JPH09124474A - Suppressant for melanogenesis and dermal preparation for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject suppressant, comprising a borneol cinnamate derivative, having strong suppressing effects on the melanogenesis of a live pigment cell, capable of preventing the skin from pigmenting and useful as a dermal preparation for external use excellent in beautifying and whitening effects. SOLUTION: This suppressant for the melanogenesis comprises a borneol cinnamate derivative of the formula (R is H, hydroxyl group or methoxy). The suppressant in an amount of 0.05-10wt.% based on the total amount can be contained to provide a dermal preparation for external use. The borneol cinnamate derivative is obtained by reacting, e.g. borneol with cinnamic acid in the presence of N,N'-dicyclocarbodiimide and dimethylaminopyridine in tetrahydrofuran at ambient temperature for 2hr, removing the solvent and then fractionating and isolating the reactional product according to the silica gel column chromatography.

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 borneol cinnamic acid ester derivatives have a strong inhibitory effect on melanin production in living pigment cells. The inventors have found that, when further blended in a base at a certain concentration or higher and used as a skin external preparation, an excellent skin-whitening effect is exhibited on the skin, and the present invention has been completed.

That is, the present invention relates to a melanin production inhibitor comprising a borneol cinnamic acid ester derivative represented by the general formula (I) shown below.

The present invention also relates to a skin external preparation characterized by containing at least one of the above-mentioned melanin production inhibitors as an active ingredient, preferably in an amount of 0.05 to 10% by weight based on the total amount of the skin external preparation. It is a thing.

[0009]

Embedded image

(In the formula, R represents hydrogen, a hydroxyl group or a methoxy group.)

Hereinafter, the present invention will be described in detail.

<1> Melanin Production Inhibitor The melanin production inhibitor of the present invention comprises a borneol cinnamic acid ester derivative represented by the general formula (I).
Here, the acid component constituting such an ester is selected from cinnamic acid, p-hydroxycinnamic acid or p-methoxycinnamic acid, and the alcohol component is borneol. Borneol is a bicyclic monoterpene alcohol that is also called Borneol, Borneo camphor.

Next, the borneol cinnamic acid ester derivative according to the present invention can be synthesized by utilizing a conventionally known esterification reaction. An example of the synthesizing method will be described below.

1) Borneol and cinnamic acid in N, N'-dicyclocarbodiimide (DCC) in tetrahydrofuran
And react with dimethylaminopyridine for 2 hours at room temperature. After removing the solvent, the reaction product is fractionally isolated by silica gel column chromatography to produce borneol cinnamic acid ester (hereinafter abbreviated as Bol-CA).
Is obtained.

Similarly, borneol-p-hydroxycinnamic acid ester (hereinafter abbreviated as Bol-pHCA) and borneol-p-methoxycinnamic acid ester (hereinafter abbreviated as Bol-pMCA) are also synthesized. You can

<2> Skin external preparation The skin external preparation of the present invention includes one or two of the melanin production inhibitors comprising the above-mentioned borneol cinnamate derivative.
More than one kind is preferably 0.05 to 1 with respect to the total amount of the external preparation.
The content is 0% by weight, more preferably 0.1 to 5% by weight. Among skin external preparations, especially due to sunburn,
The content is preferably 0.1% by weight or more for the purpose of preventing and improving the freckles and the exacerbation of color black.

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

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 (as an emulsifier), a moisturizing agent Agents, thickeners, coloring agents, fragrances, antioxidants, pH adjusters, chelating agents, preservatives, or agents such as ultraviolet ray protective agents and anti-inflammatory agents 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 and esters thereof), higher alcohols (cetanol, lanolin alcohol, stearyl alcohol, cetostearyl alcohol, etc.) and the like. Waxes (solid paraffin, microcrystalline wax, ceresin wax, polyethylene wax, beeswax, wood wax, carnauba wax, candelilla wax, etc.), natural or synthetic oils (squalane, liquid paraffin, lanolin or derivatives thereof, olive oil, camellia oil, Cottonseed oil, oleyl alcohol, castor oil, petrolatum, diethoxyethyl adipate, 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, glycerin monostearate, propylene glycol monostearate and the like.

Examples of the humectant include glycerin, propylene glycol, 1,3-butylene glycol, dipropylene glycol, ethylene glycol, 1,4-butylene glycol, diglycerin, triglycerin, sorbit and its derivatives, and polyethylene glycol. Polyhydric alcohols include glucose, maltose, maltitol, sucrose, fructose, threitol, erythritol, sorbitol, starch-degrading sugar, hyaluronic acid, chondroitin sulfate, hydrolyzed collagen, carboxymethyl chitin and the like.

Examples of the thickener include carboxyvinyl polymer, CP jelly, carboxymethyl cellulose,
Carrageenan, sodium alginate, bentonite,
Vegum, synthetic hectorite and the like.

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

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.

As preservatives, for example, 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 derivatives thereof, 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 a derivative thereof, glycyrrhizic acid or a derivative thereof, bisabolol, geraniin, malonier extract, and aloe extract.

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 may contain one or more kinds of whitening components (or whitening agents) other than the above-mentioned borneol cinnamic acid ester derivative. 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 in medicines, quasi drugs, cosmetics, etc., such as ointments, creams, emulsions, lotions and packs. , A bath agent and the like.

[0033]

BEST MODE FOR CARRYING OUT THE INVENTION The action of the borneol cinnamate 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 5 × 10 ⁴ B-16 melanoma cells were seeded in a plastic culture flask (75 cm ² ) and 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, the test sample was added so as to have a concentration of 5, 10, 15, 20 μM in the medium,
It was 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

[0037]

[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. Table 2 shows the results. 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)

[0039]

[Table 2]

As is clear from these results, although borneol alone or cinnamic acid alone had no inhibitory effect on melanin production, all borneol cinnamate derivatives were compared to the solvent control (control). It was shown that it has the effect of whitening pigment cells and the effect of significantly suppressing melanin production in pigment cells.

(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 end of irradiation, 20 μl of a test solution prepared by dissolving a predetermined amount of a test sample using 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 border 1: Poor intensity of pigmentation with demarcation 2: Moderate pigmentation with demarcation 3: Definite intensity of pigmentation With pigmentation

[0044]

[Table 3]

As shown in Table 3, each of the borneol cinnamic acid ester derivatives, when applied to the skin, caused the deposition of melanin pigment by ultraviolet rays at a concentration of 0.5% as compared with the case where the solvent control was applied. Obviously suppressed.

(3) Inhibitory action of pigmentation by ultraviolet rays (human test) On the inner part of the upper arm of 10 humans aged 20 to 35 years,
Four sites of A, B, C, and D having an area of 1.5 × 1.5 cm are set, and 3% Bol-CA (solvent is 30
% Ethanol aqueous solution), 3% Bol-pH at the B site
10 μl of CA (solvent is 30% ethanol aqueous solution), C site is 3% Bol-pMCA (solvent is 30% ethanol aqueous solution), and D site is only 10 μl of solvent (30% ethanol aqueous solution) and left for 15 minutes. did. Then, cover the area other than the application area with a black cloth having an irradiation window of the same size as the application area, and apply 1 mW / cm ² / sec of ultraviolet light for 2 minutes 30 minutes using FL20S · E 30 lamp as a light source.
Irradiation was performed on the application site for a second.

On the 14th day after the start of the experiment, the degree of pigmentation in the treated area was evaluated by visual observation according to the following criteria. The results are shown in Table 4 as an average value.

0: No pigmentation 0.5: Weak pigmentation with indistinct boundary 1: Pigmentation with weak boundary with clear boundary 2: Moderate pigmentation with clear boundary 3: Intensity with clear boundary With pigmentation

[0049]

[Table 4]

As shown in Table 4, each of the borneol cinnamic acid ester derivatives was 3% when applied to human skin before irradiation with ultraviolet rays as compared with the case where a solvent control was applied.
Concentration clearly suppressed the deposition of melanin pigment by UV light.

As shown above, the borneol cinnamic acid ester derivative according to the present invention has an action of suppressing melanin production, an action of suppressing pigmentation after irradiation with ultraviolet rays, and an action of protecting ultraviolet rays. 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.

[0052]

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

Embodiment 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 Butylparaben 0.1 Bol-CA 0.5 (B) Propylene glycol 10.0 Purified water 58.34

(Preparation 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 of the present invention obtained in the above Example 1 and the comparative cream (the cream of Example 1 in which Bol-CA was replaced with liquid paraffin) were used. , 4 each statistically equivalent
The group of 0 females suffering from black-skin, spots and freckles was used continuously for 3 months, and the effect of improving pigmentation by actual use was evaluated. Table 5 shows the results.

[0056]

[Table 5]

As is clear from these results, it was confirmed that the product of the present invention containing the borneol cinnamate derivative 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.

Embodiment 2 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 Bol-pMCA 1.0 (B) 1,3-butylene glycol 3.0 propylene glycol 7.0 caustic potash 0.2 purified water 77.44

(Preparation method) The components (A) and (B) are dissolved at 70 ° C. while 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.

Embodiment 3 Lotion (A) POE (20) sorbitan monolaurate 1.5 POE (20) lauryl ester 0.5 ethanol 10.0 γ-tocopherol 0.02 Bol-pHCA 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 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 4. 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 Bol-pHCA 3.0 Purified water 30.48

(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 4, a practical use test of the effect of improving pigmentation was conducted, and the same results as in Example 1 were obtained.

[0065]

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.

Claims (3)

[Claims] 1. A melanin production inhibitor comprising a borneol cinnamic acid ester derivative represented by the following general formula (I): Embedded image (In the formula, R represents hydrogen, a hydroxyl group or a methoxy group.) 2. An external preparation for skin comprising at least one kind of the melanin production inhibitor according to claim 1. 3. The external preparation for skin according to claim 2, wherein the content of the melanin production inhibitor according to claim 1 is 0.05 to 10% by weight based on the total amount.