JP3340928B2 - Melanin production inhibitor and whitening cosmetic - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a melanin production inhibitor and a whitening cosmetic containing the same. More specifically, melanin production is highly safe and can be combined with cosmetics, quasi-drugs, and pharmaceuticals for the purpose of improving skin pigmentation (stains, freckles, etc.) caused by exposure to ultraviolet light. Related to inhibitors.

[0002]

BACKGROUND ART Spots and freckles are those in which the balance between production and excretion of melanin is lost and melanin is excessively accumulated in epidermal cells [Yutaka Mishima et al., Fragrance Journal, 17 (1), p25, 1989]. . These causes can be varied, including inflammation, hormonal balance, and genetic factors, but are facilitated by the effects of ultraviolet radiation. Whitening agents alleviate the increased pigmentation. Among them, ascorbic acid or its derivatives, placenta extract, hydroquinone derivative (arbutin), kojic acid, etc. are known as those applied for whitening cosmetics.
Whitening cosmetics containing these compounds have been proposed.

[0003] However, although these whitening agents have an effect of suppressing the production of melanin, many of them have a problem in safety. Further, even when a whitening cosmetic containing these whitening agents is applied, a sufficiently satisfactory effect in improvement of spots and freckles was not necessarily obtained.

[0004] Melanin is produced by melanosomes, the organelles in melanocytes (pigment cells) in the basal layer of the epidermis. After that, it is transferred to keratinocytes (epidermal cells), rides on the flow of keratinization while undergoing decomposition within the keratinocytes, and finally disappears from the skin with desquamation of the keratinocytes (Masayoshi Kiyoji, a modern dermatologist, 3B, 97 pages,
Nakayama Shoten, 1982).

[0005] Therefore, since the cause of spots and freckles is complex, melanin not only suppresses the production of melanin, but also prevents inflammation which causes pigmentation and activates metabolism to cause melanin to develop in the skin. It is important to prevent it from staying inside and to restore skin function damaged by ultraviolet rays or the like.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a melanin production inhibitor which is highly safe and has an excellent melanin production inhibitory action and, at the same time, pigmentation of skin caused by exposure to ultraviolet rays. An object of the present invention is to provide a whitening cosmetic having an excellent effect of improving (spots, freckles, etc.).

[0007]

Means for Solving the Problems In view of the above circumstances, the present inventors have conducted intensive studies to develop a melanin production inhibitor having a melanin production inhibitory effect and having high safety. The present inventors have found that a saccharide has both a strong melanin production inhibitory effect and an effect of improving skin pigmentation (stains, freckles, etc.) caused by exposure to ultraviolet rays, and completed the present invention. That is, the present invention is a specific glycoside represented by the following general formula, and a whitening cosmetic containing the same.

[0008]

Embedded image

(Where R is a group selected from the residues of monosaccharides and disaccharides )

[0010]

Embodiments of the present invention will be described below in detail.

Some of the glycosides used in the present invention are known substances (Phytochemistry, Vol. 29, No. 12).
No., p. 3853, 1990) does not disclose that the reported known substance has a melanin production inhibitory action.

As a method for obtaining the glycoside of the present invention, a method already known as a method for synthesizing arbutin (USP No. 32)
No. 01385). For example, after condensing 4- (p-hydroxyphenyl) -2-butanol (hereinafter abbreviated as rhodendrol) and acetylated sugar in an organic solvent such as toluene using boron trifluoride or phosphorus oxychloride as a catalyst, By removing the acetyl group in the presence of an alkali, the glycoside of the present invention can be easily obtained as white powdery crystals. It can also be obtained by reducing raspberry ketone glycoside. Furthermore, it is also possible to isolate from natural products. Although the glycoside of the present invention has optical isomers, it may be (+)-form or (-)-form alone or a mixture thereof (referred to as JP-A-3-251548). ] Can also be used.

The sugar residue used in the present invention is a reducing monosaccharide or disaccharide , and specifically, monosaccharides such as glucose, galactose, xylose, mannose, N-acetylglucosamine, maltose, cellobiose, mention may be made of a disaccharide such as gentibiose. The glycoside of the present invention has isomers having an α bond and a β bond, but may be used alone or in a mixture thereof.

Specific glycosides used in the present invention include rhododendrol-D-glucoside (α and β forms), rhododendol-D-galactoside (α and β forms),
Rhododendrol-D-xyloside (α and β forms),
(+)-Form, (-)-form, (±) such as rhododendrol-D-maltoside (α- and β-forms). Of these, (+)-rhodendrol-D-glucoside (β-form) is most preferred because of its availability, existence in the natural world, and high whitening effect.

The melanin production inhibitor of the present invention is used
It can be incorporated into quasi-drugs and cosmetics. In particular, it is suitable to be incorporated into a whitening cosmetic which improves pigmentation. In addition, the melanin production inhibitor of the present invention can be blended into a composition for external use or a composition for internal use.

The amount of the melanogenesis inhibitor of the present invention varies depending on the system to be used, and cannot be specified unconditionally. And 0.05 to 10.0% by weight can be used.

In the whitening cosmetic of the present invention, if necessary,
Oils and fats, moisturizers, pigments, pigments, surfactants, antioxidants, ultraviolet absorbers, preservatives, which are usually incorporated in skin external preparations such as pharmaceuticals, quasi-drugs, and cosmetics And water-soluble polymers, resins and the like can be appropriately compounded.

Further, it can be in any dosage form such as ointments, lotions, emulsions, creams, packs, granules and the like.

[0019]

EXAMPLES Next, as examples for clarifying the effect of the glycoside of the present invention on the inhibitory action of melanin production, synthetic examples, test examples and blended preparation examples (whitening cosmetics) will be shown.

Synthesis Example 1: (±) -Rhodendrol-D
-Synthesis of glucoside As a specific example of the synthesis method, rhododendrol-D
A method for synthesizing a glucoside will be described, but the method for synthesizing the melanin production inhibitor used in the present invention is not limited thereto.

2.76 g (16.6 mmol) was added to a mixed solution of 40 ml of dehydrated toluene and 10 ml of dehydrated ethyl ether.
1) (±) -Rhodendrol, 8 g (20 mmo)
l) Glucose pentaacetate and 2 g of molecular sieves were added, and the mixture was stirred at room temperature for about 1 hour.
Stirred for hours. After adding 20 ml of water, the molecular sieves were filtered off. The organic layer was extracted from the filtrate with ethyl acetate. Washing the ethyl acetate layer with 1N sodium hydroxide,
Unreacted (±) -rhodendrol was removed. The ethyl acetate layer was washed with purified water and dried over sodium sulfate. After removing sodium sulfate, the organic solvent was removed under reduced pressure to obtain (±) -rhodendrol tetraacetyl-D-glucoside.

The obtained acetyl form was deacetylated with sodium methoxide according to a conventional method, and then neutralized with an ion exchange resin (Amberlite). After filtering off the ion exchange resin, the solvent was removed under reduced pressure,
(±) -Rhodendrol-D-glucoside (β form)
3.8 g were obtained. This structure was confirmed by a ¹³ C-NMR spectrum and an infrared absorption spectrum. FIG. 1 shows (±) -rhodendrol-D-glucoside (β
2 shows a ¹³ C-NMR spectrum of the compound (I).

In addition, according to Synthesis Example 1, "Sample" in Table 1 was used.
Glycosides according to the present invention shown in the column were obtained.

Test Example 1 Melanin Production Inhibition Test [In Vitro Test] In the melanin production inhibition test using pigment cells, B16 melanoma cells (3 × 10 ⁵ cells) were spread on a 90 mm diameter plastic plate and tested simultaneously. The sample was added at a concentration of 3 × 10 ⁻⁵ M (the test concentration was unified to the molar concentration), and the cells were cultured for 72 hours. The culture was performed in a MEM (containing 2 mM theophylline) medium containing 10% FBS. After completion of the culture, the cells were detached and washed according to a conventional method, and then centrifuged. The obtained cells were washed with 5% TCA, ethanol: ether = 3: 1, and then with ether. After drying, the melanin content was measured by dissolving in Solen 350 and measuring the absorbance at 400 nm. The lower the absorbance, the greater the melanin production inhibitory effect. As a comparative example, a hydroquinone glycoside (arbutin) known to have a melanin production inhibitory effect was used.

Table 1 shows the measurement results.

[0026]

[Table 1]

From the results shown in Table 1, it was clarified that the melanin production inhibitor of the present invention inhibits melanin production without inhibiting cell proliferation (meaning high safety). In addition, it was found that the degree of absorbance was lower than that of arbutin, which is widely used in pharmaceuticals, cosmetics, and the like, that is, the melanin production inhibitory effect was excellent. this,
From the results of the in vitro test, it was reconfirmed that the specific glycoside of the present invention can be added to, for example, pharmaceuticals, quasi-drugs, cosmetics, and the like as a main component of whitening cosmetics.

Test Example 2: Skin Pigmentation Recovery Test [In Vivo Test] Two ultraviolet irradiation sites (2 × 2 cm) were set on the inner skin of the upper arm of a group of 20 subjects, and the minimum erythema amount was measured. Irradiation was performed continuously for 3 days with ultraviolet rays in the middle wavelength region (Dermalei N-DMR, manufactured by Toshiba Medical Products). From the end of the irradiation, one was coated with the sample preparation three times a day for four consecutive weeks, and the other was coated with the base (the main preparation was removed from the preparation). Four weeks after the ultraviolet irradiation, the degree of pigmentation between the base application part and the sample preparation application part was compared by visual judgment of each part. According to the evaluation criteria in Table 2, the degree of recovery of pigmentation was evaluated in comparison with the base coated part. In addition, evaluation is shown by the average value of the evaluation point of 20 persons.

[0029]

[Table 2]

Examples 1 to 3 and Comparative Example 1 (Cream) Creams were prepared according to the recipe shown in Table 3 according to a conventional method.

[0031]

[Table 3]

Table 4 shows the results of the skin pigmentation recovery tests of Examples 1 to 3 and Comparative Example 1.

[0033]

[Table 4]

From Table 4, it is clear that the examples of the present invention are excellent in the effect of improving spots and freckles. In particular, (+)-rhodendrol-D-glucoside (β
Example 1 in which the compound of formula (1) was blended, had a remarkable effect. During the test period, no skin irritation reaction was observed at the site where the sample preparation was applied to the test subject, confirming that the product of the present invention is safe even in the form of the preparation.

Example 4 (Emulsion) An emulsion was prepared according to the formulation shown in Table 5 according to a conventional method.

[0036]

[Table 5]

Example 5 (Lotion) A lotion was prepared according to the formulation shown in Table 6 according to a conventional method.

[0038]

[Table 6]

Table 7 shows the results of the skin pigmentation recovery tests of Examples 4 and 5.

[0040]

[Table 7]

From Table 7, it is clear that Examples 4 and 5 are excellent in the effect of improving spots and freckles.

[0042]

As described above, the glycoside of the present invention comprises
It exhibited an excellent melanin production inhibitory effect, and its safety was also high. Further, the formulation containing the glycoside of the present invention,
It showed an excellent effect of improving skin pigmentation (stains, freckles, etc.) caused by exposure to UV light. Therefore, the glycosides of the present invention can be used in cosmetics and quasi-drugs to prevent the formation of spots, freckles, etc. due to excessive production of melanin by ultraviolet rays, treatment of pigmentation, Clearly, it provides useful melanogenesis inhibitors that can be utilized.

[Brief description of the drawings]

FIG. 1 is a view showing a ¹³ C-NMR spectrum of (±) -rhodendrol-D-glucoside (β-form) obtained in Synthesis Example 1 of the present invention.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-10-17462 (JP, A) JP-A-9-241128 (JP, A) JP-A 8-133957 (JP, A) JP-A 8- 20524 (JP, A) JP-A-6-199649 (JP, A) JP-A-6-256137 (JP, A) JP-A-6-107536 (JP, A) JP-A-5-201846 (JP, A) JP-A-4-59718 (JP, A) JP-A-10-182476 (JP, A) JP-A-5-123175 (JP, A) JP-A-2-2121891 (JP, A) JP-A-3-251548 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K ^7/ 00-7/50 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] [Claim 1] The following general formula: (Wherein, R is a group selected from the residues of monosaccharides and disaccharides ). 2. A whitening cosmetic comprising the melanin production inhibitor according to claim 1.