JP2829690B2 - Melanin production inhibitor and external preparation for skin - Google Patents

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 an external preparation for the skin, and more particularly to a stain such as spots and freckles containing 4-hydroxyphenyl disaccharide or trisaccharide as an active ingredient. An object of the present invention is to provide an external preparation for skin that suppresses the production of melanin, which is a cause of the problem, and is excellent in fair skin effect.

[0002]

2. Description of the Related Art Spots and freckles and pigmentation after sunburn are the result of a marked increase in melanin production due to the activation of pigment cells present in the skin. Has become. Generally, melanin changes from tyrosine to dopa and dopa to dopaquinone by the action of the enzyme tyrosinase biosynthesized in pigment cells, and then converts intermediates such as 5,6-dihydroxyindophenol. It is supposed to be formed after passing through.

[0003] Therefore, in order to prevent or improve skin darkness, it is conceivable to inhibit the melanin production process or to bleach the already produced melanin in pale color. Various whitening components have been conventionally proposed based on such a concept. For example, as a compound that inhibits tyrosinase activity and suppresses melanin production, a sulfur compound represented by glutathione is exemplified. In addition, hydrogen peroxide, hydroquinone, arbutin, vitamin C, and the like have been used as light-color bleaching of produced melanin.

[0004]

However, these conventional components have extremely poor stability in the formulation system, cause coloration and unpleasant odor due to decomposition, and still have insufficient efficacy at the cellular or biological level. Met. Hydroquinone has a strong fairness effect, but has problems in safety, such as causing irreversible white spots and rash. In addition, arbutin has been pointed out with regard to cytotoxicity.

[0005] As described above, none of the conventionally used components has been practically satisfactory in terms of efficacy / effect, stability and safety. The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a melanin production inhibitor and an external preparation for skin that has a sufficient effect of improving and treating skin pigmentation and that can be used safely. And

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that dihydroxyglycosides or trisaccharides of 4-hydroxyphenyl represented by the general formula It has been found that glycosides, especially 4-hydroxyphenyl-D-maltoside, have a strong inhibitory effect on melanin production of living pigment cells, and when they are added to the base at a certain concentration or more, The present inventors have found that a superior whitening effect on the skin is exhibited and the safety is further improved, and based on this, the present invention has been completed.

That is, the present invention relates to a melanin production inhibitor comprising a 4-hydroxyphenyl disaccharide glycoside or trisaccharide glycoside represented by the general formula 1, and at least one of the melanin production inhibitors The above, 0.0 to the total amount of the base
The present invention relates to a skin external preparation for suppressing melanin production, which is contained in an amount of 1 to 10% by weight.

Hereinafter, the present invention will be described in detail.

[0009] The melanin production inhibitor of the present invention comprises
A disaccharide or trisaccharide glycoside of 4-hydroxyphenyl represented by the general formula: wherein R is a disaccharide or trisaccharide containing pentose and / or hexose as a constituent component. It represents a sugar residue. Examples of the type of such disaccharide or trisaccharide residues include disaccharide residues such as maltose, isomaltose, cellobiose, kojibiose, laminaribiose, nigerose, gentiobiose, trehalose, sanbubioose, and neohesperidose; and maltotriose. And trisaccharide residues. Regarding the binding mode in this glycoside, α-glycoside and β-glycoside can be used.

Specific examples of the 4-hydroxyphenyl disaccharide or trisaccharide glycoside represented by the general formula 1 include 4-hydroxyphenyl-D-maltoside,
4-hydroxyphenyl-D-cellobioside, 4-hydroxyphenyl-D-cordiobioside, 4-hydroxyphenyl-D-laminaribioside, 4-hydroxyphenyl-D-gentiobioside, 4-hydroxyphenyl-D-trehaloside, 4-hydroxyphenyl- Examples thereof include D-neohesperidoside and 4-hydroxyphenyl-D-maltotrioside, among which 4-hydroxyphenyl-D-maltoside and 4-hydroxyphenyl- from the viewpoint of melanin production inhibitory ability and the like. The use of D-cellobioside is preferred.

Next, an outline of a method for synthesizing 4-hydroxyphenyl-β-D-maltoside among 4-hydroxyphenyl disaccharide or trisaccharide glycosides represented by the general formula (1) I do. Hydroquinone and β-D-maltoside octaacetate are added to a diethylene chloride solvent and reacted for 2 hours in an ice-cooled and nitrogen stream. Thereafter, the diethylene chloride layer is evaporated to dryness and fractionated by silica gel column chromatography. After isolation, it is deacetylated. 4-Hydroxyphenyl-β-D-cellobioside can also be easily produced by a similar method using β-D-cellobiose octaacetate.

The external preparation for skin of the present invention preferably contains at least one of the above-mentioned melanin production inhibitors in an amount of preferably 0.01 to 10% by weight, more preferably 0.1 to 5% by weight, based on the total amount of the external preparation base. It is blended in the range. Among the external preparations for skin, in particular for the purpose of preventing and improving spots, freckles and hatredness caused by sunburn, the compounding amount is preferably 0.1% by weight or more.

When the amount is less than 0.1% by weight, the effect based on the inhibitory effect on melanin production is reduced. When the amount exceeds 10% by weight, the effect is hardly changed. Does not need to exceed 10% by weight.

In addition to the above-mentioned active ingredients, the skin external preparation of the present invention contains various ingredients generally used for pharmaceuticals, cosmetics, etc., ie, aqueous ingredients, oily ingredients, powder ingredients, surfactants, humectants, Thickener, coloring agent, fragrance, antioxidant, PH
Regulators, chelating agents, preservatives or sunscreens,
Drugs such as anti-inflammatory agents and other whitening ingredients can be added.

Particularly, whitening agents include, for example, pantetheine-s-sulfonic acid, isoferulic acid, magnesium ascorbic acid phosphate, arbutin, cordiic acid, linoleic acid and the like.

The dosage form of the external preparation for skin of the present invention is not particularly limited, and those usually used for pharmaceuticals, quasi-drugs, cosmetics, etc., such as ointments, creams, emulsions, lotions,
Dosage forms such as packs and bath agents are included.

Hereinafter, the present invention will be described in more detail with reference to various experimental examples performed to evaluate the usefulness of the 4-hydroxyphenyl disaccharide or trisaccharide glycoside according to the present invention. I do.

Experimental Example 1 Cytotoxic Action on Pigment Cells and Inhibitory Action on Melanin Production 5 × 10 ⁴ B-16 melanoma cells were seeded in a plastic culture flask (75 cm ² ), and an egg containing 10% serum was added. Using MEM medium in the presence of 5% carbon dioxide, 37
The cells were cultured under the condition of ° C. Two days later, the test samples were given a concentration of 0 (control), 25, 50, 75, 100 in the medium.
It was adjusted to be μmol and cultured for further 4 days.

After completion of the culture, the medium was removed, washed with an equilibrated phosphate buffered saline (PBS), and then trypsin and EDTA were removed.
The cells were detached from the flask using the containing medium, collected in a glass centrifuge tube, and collected by centrifugation. After the obtained cells were washed once with PBS, a certain amount of PBS was added, the cells were mixed by flushing, a certain amount of the cell suspension was taken, the number of cells was counted with a Coulter counter, and The cell number ratio at the sample concentration was calculated. The remaining suspension was collected after centrifugation again, and the whiteness of the precipitate was visually observed according to the following criteria. Table 1 shows the results.

(Evaluation criteria)-: Equivalent to the solvent control +: Whitened weaker than the solvent control ++: Clearly whitened compared to the solvent control

[0021]

[Table 1]

Thereafter, 1N sodium hydroxide was further added to the precipitate to dissolve it by heating. 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 amount of melanin was determined as an amount per 10 ⁴ cells. Table 2 shows the results.
In addition, the suppression rate in the table was obtained by the following equation.

Inhibition rate (%) = (melanin content of control product−melanin content of test sample added product) × 100 / (melanin content of control product)

[0024]

[Table 2]

As is clear from the results in Tables 1 and 2,
4-Hydroxyphenyl-β-D-maltoside and 4-hydroxyphenyl-β-D-cellobioside according to the present invention have an effect of significantly suppressing melanin production in pigment cells as compared with a solvent control (control). This has been proven. It was also shown that the inhibitory concentration was lower than that of arbutin (4-hydroxyphenyl-β-D-glucoside), which is a conventional product, and that it had a strong melanin production inhibitory action. Furthermore, the lethal concentration for the cells was shifted to a higher concentration than that for arbutin, and the cytotoxicity was clearly reduced.

EXPERIMENTAL EXAMPLE 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.
m irradiation window is covered with a black cloth having a total of six in the left and right contrast, and 1 m from the cloth using a FL20S / E30 lamp as a light source.
Ultraviolet light of W / cm ² / sec was irradiated for 4 minutes and 20 seconds.

This operation was performed once a day for three consecutive days. From the day after the end of the irradiation, 0.02 ml of a test solution in which a predetermined amount of a sample was dissolved using propylene glycol / ethanol (3: 1) as a solvent was applied once a day, continuously for a total of 20 days. The same experiment was performed using only the solvent as a control. On the 21st day from the start of the experiment, the degree of pigmentation of the treated part was determined by visual observation according to the following criteria. The results are shown in Table 3 as average values.

(Judgment Criteria) 0: No pigmentation 0.5: Weak pigmentation with indistinct borders 1: Weak pigmentation with clear borders 2: Moderate pigmentation with clear borders 3: Intensity with clear borders Pigmentation

[0029]

[Table 3]

As shown in the results in Table 3, 4-hydroxyphenyl-β-D-maltoside and 4-hydroxyphenyl-β-D-cellobioside, when applied to skin, had a melanin concentration of 0.5% when exposed to ultraviolet light. Production was clearly suppressed.

Experimental Example 3 Actual use test 4-Hydroxyphenyl-β-D shown in Example 1 below
-The color of 40 persons statistically equivalent to the cream of the invention containing 0.5% maltoside and the control cream in which 4-hydroxyphenyl-β-D-maltoside in Example 1 was replaced by water. A group of women suffering from black, spots, and freckles was continuously used for three months to evaluate the improvement. Table 4 shows the results.

[0032]

[Table 4]

As is clear from the results in Table 4, the product of the present invention containing 4-hydroxyphenyl-β-D-maltoside is significantly different from the control product containing no 4-hydroxyphenyl-β-D-maltoside. It has been proved to have an effective effect of improving effective black and white, spots and freckles. Incidentally, no unfavorable reaction on the skin was observed at the application site of the product of the present invention.

[0034]

Examples of the present invention will be described below. In addition, the compounding ratio in an Example is a weight part.

EXAMPLE 1 Oil-in-water cream (A) POE (30) Cetyl ether 2.0 Glycerin monostearate 10.0 Liquid paraffin 10.0 Vaseline 4.0 Cetanol 5.0 γ-tocophero -Bol 0.05 BHT 0.01 Butylparaben 0.1 (B) Propylene Glycol 10.0 4-Hydroxyphenyl-β-D-maltoside 0.5 Purified Water 58.34 (Production Method) Each of (A) Combine the ingredients and heat to 80 ° C. Combine the components of (B) and heat to 80 ° C. The prescription of (A) is added to the prescription of (B), stirred and emulsified, and then cooled.

Example 2 Emulsion (A) Synthetic gay wax 2.5 Cetanol 1.0 Squalane 4.0 Stearic acid 1.0 Polyethylene glycol monostearate (25EO) 2.2 Glycerin monostearate 0.5 Butylparaben 1 γ-tocopherol 0.05 BHT 0.01 (B) 1,3-butylene glycol 3.0 propylene glycol 7.0 caustic potash 0.2 4-hydroxyphenyl-β-D-cellobioside 1.0 purified water 77.44 (Production method) (A) and (B) are dissolved at 70 ° C. while stirring each. (A) is added to (B), preliminary emulsification is carried out, and the mixture is uniformly emulsified by a homomixer. After the emulsification, the mixture is cooled to 30 ° C. while stirring.

Example 3 Lotion (A) POE (20) Sorbitan monolaurate 1.5 POE (20) Lauryl ester 0.5 Ethanol 10.0 γ-Tocopherol 0.02 (B) Glycerin 5.0 Propylene glycol 4.0 Citric acid 0.15 Sodium citrate 0.1 4-Hydroxyphenyl-β-D-maltoside 0.2 Purified water 78.33 (Production method) The components of (A) are combined and dissolved at room temperature. on the other hand,
Each component of (B) is also dissolved at room temperature, and this is added to (A) formulation and solubilized.

Example 4 Packing material (A) Polyvinyl alcohol 15.0 Purified water 40.0 Bisabolol 0.5 Tocopherol 0.02 (B) Ethanol 4.0 1,3-butylene Glycol 4.0 Polyoxyethylene (8) Polyoxypropylene Glycol (55) 3.0 4-Hydroxyphenyl-β-D-gentiobioside 3.0 Purified water 30.48 (Production method) (A) at room temperature Disperse and dissolve. (B) is added thereto and uniformly dissolved.

[0039]

According to the present invention, it is possible to provide a melanin production inhibitor and a skin external preparation which are excellent in fairness effect and high in stability and safety. The topical skin preparation of the present invention can be used for preventing, improving, and treating local pigmentation such as spots, freckles, and sunburn, and systemic pigmentation such as Addison's disease. Moreover, it is excellent in safety and can be used continuously for a long time.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 7/42 A61K 7/42 7/48 7/48 // C07H 15/203 C07H 15/203 (72) Inventor, Tadashi Suzuki Kanagawa 560 Paula Kasei Kogyo Co., Ltd., Totsuka Research Laboratory, Totsuka-ku, Yokohama-shi, Japan (72) Inventor Tomomi Kato 560 Paula Kasei Kogyo Co., Ltd., Totsuka Research Laboratories, Yokohama, Kanagawa, Japan (72) Michio Matsugami, inventor 560 Paula Kasei Kogyo Co., Ltd., Totsuka Research Laboratories, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture (72) Inventor Susumu Nozawa 560 Polashikasei Kogyo Co., Ltd., Totsuka Laboratories, Yokohama-shi, Kanagawa Pref. 560 Polar Kasei Kogyo Co., Ltd., Totsuka Research Laboratories, 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 31/70 ADS A61K 3 1/70 ADA A61K 7/00 A61K 7/42 A61K 7/48 C07H 15/203 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A melanin production inhibitor comprising a 4-hydroxyphenyl disaccharide or trisaccharide glycoside represented by the general formula: Embedded image (In the formula, R represents a disaccharide or trisaccharide residue containing pentose and / or hexose as a constituent.) 2. The disaccharide glycoside or trisaccharide glycoside of 4-hydroxyphenyl represented by the above formula 1, wherein R is maltose, isomaltose, cellobiose, kojibiose, laminaribiose, nigerose, gentiobiose, The melanin production inhibitor according to claim 1, which is trehalose, sambubiose, neohesperidose and maltotriose. 3. Melanin comprising at least one melanin production inhibitor according to claim 1 or 2 in an amount of 0.01 to 10% by weight based on the total amount of the base. An external preparation for skin to suppress production.