JPH07126145A - Suppressor for melanogenesis and skin external preparation - Google Patents

Abstract

PURPOSE:To obtain a suppressor for the melanogenesis and a skin external preparation excellent in preventing and improving effects on skin pigmentation. CONSTITUTION:This suppressor for the melanogenesis is composed of an O- glycoside of manool expressed by the formula (R is a residue of monosaccharises, disaccharides or trisaccharides), e.g. manool glucoside. Furthermore, this skin external preparation contains 0.0001-10wt.%, preferably 0.01-10wt.% compound expressed by the formula. Residues of monosaccharides such as galactose, fructose or mannose, residues of disaccharides such as maltose, isomaltose or cellobiose and residues of trisaccharides such as maltotriose or isomaltotriose are cited as the residue of the saccharides constituting the glycoside expressed by the formula. The skin external preparation is used as a medicine, a quasi-drug, a cosmetic, etc., and can continuously be used for a long period due to its ability to bring about excellent color whitening effects and excellence in the safety.

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. More specifically, the present invention provides a melanin production inhibitor for preventing skin pigmentation and a skin external preparation having an excellent whitening effect. .

[0002]

BACKGROUND OF THE INVENTION Pigmentation after freckles, freckles and sunburn is a result of markedly increased melanin production due to activation of pigment cells present in the skin, and is one of the troubles of the middle-aged and old-aged skin. Has become. Generally, melanin is considered to be produced by the action of the enzyme tyrosinase biosynthesized in pigment cells, changing from tyrosine to dopa and from dopa to dopaquinone, and then via intermediates such as 5,6-dihydroxyindole. ing.

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, as a substance that inhibits tyrosinase activity and suppresses melanin production, sulfur compounds represented by glutathione and hydroquinone can be mentioned.
Further, as a light-color bleaching of the generated melanin,
Hydrogen peroxide, vitamin C, etc. have been used.

[0004]

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

As described above, the conventionally used components are not truly practically satisfactory in terms of effect, efficacy, stability and safety. The present invention has been made in view of such circumstances, the melanin production inhibitory action,
It is another object of the present invention to provide a skin external preparation having a sufficient effect of improving and treating skin pigmentation, and having stability and safety.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that the monosaccharide, disaccharide or trisaccharide of manure represented by the following general formula (I) is used. It was found that a glycoside (hereinafter, also simply referred to as "Manure glycoside") has a strong inhibitory effect on the melanin production of living pigment cells, and this compound was added to a base at a certain concentration or more. The present invention has been completed when the inventors found that an excellent whitening effect on the skin was exhibited.

[0007] That is, the present invention is a melanin production inhibitor comprising an O-glycoside of manure represented by the following general formula (I).

[0008]

[Chemical 2]

In the formula, R represents a monosaccharide residue, a disaccharide residue or a trisaccharide residue. The present invention also provides a skin external preparation containing the melanin production inhibitor in an amount of 0.0001 to 10% by weight based on the total amount. Hereinafter, the present invention will be described in detail.

<1> Melanin Production Inhibitor The melanin production inhibitor of the present invention comprises the manure glycoside represented by the general formula (I). The sugar residue constituting the glycoside is a monosaccharide residue, a disaccharide residue, or a trisaccharide residue, and as the monosaccharide residue constituting these sugar residues,
It is preferably a penta- or hexa-monosaccharide residue.

For example, monosaccharide residues include glucose, galactose, fructose, mannose, xylose, etc., and disaccharide residues include maltose, isomaltose, cellobiose, gentiobiose, kojibiose, laminaribiose, nigerose, sambubiose, Examples of the trisaccharide residue such as neohesperidose include maltotriose, isomaltotriose, cellotriose, gentiotriose, and the like. In addition, in the glycosides of these sugars and manur, α
-It does not matter whether it is a glycoside or a β-glycoside.

As the melanin production inhibitor of the present invention, manure glucoside, manure galactoside, manure maltoside, manure cellobioside, manure maltotrioside and the like are preferable.

The method for synthesizing the manure glycoside used in the present invention will be described by taking manure glucoside as an example. Manure and tetra-O-acetyl-D-glucopyranosyl bromide are added to dichloromethane, and they are reacted in the presence of a catalyst of tetramethylurea and silver triflate for 2 hours under a nitrogen stream while cooling with ice. Then, the dichloromethane layer is evaporated to dryness, the reaction product is fractionated and separated by silica gel column chromatography, and then deacetylated to obtain manure glucoside. Similarly,
Manur maltoside can be produced using manur and hepta-O-acetyl-D-maltosyl bromide. Other manure glycosides can also be produced according to the above method. Incidentally, since Manur used as a raw material is commercially available, it may be used.

<2> External preparation for skin The external preparation for skin of the present invention includes 1 of the above-mentioned melanin production inhibitors.
Or two or more, preferably 0.0 based on the total amount of the external preparation.
001 to 10% by weight, more preferably 0.01 to 10%
Blend in the range of wt%. Among the external preparations for skin, especially for the purpose of preventing and improving spots, freckles, and color darkening due to sunburn, the compounding amount can be used as an effective amount of 0.01% by weight or more.

If the blending amount is less than 0.0001% by weight, the effect based on the melanin production inhibitory effect is lowered, and even if the amount is more than 10% by weight, the effect reaches the ceiling, so the blending amount is within the above range. It is preferable.

The external preparation for skin of the present invention contains, 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, a moisturizer and a thickener. Agents, colorants, fragrances, antioxidants, pH adjusters, chelating agents, preservatives, UV protectants, anti-inflammatory agents and other agents can be added.

Further, a whitening component other than manure glycoside may be blended, for example, pantetheine-s-sulfonic acid, isoferric acid, ascorbic acid, magnesium ascorbyl phosphate, arbutin, kojic acid, linoleic acid, Examples include methyl linoleate.

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

[0019]

The action of the manure glycoside used in the present invention will be described below based on experimental examples. In addition, the manure glycoside used in the following experimental examples was obtained as described above and is a β-glycoside.

(1) Inhibitory effect 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 using Eagle MEM medium containing 10% serum. 37 in the presence of carbon
Cultured at ° C. Two days later, each of the various types of manure glycosides shown in Table 1 was added so that the concentration in the medium was 0, 5, 10, 15, 20 μM, and the cells were further cultured for 4 days.

After the completion of the culture, the medium was removed, washed with phosphate buffered saline (PBS), the cells were detached from the flask using a medium containing trypsin and EDTA, and the cells were separated from the cell suspension by centrifugation. Recovered. After washing the obtained cells once with PBS, a fixed amount of PBS was added, 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. The number of cells (%) in the table represents the number of cells (%) when the number of cells when a solvent is used instead of the test sample (solvent control) is 100.

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

[0023]

[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 at 400 nm of the obtained supernatant was measured, and the amount of melanin was determined from a calibration curve prepared in advance using synthetic melanin. The melanin amount was calculated as the amount per 10 ⁴ cells. The results are shown in Table 2.

The inhibition rate in the table was calculated by the following formula.

[0026]

[Equation 1] Inhibition rate (%) = (melanin amount in control-melanin amount in test sample) × 100 / (melanin amount in control)

[0027]

[Table 2]

As is clear from these results, the manure glycoside used in the present invention was treated with a solvent control.
It was shown that it has a whitening effect on pigment cells, and further has an effect of remarkably suppressing melanin production in pigment cells.

(2) Inhibition of pigmentation by ultraviolet rays The back skin of brown guinea pigs (7 animals) was shaved and shaved with an electric hair clipper and a shaver, and this site was 1.5 × 1.5c.
A black cloth that has a total of 6 m irradiation windows on the left and right sides is covered.
Ultraviolet rays of W / cm ² / sec were irradiated for 4 minutes and 20 seconds.

This operation was performed once a day for 3 consecutive days. From the day after the end of irradiation, 0.02 ml of a sample solution containing a predetermined amount of manure glycoside dissolved in propylene glycol / ethanol (3: 1) as a solvent was added once a day for a total of 20 times.
It was continuously applied for a day. Further, the same experiment was conducted using only the solvent as a control. On the 21st day from the start of the experiment, the degree of pigmentation in the treated area was visually determined according to the following criteria. The results are shown in Table 3 as an average value.

0: No pigmentation 0.5: Weak pigmentation with unclear boundary 1: Weak pigmentation with clear boundary 2: Moderate pigmentation with clear boundary 3: Strong pigmentation with clear boundary

[0032]

[Table 3]

As shown in Table 3, the manure glycoside according to the present invention, when applied to the skin, obviously suppressed the melanin production by ultraviolet rays at a concentration of 0.5%. As described above, the manure glycoside used in the present invention has an action of suppressing melanin production and an action of suppressing pigment deposition. As a result, a mixture containing a certain proportion or more of this in a skin external preparation base brings a markedly excellent whitening effect on the skin, and local pigmentation diseases such as spots, freckles, and dark skin due to sunburn, as well as Addison's It can be used for the improvement and treatment of systemic pigmentation diseases such as diseases. Moreover, it has excellent safety and can be used for a long period of time.

[0034]

EXAMPLES Examples of the present invention will be described below. In addition, the compounding amount in the following examples is parts by weight. In addition, the manure glycosides used in the following examples are those obtained as described above, the manure glycosides used in Examples 3 and 6 are α-glycosides, and all others are It is a β-glycoside.

[0035]

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) The components shown in Tables 4A and 4B are mixed and heated to 80 ° C. These are added and stirred to emulsify, and then cooled.

[0036]

[Table 4]

(Actual use test of pigmentation improving effect) The cream obtained above and the cream of the comparative product (the manor maltoside in the cream of the example being replaced with water) were statistically equivalent to 40 A group of women suffering from the famous black-black, spots and freckles was used continuously for 3 months, and the effect of improving pigmentation was evaluated. The results are shown in Table 5.

[0038]

[Table 5]

As is clear from these results, it was shown that the product of the present invention containing manurmaltoside has a markedly effective pigmentation-improving effect as compared with the comparative product containing no manurmaltoside. No unfavorable reaction on the skin was observed at the site to which the product of the present invention was applied.

[0040]

[Embodiment 2] Next, an embodiment of the emulsion will be described. Dissolve the ingredients of Tables 6A and B 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.

[0041]

[Table 6]

[0042]

Example 3 Description of Other Examples of Emulsion The ingredients of Tables 7A and 7B 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 7]

[0044]

[Example 4] As an example of the present invention, each component of Table 8A for explaining lotion was combined and dissolved at room temperature. On the other hand, B
Each component of (3) also dissolves at room temperature, and this is added to the component of A and solubilized.

[0045]

[Table 8]

[0046]

[Example 5] With respect to lotion, other examples will be described. Each component of Table 9A is combined and dissolved at room temperature. On the other hand, B
Each component of (3) also dissolves at room temperature, and this is added to the component of A and solubilized.

[0047]

[Table 9]

[0048]

[Sixth Embodiment] Further, an embodiment of the pack charge will be described. Disperse and dissolve the ingredients of Table 10A at room temperature. B to this
Add the ingredients of and dissolve evenly.

[0049]

[Table 10]

[0050]

[Seventh Embodiment] Further, an embodiment of the pack charge will be described. Disperse and dissolve the ingredients of Table 11A at room temperature. B to this
Add the ingredients of and dissolve evenly.

[0051]

[Table 11]

In addition, the actual use test of the pigmentation improving effect was also performed for Examples 2 to 7, and the same effect as that of Example 1 was obtained.

[0053]

According to the present invention, the whitening effect is excellent, and
It is possible to provide a melanin production inhibitor and a skin external preparation having high stability and safety.

The external preparation for skin of the present invention comprises spots, freckles,
It can be used for the prevention, amelioration and treatment of local pigmentation diseases such as dark skin due to sunburn and systemic pigmentation diseases such as Addison's disease.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 31/70 AED // C07H 15/18 (72) Inventor Akihiro Tada Kashio Totsuka-ku, Yokohama-shi, Kanagawa 560 Pola Chemical Industry Co., Ltd., Totsuka Research Laboratory (72) Inventor Ichiro Koiso 560 Pola Chemical Industry Co., Ltd., Totsuka Ward, Yokohama City, Kanagawa Prefecture

Claims (3)

[Claims] 1. A melanin production inhibitor comprising an O-glycoside of Manur represented by the following general formula (I). [Chemical 1] In the formula, R represents a monosaccharide residue, a disaccharide residue, or a trisaccharide residue. 2. In the general formula (I), R is glucose, galactose, fructose, mannose, xylose, maltose, isomaltose, cellobiose, gentiobiose, kojibiose, laminaribiose,
The melanin production inhibitor according to claim 1, which is a sugar residue selected from nigerose, sambibiose, 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-
An external preparation for skin characterized by containing 10% by weight.