JP2986966B2 - Melanin production inhibitor - 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 a whitening cosmetic, and more particularly, to a melanin production inhibitor which directly acts on a melanogenesis system of living pigment cells (melanocytes) to suppress melanin production, and storage. An object of the present invention is to provide a whitening cosmetic which has good stability at the time of use or use and is excellent in preventing and improving skin pigmentation.

[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 formed via an intermediate such as 5,6-dihydroxyindole. .

[0003] Therefore, in order to prevent or improve the color darkness, it is necessary to inhibit the activity in the process of producing melanin or to bleach existing melanin in a light color. Based on this, various whitening components have been proposed. For example, sulfur compounds typified by glutathione are used for inhibiting tyrosinase activity, and hydrogen peroxide, hydroquinone, vitamin C and the like have been used for pale bleaching.

[0004]

However, these conventional components have extremely poor stability in the formulation system, causing coloration and off-flavor due to decomposition, and are still unsatisfactory at the cellular or biological level in terms of their effects and efficacy. It was enough. Further, hydroquinone has a strong fairness effect, but has problems in safety, such as causing irreversible vitiligo and rash. In this way, the conventionally used ingredients are
No satisfactorily practically satisfactory effects, stability and safety have been obtained.

The present invention has been made in view of the above circumstances, and has a melanin production inhibitor which has a sufficient pharmacological effect such as improvement and treatment of skin pigmentation and can be used safely, and a compound comprising the same. It is an object to provide a whitening cosmetic.

[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 esculin has a strong inhibitory effect on melanin production of living pigment cells. It has been found that when this is mixed in a base at a certain concentration or more, an excellent fairness effect on the skin is exhibited, and the present invention has been completed based on this.

That is, the present invention relates to a melanin production inhibitor consisting of esculin and 0.1 to 10
The present invention relates to a whitening cosmetic containing 10% by weight, and is preferably used in combination with 0.01 to 5% by weight of an ultraviolet ray protective agent or 0.01 to 5% of an antioxidant in the whitening cosmetic. Weight% or the pH of the base
Whitening cosmetics in which is adjusted to an acidic region or a combination thereof.

Hereinafter, the present invention will be described in detail.

Esculin, which is a melanin production inhibitor of the present invention, is one of coumarin glycosides, also called esculetin-6-β-glucoside. Esculin is contained in the bark of horse chestnut (malonnier) and ash in the natural world, is a white, odorless crystal isolated by various isolation methods, and has ultraviolet absorbing ability. It is known to have vascular resistance enhancement and lipoxygenase inhibitory activity, but it is not known at all that this substance has a melanin production inhibitory effect on living pigment cells. There was no example of practical use for whitening cosmetics by using the same.

Next, in the whitening cosmetic of the present invention, the above-mentioned esculin is used in a range of 0.1 to 10% by weight based on the whole base. Among them, 0.1% by weight when used for the purpose of preventing spots, freckles and hatred of sunburn due to sunburn.
As described above, when used for the purpose of improving pigmentation, 1% by weight or more can be used as an effective amount.
If the amount is less than 0.1% by weight, the effect based on the melanin production inhibitory effect cannot be expected. Even if an amount exceeding 10% by weight is used, the effect is hardly changed. There is no need to exceed. A particularly preferred amount is selected from 0.5 to 3% by weight.

The use of horse chestnut extract as a sunburn-preventing cosmetic, a remedy for hemorrhoids and congestion has been known for a long time, but the esculin contained in commercially available, that is, industrially used horse chestnut extract is used. The content is only 0.2% by weight at most, and therefore, even in the case of the medicine containing the horse chestnut extract,
The content was extremely small, and a practical melanin production inhibitory effect was not obtained, and a sufficient fairness effect was not obtained. In the first place, the horse chestnut extract, which is a plant extract, contains a large amount of saponins and other contaminant pigments, including escin, which is known as a prominent active ingredient of horse chestnut extract, in addition to esculin.
The compounding at a high concentration impairs the appearance due to separation phenomena such as sedimentation or coloring, so that the amount of the compounding agent for a drug or the like must be significantly restricted.

Next, in the whitening cosmetic of the present invention, an ultraviolet protective agent or an antioxidant is used in combination with the above-mentioned esculin, or the pH of the base is adjusted to an acidic range, or a water-in-oil It is preferred to use a dosage form of the type. That is, according to the study of the present inventors, it has been clarified that when esculin is blended in a base such as a solution or an emulsion in the above-mentioned blending range, it is partially decomposed and colored by sunlight. Therefore, as a result of further investigation, it was determined whether to add an ultraviolet protection agent, an antioxidant,
Esculin was found to be stable from ultraviolet light by adjusting H to the acidic region, or by using a water-in-oil base in emulsified systems, or a combination of these.

The ultraviolet ray protective agent applied to the present invention includes: isoferulic acid or a salt thereof, oxybenzone or a derivative thereof, dibenzoylmethane or a derivative thereof, p-aminobenzoic acid or a derivative thereof, cinnamic acid or a derivative thereof, urocanin One or more selected from acids or derivatives thereof, titanium oxide, zinc oxide, and the like, and the compounding ratio is 0.01 to 5% by weight based on the entire base.
Preferably, 4- (1,1-dimethylethyl) -4′-
An ultraviolet absorber having a strong absorption in the UV-A region such as a dibenzoylmethane type represented by methoxydibenzoylmethane and an oxybenzone type represented by 2-hydroxy-4-methoxybenzophenone is selected.

The antioxidant applied to the present invention is one or more selected from butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tocopherols, ascorbic acid or derivatives thereof, and the like. The mixing ratio is 0.01 to 5% by weight based on the whole base.

Examples of the pH adjuster applied to the present invention include a citrate buffer, a phosphate buffer, an acetate buffer and the like. The pH of the base is in the acidic region, preferably pH 4.0 to 6.0.
It is adjusted to the range of 5.

Also, the whitening cosmetic of the present invention contains the above-mentioned esculin, and a sunscreen agent, an antioxidant,
In addition to the pH adjuster, various components generally used in cosmetics, that is, aqueous components, oil components, powder components, surfactants, humectants, thickeners, coloring agents, fragrances, preservatives, or anti-inflammatory agents, esculin Drugs such as whitening ingredients other than the above can be added. Further, the dosage form of the present invention is arbitrary, and any dosage form conventionally used in this type of whitening cosmetics may be used, and examples thereof include dosage forms such as creams, emulsions, lotions, packs, and bath preparations.

Next, the experiments conducted to evaluate the usefulness of the esculin according to the present invention as a melanin production inhibitor and various experiments conducted for stability will be described below.

Experimental Example 1 Inhibition of Melanin Production on Pigment Cells 5 × 10 ⁴ B-16 melanoma cells were seeded in a plastic culture flask (75 cm ² ), and cultured in an Eagle MEM medium containing 10% serum at 5% carbon dioxide at 37 ° C. Cultured. Two days later, esculin was added to the medium at a concentration of 5,
It was added to a concentration of 10, 15 μM, and the cells were further cultured for 4 days. After completion of the culture, the medium was removed, and the cells were washed with an equilibrated phosphate buffered saline (PBS). The cells were detached using a solution containing trypsin and EDTA, collected in a glass centrifuge tube, and collected by centrifugation. After the cells were washed twice with an equilibrated phosphate buffered saline solution, 1N sodium hydroxide was added to the sediment to dissolve by heating, and after cooling, chloroform was added and centrifuged again. The supernatant thus obtained was measured at an absorbance of 400 nm, and the amount of melanin was determined from a calibration curve previously prepared using synthetic melanin. The amount of melanin was 10 ⁶
It was determined as the amount per individual cell. Table 1 shows the results.

[0019]

[Table 1]

As is clear from the results in Table 1, it was demonstrated that esculin has a remarkable inhibitory effect on melanin production in pigment cells.

Experimental Example 2 Inhibition of pigmentation by ultraviolet rays The back skin of brown guinea pigs (7 animals) was dehaired with an electric clipper and a shever. Next, the irradiation window of 1.5 × 1.5 cm was covered with a black cloth having a total of six for left and right contrast, and FL20S · E
1 mW / cm ² / sec. 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, 0.2 ml of a test solution in which a predetermined amount of esculin was dissolved in propylene glycol / ethanol (3: 1) as a solvent and a commercially available horse chestnut extract as a comparative product were dissolved each day were used.
For 10 consecutive days. The solvent itself was used as a control. On the 14th 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 2 as average values. (Judgment criteria) 0: No pigmentation was observed 0.5: Weak pigmentation with indistinct boundaries 1.0: Mild pigmentation with distinct boundaries 2.0: Moderate pigmentation with distinct boundaries 3.0 : Pigmentation with clearly defined intensity

[0022]

[Table 2]

As shown in the results in Table 2, when applied to the skin, esculin clearly inhibits melanin production by ultraviolet rays at 0.1% or more, but in the case of horse chestnut extract, the upper limit concentration which can be practically incorporated. That is, no satisfactory effect was observed even in the case of 20% blending.

Experimental Example 3 Stability test for ultraviolet rays A 0.5% solution or a 1% ointment containing esculin was prepared, and the stability to ultraviolet rays was compared and examined.

(Experimental Example 3-1) PH stability A 5% propylene glycol / ethanol (3: 1) solution of esculin was added to a previously prepared 0.1 M phosphate buffer of each PH at 1/10 amount. A test sample was used. This was taken in a glass test tube with a stopper in an amount of 3 ml, and left outdoors for one day on a sunny day. After completion of the experiment, the color tone of the solution was visually evaluated, and the residual ratio of esculin was measured by high performance liquid chromatography. In preparing the phosphate buffer, PH5 and 6 were adjusted with HCl, and PH8 was adjusted with NaOH. The results are shown in Table 3-1.

[0026]

[Table 3-1]

As shown in the results of Table 3-1, the aqueous solution of esculin shows a yellow color immediately after dissolution in an alkaline region at pH 7 or higher and is unstable to sunlight irradiation, whereas it is unstable from sunlight to acidic region. It was found to be stable.

(Experimental Example 3-2) Effect of Addition of Ultraviolet Protecting Agent or Antioxidant A 5% propylene glycol / ethanol (3: 1) solution of esculin was added to 1/10 of a 50% aqueous ethanol solution.
A test sample was prepared by adding an amount. Furthermore, UV protection agents (4-
When (1,1-dimethylethyl) -4'-methoxydibenzoylmethane) or an antioxidant (butylhydroxytoluene) was added, a 5% ethanol solution of these substances was prepared, and then 1/5 was added. 3 ml of each of these test solutions was placed in a glass test tube with a stopper, and left outdoors for one day on a sunny day. After completion of the experiment, the color tone of the solution was visually evaluated, and the residual ratio of esculin was measured by high performance liquid chromatography. The results are shown in Table 3-2.

[0029]

[Table 3-2]

As shown in Table 3-2, it was found that coloring and decomposition of esculin were suppressed by the addition of an ultraviolet ray protective agent or an antioxidant.

(Experimental example 3-3) Effect of water-in-oil (W / O) emulsifying system Esculin was kneaded into a water-absorbing ointment and a hydrophilic ointment of the Japanese Pharmacopoeia so as to be 1%, and the hair was removed beforehand. Hartley guinea pig applied to the back skin, then FL40S ・ B
Using an LB lamp as a light source, 4 mW / cm ² / sec. Irradiation at an energy intensity of 2 hours. After completion of the experiment, the degree of coloring of the skin surface was visually evaluated. As a result, the hydrophilic ointment exhibited a yellow tint, but the water-in-oil (W / O) type water-absorbing ointment did not show any change.

Experimental Example 4 Actual use test of melanin-suppressing effect The cream of the present invention shown in Example 1 to be described later and a cream of a comparative product containing 5% horse chestnut extract instead of esculin were statistically equivalent to 40 black and white spots, The female group suffering from freckles was continuously used for 3 months, and the melanin-suppressing effect was evaluated. Table 4 shows the results.

[0033]

[Table 4]

As is apparent from the results in Table 4, the product of the present invention containing esculin was proved to be significantly more effective than the comparative product containing 5% horse chestnut extract. still,
No undesired reactions on the skin were observed at the application site of the product of the present invention.

[0035]

EXAMPLES Examples of the present invention will be described below, but the present invention is not limited to these examples. The mixing ratio is part by weight.

Embodiment 1 Water-in-oil cream (A) Squalane 12.0 Beeswax 2.0 Microcrystalline wax 2.0 Glycerin (PO20) Pyroglutamic acid monopalmitate 5.0 4- (1,1-Dimethylethyl) -4'-methoxydi Benzoylmethane 0.5 γ-Tocopherol 0.05 Butylparaben 0.2 (B) Marbit 8.0 1,3-butanediol 7.0 Esculin 2.0 Purified water 61.25 (Production method) (A) at 80 ° C. At 80 ℃
(A) is added to (A) while stirring with a homomixer and emulsified, and then cooled to 30 ° C.

Embodiment 2 FIG. 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 2-hydroxy- 4-methoxybenzophenone 0.5 butylparaben 0.2 (B) propylene glycol 10.0 esculin 1.0 Purified water 57.24 (Preparation method) Combine the components of (A) and heat to 80 ° C.
Combine the components of (B) and heat to 80 ° C. The formulation of (A) is added to the formulation of (B), and the mixture is emulsified with stirring, and then cooled.

Embodiment 3 FIG. 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 0.1 γ-Tocopherol 05 BHT 0.01 4- (1,1-dimethylethyl) -4′-methoxydibenzoylmethane 0.5 (B) 1,3-butylene glycol 3.0 propylene glycol 7.0 Xanthan gum 0.1 Carboxyvinyl polymer 0.2 Caustic potash 0.2 Esculin 1.0 Purified water 76.64 (Preparation method) Dissolve (A) and (B) at 70 ° C. while stirring each. Add (A) to (B), pre-emulsify and homogenize uniformly with a homomixer. After emulsification, stir at 30 ° C.
Cool down to

Embodiment 4 FIG. Lotion (A) POE (20) sorbitan monolaurate 1.5 POE (20) lauryl ether 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 Esculin 0.5 Purified water 78.23 (Production method) Combine the components of (A) and dissolve at room temperature.
On the other hand, each component of (B) was also dissolved at room temperature, and this was dissolved in (A)
Solubilize in addition to prescription.

Embodiment 5 FIG. Packing charge (A) Polyvinyl alcohol 15.0 Purified water 40.0 (B) Bisabolol 0.5 γ-Tocopherol 0.02 Ethanol 4.0 1,3-butylene glycol 4.0 Polyoxyethylene (8) Polyoxypropylene glycol (55) 3.0 Purified water 32.98 Esculin 0.5 (Production method) (A) is dispersed and dissolved at room temperature. To this (B)
And dissolve uniformly.

[0041]

According to the present invention, esculin exerts a strong melanin production inhibitory effect on living pigment cells, and when incorporated into a base at a certain ratio or more, esculin has a remarkably excellent skin-whitening effect on the skin. It can be used for the improvement and treatment of 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.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 7/42 A61K 7/42 9/06 9/06 G 31/00 643 31/00 643D 31/70 31/70 // C07H 17/075 C07H 17/075 (72) Inventor Takayuki Katagiri 27-1 Takashimadai, Kanagawa-ku, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture Inside the Yokohama Research Laboratory (72) Inventor Koji Yokoyama 27, Takashimadai, Kanagawa-ku, Yokohama-shi, Kanagawa No. 1 Pola Kasei Kogyo Co., Ltd., Yokohama Research Center (72) Inventor Keiko Onuki 27-1, Takashimadai, Kanagawa-ku, Kanagawa-ku, Kanagawa Prefecture Pola Kasei Kogyo Co., Ltd. Yokohama Research Center (72) Inventor Hiroyuki Nakano Kanagawa, Kanagawa Prefecture 27-1 Takashima-ku, Ward POLA CHEMICAL INDUSTRIES, LTD. Yokohama Research Laboratory (56) Reference JP-A-52-105221 (JP, A) JP-A-63-303919 (JP, A) JP-B-48-5022 (JP, B1) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 7/48 A61K 7/00 A61K 7/42 A61K 9/06 C07H 17/075

Claims (5)

(57) [Claims] 1. A melanin production inhibitor comprising esculin. 2. A whitening cosmetic comprising a melanin production inhibitor comprising esculin in an amount of 0.1 to 10% by weight based on the whole base. 3. The whitening cosmetic according to claim 2, comprising 0.01 to 5% by weight of an ultraviolet ray protective agent. 4. The whitening cosmetic according to claim 2, comprising 0.01 to 5% by weight of an antioxidant. 5. The whitening cosmetic according to claim 2, wherein the pH of the base is adjusted to an acidic range.