JPH07206625A - Melanin production inhibitor and external preparation for skin - Google Patents

Abstract

PURPOSE:To obtain a melanin formation inhibitory agent and an external preparation for skin excellent in prophylactic and improving effect on skin pigmentation with no harmful influence on safety and feeling. CONSTITUTION:A melanin formation inhibitor comprising tetrahydromanool represented by the formula is added to the external preparation for skin in an amount of 0.0001 to 10wt.% based on the total weight.

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-mentioned problems, the present inventors have found that tetrahydromannur represented by the following general formula (I) results in melanin of living pigment cells. The present invention was found to have a strong inhibitory effect on the production, and further to find that when this compound was incorporated into a base material at a certain concentration or more, an excellent whitening effect on the skin was exhibited, and the present invention was accomplished.

That is, the present invention is a melanin production inhibitor comprising tetrahydromannur represented by the following general formula (I).

[0008]

[Chemical 2]

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 tetrahydromannur represented by the general formula (I). The tetrahydromannur used in the present invention can be synthesized from manur (lavada-8 (17), 14-diene-13-ol). An example of the synthesizing method will be described below.

Manur was added to methanol, and the mixture was allowed to react at room temperature for 5 hours in a hydrogen stream under a palladium carbon catalyst.
Then, the reaction product is fractionally isolated by silica gel column chromatography to obtain tetrahydromannur. In addition, since Manur as a raw material is commercially available, it may be used. Further, according to the above-mentioned method, tetrahydromannur is obtained as a mixture of optical isomers and conformational isomers, but since these isomers all have the same whitening effect, they may be used as a mixture.

<2> Skin external preparation The skin external preparation of the present invention contains the above-mentioned melanin production inhibitor,
The amount of the external preparation is preferably 0.0001 to 10% by weight, more preferably 0.01 to 10% by weight based on the total amount. Among the external preparations for skin, especially those for the purpose of preventing and improving spots, freckles, and dark-skinned hatred by sunburn,
The compounding amount of 0.01% by weight or more can be used as an effective amount.

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

In addition to the above-mentioned active ingredients, the external preparation for skin of the present invention contains various components generally used in pharmaceuticals, cosmetics and the like, that is, an aqueous component, an oil component, a powder component, 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 tetrahydromannur may be blended, for example, pantetheine-s-sulfonic acid, isoferric acid, ascorbic acid, magnesium ascorbic acid phosphate, arbutin, kojic acid,
Examples thereof include linoleic acid and methyl linoleate.

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 and the like, for example, ointments, creams, emulsions, lotions,
The dosage forms include packs and bath agents.

[0017]

The function of tetrahydromannur used in the present invention will be described below based on experimental examples. The tetrahydromannur used in the following experimental examples and examples was obtained in the same manner as in the production examples described below.

(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% dioxide was used using Eagle MEM medium containing 10% serum. 37 in the presence of carbon
Cultured at ° C. Two days later, tetrahydromannur 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 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 suspended 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

[0021]

[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.

[0024]

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

[0025]

[Table 2]

As is clear from these results, the tetrahydromannur used in the present invention has an action of whitening pigment cells as compared with the solvent control (control), and further produces melanin in pigment cells remarkably. It has been shown to have an inhibitory action on.

(2) Effect of suppressing 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 cut at 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 in which a predetermined amount of tetrahydromannur was dissolved using propylene glycol / ethanol (3: 1) as a solvent, once a day,
It was continuously applied for a total of 20 days. 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: Clear pigmentation with weak boundary 2: Medium pigmentation with clear boundary 3: Strong pigmentation with clear boundary

[0030]

[Table 3]

As shown in Table 3, the tetrahydromannur according to the present invention, when applied to the skin, obviously suppressed the melanin production by ultraviolet rays at a concentration of 0.5%. A solution prepared by dissolving tetrahydromannur in 3% by weight in 70% ethanol was stable to exposure to sunlight for at least 2 days in midsummer and heating at 100 ° C. for 3 hours. Therefore, the tetrahydromannur according to the present invention is stable to ultraviolet rays and heat.

As shown above, the tetrahydromannur used in the present invention has the action of suppressing melanin production and the 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.

[0033]

EXAMPLES Examples of the present invention will be described below. In addition, the compounding amount in the following examples is parts by weight.

[0034]

[Production Example] 1.68 g of palladium carbon was placed in the reactor, and hydrogen in the reactor was replaced. A solution prepared by dissolving 8.4 g of Manur in 50 ml of methanol was gradually added to this, and reacted at room temperature under a hydrogen stream for 5 hours. After methanol was evaporated to dryness from the reaction solution, tetrahydromannur was obtained as a mixture of optical isomers and conformational isomers by silica gel column chromatography (yield 6.5).
g).

The tetrahydromannur used in the following examples was the one thus obtained.

[0036]

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.

[0037]

[Table 4]

(Actual Use Test of Pigmentation Improving Effect) The cream obtained above and the cream of the comparative product (the tetrahydromannur in the cream of the example being replaced with water) were statistically equivalent to 40 persons. The effect of improving pigmentation was evaluated by continuously applying it to a female group suffering from dark-black, spots and freckles for 3 months. The results are shown in Table 5.

[0039]

[Table 5] As is clear from these results, it was shown that the product of the present invention containing tetrahydromannur has a markedly effective pigmentation-improving effect as compared with the comparative product containing no tetrahydromannur. 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 As an example of the present invention, the components of Table 7A for explaining the lotion were 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.

[0043]

[Table 7]

[0044]

[Example 4] With respect to lotion, the components shown in Table 8A for explaining other examples are combined and dissolved at room temperature. On the other hand, each component of B is also dissolved at room temperature and added to the component of A to be solubilized.

[0045]

[Table 8]

[0046]

[Fifth Embodiment] Further, an embodiment of the pack charge will be described. Disperse and dissolve the ingredients of Table 9A at room temperature. The component B is added to this and uniformly dissolved.

[0047]

[Table 9]

In addition, the actual use test of the pigmentation improving effect was also performed for Examples 2 to 5, and the same effect as that of Example 1 was obtained.

[0049]

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 (72) Inventor Ichiro Koiso 560 Pola Chemicals, Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Prefecture Totsuka Research Institute Co., Ltd. (72) Inventor Michio Ochiai 560 Polar, Kashio-cho, Totsuka-ku, Yokohama Seiko Co., Ltd. Totsuka Research Center

Claims (2)

[Claims] 1. A melanin production inhibitor comprising tetrahydromannur represented by the following general formula (I). [Chemical 1] 2. The melanin production inhibitor according to claim 1,
A skin external preparation characterized by containing 0.0001 to 10% by weight relative to the total amount.