patents

Abstract

PURPOSE: To obtain a melanogenesis inhibitor and skin external preparation excellent in skin whitening effect and high in stability and safety, containing, as active ingredient, a 2-hydroxy-4-(2,2,6-trimethyl-1-yl-cyclohexane)butane glycoside. CONSTITUTION: This melanogenesis inhibitor contains, as active ingredient, pref. 0.0001-10wt.% of a compound selected from monosaccharide, disaccharide and trisaccharide of 2-hydroxy-4-(2,2,6-trimethyl-1-yl-cyclohexane)butane of the formula [R is monosaccharide, disaccharide or trisaccharide residue (e.g. a residue of glucose, galactose, mannose, xylose, fructose, maltose, isomaltose)]. This skin external preparation can be used for preventing, remedying or treating systemic dyspigmentation such as Addison's disease as well as focal dyspigmentation such as suntan, spots or freckles.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a melanin production inhibitor and a skin external preparation, and more specifically, it provides a melanin production inhibitor which prevents skin pigmentation and a skin external preparation having an excellent whitening effect. .

[0002]

2. Description of the Related Art Pigmentation after freckles and sunburn is a marked increase in melanin production due to the activation of pigment cells in the skin, which is one of the troubles of the middle-aged and old-aged skin. There is. In general, melanin is changed from tyrosine to dopa and dopa to dopaquinone by the action of the enzyme tyrosinase biosynthesized in pigment cells, and then an intermediate such as 5,6-dihydroxyindophenol is formed. It is supposed to be formed through.

Therefore, in order to prevent or improve the darkness of the skin, it is considered to inhibit the melanin production process or to bleach already produced melanin. Based on such an idea, various whitening components have been conventionally proposed. For example, a sulfur compound represented by glutathione or hydroquinone is mentioned as a substance that inhibits tyrosine enzyme activity and suppresses melanin production. Further, hydrogen peroxide, vitamin C, and the like have been used as the ones that lightly bleach the produced melanin.

[0004]

However, these conventional whitening ingredients are extremely poor in stability in the formulation system and cause discoloration or offensive odor due to decomposition, and their effects at the cell or biological level are still insufficient. Met. Further, hydroquinone has a strong lightening effect, but has a problem in safety such as causing irreversible white spots and rashes.

As described above, the conventionally used whitening ingredients are effective, stable and safe.
Not really practically satisfying. The present invention has been made in view of such circumstances, using a melanin production inhibitor, and this melanin production inhibitor as an active ingredient, having a sufficient improvement and therapeutic effect on skin pigmentation,
Another object of the present invention is to provide an external preparation for skin which can practically satisfy safety and stability.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that 2-hydroxy-4- (2,2,6 represented by the following general formula (I).
-Trimethyl-1-yl-cyclohexane) butane glycoside was found to have a strong inhibitory effect on the melanin production of living pigment cells, and it was further added to the base at a certain concentration or higher for external use on the skin. It was found that when used as an agent, an excellent whitening effect on the skin was exhibited, and the present invention was accomplished.

That is, the present invention is a compound represented by the general formula (I) of Chemical formula 2, namely 2-hydroxy-4- (2,2,6).
It is a melanin production inhibitor consisting of -trimethyl-1-yl-cyclohexane) butane glycoside.

The present invention also provides a skin external preparation containing one or more of the melanin production inhibitors as an active ingredient in an amount of 0.0001 to 10% by weight based on the total amount of the skin external preparation. To do.

[0009]

Embedded image

(In the formula, R represents a monosaccharide residue, a disaccharide residue or a trisaccharide residue.) The present invention is described in detail below. <1> Melanin production inhibitor The melanin production inhibitor of the present invention is a 2-hydroxy-4- (2,2,6-trimethyl-1-yl-cyclohexane) butane glycoside represented by the general formula (I). It consists of a body.

Examples of the R group in the general formula (I) include glucose, galactose, mannose, xylose,
Fructose, maltose, isomaltose, cellobiose, gentiobiose, kojibiose, laminaribiose, nigerose, sambubiose, neohesperidose, maltotriose, isomaltotriose, cellotriose, gentiotriose, etc., preferably glucose, galactose, maltose, maltose. Triose,
Cellobiose can be mentioned.

The glycoside compound represented by the general formula (I) is 2-
Hydroxy-4- (2,2,6-trimethyl-1-yl-cyclohexane) butane (in the general formula (I),
Compounds in which R is a hydrogen atom) can be synthesized. The synthesis method is described below using 2-O-glucoside-
An example of 4- (2,2,6-trimethyl-1-yl-cyclohexane) butane will be described.

2-Hydroxy-4- (2,2,6-trimethyl-1-yl-cyclohexane) butane and tetra-0-acetyl-D-glucopyranosyl bromide were added to dichloromethane and tetramethylurea and silver were added. In the presence of a mixed catalyst with triflate, the mixture was reacted in a nitrogen stream for 2 hours while cooling with ice, then the dichloromethane layer was evaporated to dryness, and the reaction product was fractionally isolated by silica gel column chromatography, followed by deacetylation. Then, the corresponding glucose derivative was obtained.

The raw material 2-hydroxy-4-
(2,2,6-trimethyl-1-yl-cyclohexane) butane is reacted with β-ionone in a methanol solvent in the presence of palladium carbon and hydrogen to give tetrahydroionone (the reaction proceeds quantitatively). Further, it can be synthesized by reacting this tetrahydroionone with sodium borohydride (NaBH ₄ ) in methanol.

Other glycoside compounds can also be produced according to the above method using the corresponding pyranosyl bromide derivative. <2> External preparation for skin The external preparation for skin of the present invention is one or two or more kinds of the above-mentioned melanin production inhibitors, preferably 0.00 based on the total amount of the external preparation.
It is blended in the range of 01 to 10% by weight, and more preferably 0.01 to 10% by weight. Among the external preparations for skin, the purpose of the invention is to prevent and improve exacerbation of spots, freckles, and black and white due to sunburn. It is preferable that the compounding amount is 0.01% by weight or more.

If the amount is less than 0.0001% by weight, the whitening effect due to the melanin production inhibitory effect is lowered, and if the amount is more than 10% by weight, the effect will reach the ceiling. It is preferable to mix them.

In the external preparation for skin of the present invention, in addition to the above-mentioned active ingredients, various ingredients generally used in pharmaceuticals, cosmetics and the like, that is, an aqueous ingredient, an oily ingredient, a powder ingredient, a surfactant (as an emulsifier), a moisturizing agent Agents, thickeners, colorants, fragrances, antioxidants, pH regulators, chelating agents, preservatives, etc., or one or more agents such as UV protectants, anti-inflammatory agents, etc. can be blended. .

Examples of the aqueous component include water (purified water),
Examples thereof include lower alcohols (lower alcohols such as ethanol, propanol and isopropanol). Examples of the oily component include higher fatty acids (stearic acid, palmitic acid, myristic acid, lauric acid, and their esters), higher alcohols (cetanol, lanolin alcohol, stearyl alcohol, cetostearyl alcohol, etc.) and waxes ( Solid paraffin, microcrystalline wax, ceresin wax, polyethylene wax, beeswax, wax, carnauba wax, candelilla wax, etc., natural or synthetic oily substances (squalane, liquid paraffin, lanolin or its derivatives, olive oil, camellia oil, cottonseed oil, oleyl) Alcohol, castor oil, petrolatum, adipic acid diethoxyethyl ester,
Silicon oil, fluorine oil, etc.) and the like.

Examples of powder components include aluminum powder, titanium oxide powder, zinc oxide powder, iron oxide powder, acrylic powder, silica beads, talc, and sericite.

Examples of the surfactant include polyoxyethylene monooleate, polyoxyethylene cetyl ether, aluminum stearate, octyldodecanol, lipophilic glycerin monostearate, propylene glycol monostearate and the like.

Examples of moisturizing agents include glycerin, propylene glycol, 1,3-butylene glycol, dipropylene glycol, ethylene glycol, 1,4-butylene glycol, diglycerin, triglycerin, sorbit and its derivatives, polyethylene glycol and the like. Polyhydric alcohols: glucose, maltose, maltitol, sucrose, fructose, threitol, erythritol, sorbit, starch-degrading sugar, hyaluronic acid, chondroitin sulfate, hydrolyzed collagen, carboxymethyl chitin and the like.

Examples of the thickener include carboxyvinyl polymer, CP jelly, sodium alginate, bentonite, veegum, synthetic hectorite and the like.
Examples of the antioxidant include dibutylated hydroxytoluene (BHT) and butylated hydroxyanisole (BH).
A), tocopherol sodium pyrosulfite, acetone sodium bisulfate, tocopherol acetate, vitamin E, rosemary extract and the like.

Examples of the pH adjusting agent include citric acid, lactic acid, tartaric acid, phosphoric acid and the like. Examples of the chelating agent include EDTA (ethylenediaminetetraacetic acid),
Examples thereof include thioglycolic acid, thiolactic acid, and thioglycerin.

Examples of preservatives include methyl, ethyl, propyl and butyl esters of p-oxybenzoic acid (referred to as methylparaben, ethylparaban, propylparaben and butylparaben, respectively), o-phenylphenol, dehydroacetic acid and the like. Salt, p-cresol,
Examples thereof include m-cresol and o-chloro-m-xylenol.

Examples of the UV protective agent include ascorbic acid or its derivative, isoferulic acid or its salt, glutathione or its derivative, oxybenzone or its derivative, p-aminobenzoic acid or its derivative, urocanic acid or its derivative, kojic acid, Examples thereof include dibenzoylmethane or its derivative, p-methoxycinnamic acid or its derivative, fine particle titanium oxide, fine particle zinc oxide, and fine particle iron oxide.

Examples of the anti-inflammatory agent include glycyrrhetinic acid or its derivative, glycyrrhizic acid or its derivative, bisabolol, geraniin, horse chestnut extract, aloe extract and the like.

Each of these components or agents may be used alone or in admixture of two or more. In the external preparation for skin of the present invention, a whitening component other than 2-hydroxy-4- (2,2,6-trimethyl-1-yl-cyclohexane) butane glycoside represented by the general formula (I) (or You may mix 1 type (s) or 2 or more types of (whitening agent). Other whitening ingredients include, for example, pantetheine-s-sulfonic acid, isoferulic acid, ascorbic acid and its magnesium phosphate salts, arbutin, cordic acid, linoleic acid, esculin, tranexamic acid and the like.

The dosage form of the external preparation for skin of the present invention is not particularly limited, and it is usually used for medicines, quasi drugs, cosmetics, etc., such as ointments, creams, emulsions, lotions,
The dosage forms include packs and bath agents.

[0029]

The following is the general formula (I) used in the present invention.
The action of the 2-hydroxy-4- (2,2,6-trimethyl-1-yl-cyclohexane) butane glycoside compound group represented by is explained based on experimental examples. In addition, 2-hydroxy-4- used in the following experimental examples and examples.
The (2,2,6-trimethyl-1-yl-cyclohexane) butane glycoside is obtained as described above. (1) Inhibition of melanin production on pigment cells 5 × 10 ⁴ B-16 melanoma cells were seeded in a plastic culture flask (75 cm ² ) and 5% carbon dioxide was added to Eagle MEM medium containing 10% serum. In the presence of
Culture was carried out at the temperature of. Two days later, 2-hydroxy-4-
A test sample of (2,2,6-trimethyl-1-yl-cyclohexane) butane glycoside was added at a concentration of 5 in the medium,
It was added so as to have a concentration of 10, 15, and 20 μM, and the cells were further cultured for 4 days.

After completion of the culture, the medium was removed and washed with phosphate buffered saline (hereinafter referred to as PBS), and then the cells were detached from the flask using trypsin and EDTA-containing medium and centrifuged from the cell suspension. The cells were collected by. After washing the obtained cells once with PBS, a certain amount of PBS
Was added, and the cells were mixed by flushing, a fixed amount of the cell suspension was taken, and the number of cells was counted with a Coulter counter. The remaining suspension was centrifuged again and the whiteness of the sediment was visually observed. The results are shown in Table 1 according to the following criteria.
Shown in The number of cells (%) in the table is 100 when the solvent is used instead of the test sample (solvent control).
Represents the number of cells (%).

-: Equivalent to solvent control +: Slightly whiter than solvent control ++: Clearly whiter than solvent control

[0032]

[Table 1] Then, 1N sodium hydroxide was added to the precipitate to dissolve it by heating, and after cooling, chloroform was added and the mixture was centrifuged again.
The absorbance of the obtained supernatant was measured at 400 nm, and the amount of melanin was determined from a calibration curve prepared in advance using synthetic melanin. The amount of melanin was calculated as the amount per 10 ⁴ cells. The results are shown in Table 2. The suppression rate in the table was calculated by the following formula. Suppression rate (%) = [(amount of melanin in control product)-
(Melanin amount of test sample added product)] × 100 / (Melanin amount of control product)

[0033]

[Table 2]As is clear from these results, 2-hydroxy-
4- (2,2,6-trimethyl-1-yl-cyclohexyl
All of the sun) butane glycosides are solvent control (control
Remarkably suppresses melanin production in pigment cells
It has been confirmed that it has an action. (2) Inhibition of pigmentation by ultraviolet rays The back skin of brown guinea pigs (7 animals) was treated with electric clippers
The hair is removed and shaved with a fiber, and this site is cut by 1.5 × 1.
Cover with a black cloth that has a total of 6 5 cm irradiation windows on the left and right sides,
Use the FL20S / E30 lamp as the light source from above this cloth
1 mW / cm ²/ 4 sec UV irradiation for 4 minutes and 20 seconds
did.

This operation was performed once a day for 3 consecutive days. A sample in which a predetermined amount of 2-hydroxy-4- (2,2,6-trimethyl-1-yl-cyclohexane) butane glycoside was dissolved using propylene glycol / ethanol (3: 1) as a solvent from the day after the end of irradiation. Solution 0.02
ml was applied once a day for a total of 20 days. Further, the same experiment was conducted using only the solvent as a control. Experiment start 2
On the first day, the degree of pigmentation of the treated area was visually determined according to the following criteria. Table 3 shows the result as an average value.
Shown in

0: no pigmentation 0.5: weak pigmentation with unclear boundary 1: weak pigmentation with clear boundary 2: moderate pigmentation with clear boundary 3: clear boundary with strong intensity With pigmentation

[0036]

[Table 3] As shown in Table 3, 2-hydroxy-4- (2,
When applied to the skin, each of the 2,6-trimethyl-1-yl-cyclohexane) butane glycosides clearly suppressed the deposition of melanin pigment by ultraviolet rays at a concentration of 3.0%.

As described above, 2-
Hydroxy-4- (2,2,6-trimethyl-1-yl-cyclohexane) butane glycoside has an effect of suppressing melanin production and an effect of suppressing pigment deposition.
As a result, what was mixed in a certain ratio or more in the skin external preparation base material brings an excellent whitening effect to the skin,
It can be used for the prevention, improvement and treatment of not only local pigmentation diseases such as stains, freckles and sunburn, but also systemic pigmentation diseases such as Addison's disease. Moreover, since the compound is excellent in safety and stability, it can be used continuously for a long period of time.

[0038]

EXAMPLES Examples of the present invention will be described below.

[0039]

Example 1 An oil-in-water cream will be described as an example of the external preparation for skin of the present invention. <Manufacturing method> Each of the components A and B in Table 4 is mixed at 80 ° C.
Heat to. These are added and stirred, emulsified, and then cooled.

[0040]

[Table 4] <Practical use test of pigmentation improving effect> The cream obtained above and a comparative cream (in the cream of Example 1, 2-O-maltoside-4- (2,2,6-trimethyl-1-yl-cyclohexane) was used. ) (Butane was replaced with water) was continuously applied to a statistically equivalent group of 40 women suffering from black-black, spots and freckles for 3 months, and the effect of improving pigmentation by actual use was evaluated. The results are shown in Table 5.

[0041]

[Table 5] As is clear from this table, 2-O-maltoside-4-
It was confirmed that the product of the present invention containing (2,2,6-trimethyl-1-yl-cyclohexane) butane has a significantly more effective pigmentation-improving effect than the comparative product not containing this compound. No unfavorable reaction on the skin was observed at the application site of the product of the present invention.

[0042]

[Embodiment 2] Next, an embodiment of the emulsion will be described. <Production Method> Components A and B shown in Table 6 are dissolved at 70 ° C. with stirring. The component A is added to the component B to carry out preliminary emulsification, uniformly emulsify with a homomixer, and after emulsification, cool to 30 ° C. with stirring.

[0043]

[Table 6]

[0044]

[Embodiment 3] Another embodiment of the emulsion will be described. The manufacturing method is the same as in Example 2 except that the components shown in Table 7 below are used.

[0045]

[Table 7]

[0046]

Example 4 A lotion will be described as an example of the present invention. <Manufacturing Method> Components A in Table 8 are mixed and dissolved at room temperature. On the other hand, the component B is also dissolved at room temperature and added to the component A to be solubilized.

[0047]

[Table 8]

[0048]

[Embodiment 5] Another lotion will be described as an embodiment of the present invention. The manufacturing method is the same as in Example 4 except that the components shown in Table 9 below are used.

[0049]

[Table 9]

[0050]

[Sixth Embodiment] Further, an embodiment of the pack charge will be described. <Manufacturing Method> The component A shown in Table 10 is dispersed and dissolved at room temperature.
Component B is added to this and dissolved uniformly.

[0051]

[Table 10]

[0052]

[Embodiment 7] Another embodiment of the pack charge will be described. The manufacturing method is the same as in Example 6 except that the components shown in Table 11 below are used.

[0053]

[Table 11] In addition, the actual use test of the pigmentation improving effect was also performed on Examples 2 to 7, and the same results as in Example 1 were obtained.

[0054]

Industrial Applicability According to the present invention, it is possible to provide a melanin production inhibitor and an external preparation for skin which are excellent in whitening effect and are highly stable and safe. The external preparation for skin of the present invention is
It can be used for the prevention, improvement and treatment of not only local pigmentation diseases such as stains, freckles and sunburn, but also systemic pigmentation diseases such as Addison's disease.

Front page continuation (72) Inventor Ichiro Koiso 560 Pola Kasei Co., Ltd., Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Pref. Totsuka Laboratory Co., Ltd. Company Totsuka Institute

Claims (3)

[Claims] 1. A monosaccharide, disaccharide or trisaccharide glycoside of 2-hydroxy-4- (2,2,6-trimethyl-1-yl-cyclohexane) butane represented by the following general formula (I): A melanin production inhibitor comprising a selected compound. Embedded image (In the formula, R represents a monosaccharide residue, a disaccharide residue, or a trisaccharide residue.) 2. The sugar residue represented by R in the general formula (I) is glucose, galactose, mannose, xylose, fructose, maltose, isomaltose, cellobiose, gentiobiose, kojibiose, laminaribiose, nigerose, sambibiose. The melanin production inhibitor according to claim 1, wherein the melanin production inhibitor is one kind selected from the group consisting of :, neohesperidose, maltotriose, isomaltotriose, cellotriose, and gentiotriose. 3. One or more melanin production inhibitors according to claim 1 or 2 with respect to the total amount of 0.0001 to 1
A skin external preparation characterized by containing 0% by weight.