JPH0971525A - Melanogenesis suppressing agent and skin preparation for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a melanogenesis suppressing agent and a skin preparation for external use exhibiting excellent skin-beautifying effect and preventive, amelioration and remedying effect on dyspigmentation and having high stability and safety. SOLUTION: This melanogenesis suppressing agent is produced by using 0.05-10wt.% (based on the total agent) of a farnesylisopropanol derivative of formula (R is H, a monosaccharide residue, a disaccharide residue or acetyl) as an active component. The compound of formula can be produced by reacting farnesylacetone with sodium borohydride in 2-propanol for 20min at room temperature and adding acetone to the reaction product. The skin preparation for external use is obtained by using 0.05-10wt.% (based on the total external preparation) of one or more kinds of the above melanogenesis suppressing agents. The agent is useful for the prevention, amelioration and remedy of systemic dyspigmentation such as Addison's disease in addition to local dyspigmentation such as spot, freckle and dark skin by sunburn. It is prepared in the form of ointment, cream, milky lotion, lotion, pack, bathing agent, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a melanin production inhibitor and an external preparation for skin, and more particularly to a melanin production inhibitor for preventing skin pigmentation and an external preparation for skin having an excellent whitening effect. .

[0002]

2. Description of the Related Art Spots and freckles and pigmentation after tanning are caused by the remarkable enhancement of melanin production due to the activation of pigment cells existing in the skin. I have. Generally, melanin is converted from tyrosine to dopa and dopa to dopaquinone by the action of the enzyme tyrosinase biosynthesized in pigment cells, and then intermediates such as 5,6-dihydroxyindophenol are formed. It is supposed to be formed after passing through.

[0003] Therefore, in order to prevent or improve the darkness, it is conceivable to inhibit the melanin production process or to bleach the already formed melanin in light color. Based on such an idea, various whitening (or whitening) components have been conventionally proposed. For example, sulfur compounds typified by glutathione are mentioned as those that inhibit tyrosinase activity and suppress melanin production. In addition, hydrogen peroxide, hydroquinone, vitamin C, and the like have been used as light color bleaching of generated melanin.

[0004]

However, these conventional whitening ingredients have extremely poor stability in the formulation system, cause coloration and off-flavor due to decomposition, and have insufficient effects at the cellular or biological level. there were. 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 whitening ingredients are effective, stable and safe.
Not truly practically satisfactory. The present invention has been made in view of such a situation, and has a sufficient effect of improving and treating skin pigmentation, using a melanin production inhibitor, and the melanin production inhibitor as an active ingredient, and is safe. It is an object of the present invention to provide a skin external preparation that can practically satisfy the properties 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 a specific farnesyl isopropanol derivative has a strong inhibitory effect on melanin production in living pigment cells. Locate
Further, it was found that when this was blended in a base at a certain concentration or more and used as an external preparation for the skin, an excellent whitening effect on the skin was exhibited, and the present invention was accomplished.

That is, the present invention relates to a melanin production inhibitor comprising a farnesyl isopropanol derivative represented by the following general formula (I).

In the present invention, the melanin production inhibitor as an active ingredient is preferably used in an amount of 0.
The present invention relates to an external preparation for skin, which is characterized by containing 05 to 10% by weight.

[0009]

Embedded image

(In the formula, R represents hydrogen, a monosaccharide residue, a disaccharide residue or an acetyl group.) The present invention is described in detail below.

<1> Melanin Production Inhibitor The melanin production inhibitor of the present invention comprises a farnesyl isopropanol derivative represented by the general formula (I).

As the R group in the above general formula (I), hydrogen,
Monosaccharide residues or disaccharide residues such as glucose, galactose, mannose, xylose, fructose, maltose, isomaltose, cellobiose, gentiobiose, kojibiose, laminaribiose, nigerose,
Examples thereof include residues such as sanbubiose and neohesperidose, and acetyl groups, and preferred examples include hydrogen, glucose residues, maltose residues, and acetyl groups.

The farnesyl isopropanol derivative according to the present invention can be synthesized from farnesyl acetone. An example of the synthesizing method will be described below.

1) Farnesyl acetone and sodium borohydride are reacted in 2-propanol at room temperature for 20 minutes, and acetone is added. After removing the solvent, the reaction product was fractionally isolated by silica gel column chromatography to obtain farnesyl isopropanol.

Next, a method for synthesizing farnesyl isopropanol glycoside will be described by taking maltoside as an example. 2) Farnesyl isopropanol and octaacetyl-
β-D-maltose is reacted with Lewis acid as a catalyst in dichloromethane at room temperature for 24 hours. afterwards,
The dichloromethane layer was evaporated to dryness, the reaction product was fractionally isolated by silica gel column chromatography, and then deacetylated to obtain farnesyl isopropanol maltoside.

Other glycosides can also be produced according to the above method using the corresponding acetylated sugar derivative.

3) For farnesyl isopropanol acetate, farnesyl isopropanol, p-toluenesulfonic acid, acetic acid and acetic anhydride are stirred at room temperature for 4 minutes, and the reaction is stopped with water. It was extracted with ethyl acetate, the obtained ethyl acetate layer was evaporated to dryness, and the reaction product was fractionally isolated by silica gel column chromatography to obtain farnesyl isopropanol acetate.

<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 of them are preferably added in an amount of 0.
It is contained in the range of 05 to 10% by weight, more preferably 0.1 to 5% by weight. Among the external preparations for skin, the content is preferably 0.1% by weight or more, particularly in the case of the one for the purpose of preventing and improving exfoliation of spots, freckles, and darkening due to sunburn.

If the content is less than 0.05% by weight, the whitening effect due to the melanin production inhibitory effect is reduced,
Further, even if the amount exceeds 10% by weight, the effect reaches a plateau, so that the content is preferably within the above range.

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 (as an emulsifier), a moisturizing agent. Agents, thickeners, colorants, fragrances, antioxidants, pH adjusters, chelating agents, preservatives, UV protectors, anti-inflammatory agents and the like can be blended alone or in combination of two or more.

Examples of the aqueous component include water (purified water),
Lower alcohols (ethanol, propanol, isopropanol) and the like.

Examples of the oily component include higher fatty acids (stearic acid, palmitic acid, myristic acid, lauric acid, esters thereof, etc.), higher alcohols (cetanol, lanolin alcohol, stearyl alcohol, cetostearyl alcohol, etc.) and Waxes (solid paraffin, microcrystalline wax, ceresin wax, polyethylene wax, beeswax, wood wax, carnauba wax, candelilla wax, etc.), natural or synthetic oil substances (squalane, liquid paraffin, lanolin or its derivatives, olive oil, camellia oil, Cottonseed oil, oleyl alcohol, castor oil, petrolatum, adipic acid diethoxyethyl ester, silicone oil, fluorine oil, etc.)
Is mentioned.

Examples of the powder component 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, new oil type glyceryl monostearate, and propylene glycol monostearate.

Examples of moisturizers 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, carboxymethylcellulose,
Carrageenan, sodium alginate, bentonite,
Vegum, synthetic hectorite and the like.

Examples of antioxidants include dibutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium tocopherol pyrosulfite, sodium bisulfate, tocopherol acetate, vitamin E and rosemary extract. .

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

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

Examples of the ultraviolet protective agent include ascorbic acid or its derivative, isoferulic acid or its salt, oxybenzone or its derivative, p-aminobenzoic acid or its derivative, urocanic acid or its derivative, kojic acid, dibenzoylmethane or its derivative. Derivatives, p-methoxycinnamic acid or its derivatives, fine particle titanium oxide, fine particle zinc oxide,
Fine particle iron oxide and the like.

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 can be used alone or in admixture of two or more.

The external preparation for skin of the present invention includes the above-mentioned general formula (I)
The whitening component (or whitening agent) other than the farnesyl isopropanol derivative represented by may be blended with one or more kinds. Other whitening ingredients include, for example, pantetheine-S-sulfonic acid, isoferric acid, ascorbic acid and its magnesium phosphate salts, arbutin, kojic acid, linoleic acid, tranexamic acid, esculin, vitamin A acid, retinol 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 and the like, such as ointments, creams, emulsions, lotions and packs. , A bath agent and the like.

[0035]

BEST MODE FOR CARRYING OUT THE INVENTION The action of the farnesyl isopropanol derivative represented by the general formula (I) used in the present invention will be described below based on experimental examples.

(1) Inhibitory action of melanin production on pigment cells Plastic culture flasks (75 cm ² ) were inoculated with 5 × 10 ⁴ B-16 melanoma cells in an Eagle MEM medium containing 10% serum. In the presence of 5% carbon dioxide, 3
The cells were cultured at a temperature of 7 ° C. After 2 days, a test sample of farnesyl isopropanol derivative was added at a concentration of 5, 1 in the medium.
It was added to 0, 15, and 20 μM, and the cells were further cultured for 4 days.

After completion of the culture, the medium is removed and washed with a phosphate buffered saline solution (hereinafter referred to as PBS), and then the cells are 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 twice with PBS, a fixed amount of PBS is added.
Was added thereto, and the cells were mixed by flushing. An aliquot of the cell suspension was taken, and the number of cells was counted using a Coulter counter. The remaining suspension was centrifuged again, and the whiteness of the sediment was visually observed. Table 1 shows the results based on the following criteria.
Shown in 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

[0039]

[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 previously prepared using synthetic melanin. The amount of melanin was determined as an amount per 10 ⁴ cells. The results are shown in Table 2. In addition, the suppression rate in the table was obtained by the following equation. Inhibition rate (%) = [(melanin amount of control product−melanin amount of test sample added product)] × 100 / (melanin amount of control product)

[0041]

[Table 2]

As is clear from these results, the farnesyl isopropanol derivative has a whitening effect on the pigment cells, as compared with the solvent control (control), and further an effect of remarkably suppressing the melanin production in the pigment cells. It was shown to have.

(2) Inhibitory effect of pigmentation by ultraviolet rays (animal test) 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 to 1.5 × 1. .5 cm
The irradiation window of 6 is covered with a black cloth that has a total of 6 on the left and right, and the FL20S / E30 lamp is used as a light source for 1 m from the top of this cloth.
Ultraviolet light of W / cm ² / sec was irradiated for 4 minutes and 20 seconds.

This operation was performed once a day for 3 consecutive days. From the day after the irradiation was completed, 20 μl of a test solution containing a predetermined amount of farnesylisopropanol derivative dissolved in ethanol as a solvent was continuously applied once a day for a total of 20 days. In addition, an experiment was similarly performed using only ethanol 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 an average value.

0: No pigmentation 0.5: Weak pigmentation with indistinct borders 1: Weak pigmentation with definite borders 2: Moderate pigmentation with definite borders 3: Definite intensity of pigmentation With pigmentation

[0046]

[Table 3]

As shown in Table 3, the farnesyl isopropanol derivative clearly inhibited the deposition of melanin pigment by ultraviolet rays at a concentration of 0.5% when applied to the skin, as compared with the case where the solvent control was applied.

As shown above, the farnesyl isopropanol derivative according to the present invention has an action of suppressing melanin production and an action of suppressing pigmentation after ultraviolet irradiation. As a result, those formulated with a certain percentage or more in the skin external preparation base provide an excellent whitening effect on the skin, and not only spots, freckles, and localized pigmentation such as darkness due to sunburn, but also It can be used to improve and treat systemic pigmentation 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.

[0049]

EXAMPLES Examples of the present invention will be described below. The amounts in the examples are parts by weight.

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-tocopherol 0.05 BHT 0. 01 butyl paraben 0.1 farnesyl isopropanol glucoside 0.5 (B) propylene glycol 10.0 purified water 58.34

(Production method) The components (A) and (B) are dissolved at 80 ° C. with stirring. These are added and stirred to emulsify, and then cooled.

<Actual Use Test of Pigmentation Improving Effect> The cream obtained above and the cream of the comparative product (the farnesylisopropanol glucoside in the cream of Example 1 being replaced with water) were statistically equivalent to 40. The effect of pigmentation improvement by actual use was evaluated by continuously applying it to a female group suffering from dark skin, spots and freckles for 3 months. The results are shown in Table 4.

[0053]

[Table 4]

As is clear from these results, it was confirmed that the product of the present invention containing farnesyl isopropanol glucoside has a markedly effective pigmentation-improving effect as compared with the comparative product not containing this compound. Incidentally, no unfavorable reaction on the skin was observed at the application site of the product of the present invention.

Example 2. 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-tocopherol 0.05 BHT 0. 01 butyl paraben 0.1 farnesyl isopropanol maltoside 3.0 (B) propylene glycol 10.0 purified water 55.84

(Production Method) The components (A) and (B) are dissolved at 80 ° C. with stirring. These are added and stirred to emulsify, and then cooled.

Example 3. Emulsion (A) Synthetic Gairow 2.5 Cetanol 1.0 Squalane 4.0 Stearic Acid 1.0 POE (25) Monostearate 2.2 Glycerin Monostearate 0.5 Butylparaben 0.1 γ-Tocopherol 0.1 05 BHT 0.01 Farnesyl isopropanol acetate 1.0 (B) 1,3-butylene glycol 3.0 propylene glycol 7.0 caustic potash 0.2 purified water 77.44

(Production Method) The components (A) and (B) are dissolved at 70 ° C. with stirring. The component (A) is added to the component (B), and the mixture is pre-emulsified, uniformly emulsified by a homomixer, and cooled to 30 ° C. while stirring after emulsification.

Example 4. Emulsion (A) Synthetic Geyrow 2.5 Cetanol 1.0 Squalane 4.0 Stearic acid 1.0 POE (25) monostearate ester 2.2 Glycerin monostearate 0.5 Butylparaben 0.1 γ-tocopherol 0. 05 BHT 0.01 farnesyl isopropanol maltoside 1.0 (B) 1,3-butylene glycol 3.0 propylene glycol 7.0 caustic potash 0.2 purified water 77.44

(Production Method) The components (A) and (B) are dissolved at 70 ° C. with stirring. The component (A) is added to the component (B), and the mixture is pre-emulsified, uniformly emulsified by a homomixer, and cooled to 30 ° C. while stirring after emulsification.

Example 5. Lotion (A) POE (20) sorbitan monolauric acid ester 1.5 POE (20) lauryl ester 0.5 ethanol 10.0 γ-tocopherol 0.02 farnesyl isopropanol 0.5 (B) glycerin 5.0 propylene glycol 4 0.0 citric acid 0.15 sodium citrate 0.1 purified water 78.23

(Production method) The respective 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 is added to the component of (A) to be solubilized.

Example 6. Lotion (A) POE (20) sorbitan monolauric acid ester 1.5 POE (20) lauryl ester 0.5 ethanol 10.0 γ-tocopherol 0.02 farnesyl isopropanol glucoside 0.05 (B) glycerin 5.0 propylene glycol 4.0 Citric acid 0.15 Sodium citrate 0.1 Purified water 78.68

(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 is added to the component of (A) to be solubilized.

Example 7. Packing material (A) Polyvinyl alcohol 15.0 Purified water 40.0 (B) Ethanol 4.0 1,3-Butylene glycol 4.0 Polyoxyethylene (8) Polyoxypropylene glycol (55 ) 3.0 bisaborole 0.5 tocopherol 0.02 farnesyl isopropanol galactoside 1.5 purified water 31.98

(Production method) The component (A) is dispersed and dissolved at room temperature. The component (B) is added to this and dissolved uniformly.

Example 8. Packing material (A) Polyvinyl alcohol 15.0 Purified water 40.0 (B) Ethanol 4.0 1,3-Butylene glycol 4.0 Polyoxyethylene (8) Polyoxypropylene glycol (55 ) 3.0 bisaborole 0.5 tocopherol 0.02 farnesyl isopropanol cellobioside 2.0 purified water 31.48

(Production Method) The component (A) is dispersed and dissolved at room temperature. The component (B) is added to this and dissolved uniformly.

In addition, also in Examples 2 to 8, a practical use test of the effect of improving pigmentation was conducted, and the same results as in Example 1 were obtained.

[0070]

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

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/23 A61K 31/23 31/70 AED 31/70 AED // C07C 33/02 9155-4H C07C 33/02 (72) Inventor Yukiko Yokoyama 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd. Totsuka Laboratory

Claims (4)

[Claims] 1. A melanin production inhibitor comprising a farnesyl isopropanol derivative represented by the following general formula (I): Embedded image (In the formula, R represents hydrogen, a monosaccharide residue, a disaccharide residue, or an acetyl group.) 2. The monosaccharide residue and disaccharide residue represented by R in the general formula (I) are glucose, galactose, mannose, xylose, fructose, maltose, isomaltose, cellobiose, gentiobiose, kojibiose, lamina. The melanin production inhibitor according to claim 1, which is one kind selected from ribiose, nigerose, sambibiose, and neohesperidose. 3. An external preparation for skin, comprising the melanin production inhibitor according to claim 1 or 2. 4. The content of the melanin production inhibitor according to claim 1 or 2 is 0.05 with respect to the total amount.
The external preparation for skin according to claim 3, which is 10 to 10% by weight.