JPH05934A - External preparation for skin - Google Patents

Abstract

PURPOSE:To provide an external preparation for skin, excellent in prevention and therapy of chromatosis based on melanin generation-inhibitory effect. CONSTITUTION:Esculin is used as the active component in an amount of 0.1-10wt.% based on the whole basal agents. A more preferable preparation can be obtained by using 0.01-5wt.% ultraviolet-screening agent and/or antioxidant in combination therewith, adjusting pH of the base to a value in an acidic range or preparing the closing form as a water in oil type emulsion. This preparation shows a melanin generation-inhibitory effect on pigment cells, an excellent therapeutic effect on chromatosis and a whitening effect and is free from a fault in safety or touch.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an external preparation for skin, more specifically, it directly acts on the melanogenic system of living pigment cells (melanocytes) to suppress melanin production and has good stability during storage or use. It is intended to provide an external preparation for skin which is excellent in preventing and improving skin pigmentation.

[0002]

2. Description of the Related Art Pigmentation after freckles and sunburn is a marked increase in melanin production due to the activation of pigment cells in the skin, which is one of the troubles of the middle-aged and old-aged skin. There is. Generally, melanin is considered to be formed from tyrosine to dopa and dopa to dopaquinone by the action of the enzyme tyrosinase biosynthesized in pigment cells, and then formed via intermediates such as 5,6-dihydroxyindole. .

[0003] Therefore, in order to prevent or improve the color black, it is necessary to inhibit the activity in the process of melanin production and to lightly bleach the existing melanin, and various whitening components have been proposed based on this. For example, sulfur compounds typified by glutathione have been used for inhibition of tyrosinase activity, and hydrogen peroxide, hydroquinone, vitamin C, etc. have been used for light color bleaching.

[0004]

However, these conventional ingredients have extremely poor stability in the formulation system and cause discoloration or offensive odor due to decomposition, and are still unsatisfactory at the cell or biological level in terms of effects and efficacy. It was enough. Further, although hydroquinone has a strong whitening effect, it has safety problems such as causing irreversible white spots and rashes. In this way, the conventionally used ingredients are
In terms of efficacy, stability, and safety, nothing that is truly practically satisfactory has been obtained.

The present invention has been made in view of the above circumstances, and it is an object of the present invention to provide a skin external preparation that has sufficient pharmacological effects such as improvement and treatment of skin pigmentation and can be used safely. And

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that esculin has a strong inhibitory effect on melanin production in living pigment cells, and further It was found that an excellent skin-whitening effect on the skin was exhibited when this was mixed in a base material at a certain concentration or more, and the present invention was completed based on this.

That is, the present invention is an external preparation for skin prepared by mixing esculin as an active ingredient in an amount of 0.1 to 10% by weight with respect to the entire base. In a preferred embodiment, an ultraviolet protective agent is added in an amount of 0.01 to 5% by weight. %, Or 0.01 to 5% by weight of antioxidant, or the base PH
The present invention relates to an external preparation for skin which is adjusted to an acidic range of, or is adjusted with a water-in-oil type emulsion system, or a combination thereof.

The present invention will be described in detail below.

Esculin applied to the present invention is one of the coumarin glycosides which is also called esculetin-6-β-glucoside. About esculin, it is contained in the bark of horse chestnut (horse chestnut) and ash in the natural world, it is a white, odorless crystal isolated by various isolation methods, has an ultraviolet absorbing ability, and is physiologically It is known to have a potentiating effect on vascular resistance and a lipoxygenase inhibitory activity, but there is no practical use of this substance as an external preparation for the skin, and this substance has an inhibitory action on melanin production in living pigment cells. It was not known at all to have a whitening effect based on.

Next, in the external preparation for skin of the present invention, the above-mentioned esculin is used in the range of 0.1 to 10% by weight based on the whole base. Among these, 0.1% by weight or more when used in an external preparation such as a cosmetic for the purpose of preventing and improving spots, freckles, and color darkening due to sunburn, and as a drug for treating pigmentation. When used as an external preparation, 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, and even if the amount is more than 10% by weight, the effect is hardly changed. There is no need to exceed. A particularly preferable amount is 0.5 to 3% by weight.

It has been known for a long time that the horse chestnut extract is used as a sunburn preventing cosmetic, a therapeutic agent for hemorrhoids and blood stasis, but esculin in the horse chestnut extract commercially available, that is, industrially used. The content is only 0.2% by weight at most, so even if the drug containing horse chestnut extract is added,
The content was extremely small, and a practical melanin production suppressing effect was not obtained, and a sufficient whitening effect was not obtained. The horse chestnut extract, which is a plant extract in the first place, contains a large amount of pigments that are saponins and contaminants including escin, which is known as a prominent active ingredient of horse chestnut extract, in addition to esculin,
Since the compounding at a high concentration impairs the external appearance due to a separation phenomenon such as precipitation and coloring, the fact is that the compounding amount with respect to a drug or the like must be significantly restricted.

Next, in the external preparation for skin of the present invention, an ultraviolet protective agent or an antioxidant is used together with the above-mentioned esculin, or the pH of the base is adjusted to an acidic region, or water in oil is used in an emulsifying system. It is preferable to use a dosage form of a mold. That is, according to the research conducted by the present inventors, it was revealed that when esculin was mixed in a base such as a solution or an emulsion within the above-mentioned mixing range, it was partially decomposed and colored by sunlight. Therefore, as a result of further study, it was determined whether an ultraviolet protection agent was added, an antioxidant was added, or P
It has been found that the esculin can be kept stable from ultraviolet rays by adjusting H to an acidic region, or by using a water-in-oil type formulation in an emulsion system, or a combination thereof.

The ultraviolet protective agent applied to the present invention is 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, urocanine. It is one or more selected from acids or derivatives thereof, titanium oxide, zinc oxide and the like, and the mixing ratio thereof is 0.01 to 5% by weight based on the whole base.
Preferably, 4- (1,1-dimethylethyl) -4'-
An ultraviolet absorber having strong absorption in the UV-A region, such as a dibenzoylmethane type typified by methoxydibenzoylmethane and an oxybenzone type typified 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 its derivatives, 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 solution, a phosphate buffer solution, an acetic acid buffer solution, and the like.
It is adjusted to the range of 5.

Further, the external preparation for skin of the present invention includes the above-mentioned esculin, an ultraviolet protective agent as a concomitant agent, an antioxidant,
In addition to the pH adjuster, various components commonly used in pharmaceuticals, cosmetics, etc., that is, an aqueous component, an oil component, a powder component,
Surfactants, moisturizers, thickeners, colorants, fragrances, antiseptics, anti-inflammatory agents, and agents such as whitening ingredients other than esculin can be added. Further, the dosage form of the present invention is arbitrary and may be any one conventionally used for this type of external preparation for skin, and examples thereof include ointments, creams, emulsions, lotions, packs and bath agents.

Next, an experiment conducted to evaluate the usefulness of the esculin according to the present invention and various experiments conducted on the stability are shown 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 Eagle MEM medium containing 10% serum under the conditions of 5% carbon dioxide and 37 ° C. Cultured. After 2 days, esculin was added at a concentration of 5, 5,
It was added to 10 and 15 μM and further cultured for 4 days. After completion of the culture, the medium was removed, and after washing with equilibrium 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. The cells were washed twice with an equilibrium phosphate buffered saline solution, 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 supernatant thus obtained was measured for absorbance at 400 nm, and the amount of melanin was determined from a calibration curve prepared in advance using synthetic melanin. The amount of melanin is 10 ^6.
It was determined as the amount per individual cell. The results are shown in Table 1.

[0019]

[Table 1]

As is clear from the results shown 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 shaved with an electric hair clipper and a shever. Then, cover the irradiation window of 1.5 x 1.5 cm with a black cloth that has a total of 6 on the left and right, and then press FL20S ・ E.
Using 30 lamps as a light source, 1 mW / cm ² / sec. Of ultraviolet rays of 4 minutes and 20 seconds. This operation was performed once a day for 3 consecutive days. From the day after the end of irradiation, 0.2 ml of a test solution prepared by dissolving a predetermined amount of esculin as a solvent and propylene glycol / ethanol (3: 1) as a solvent and a commercially available horse chestnut extract as a comparison product were used 1 day a day.
The application was repeated once for a total of 10 days. The solvent itself was used as a control. On the 14th day from the start of the experiment, the degree of pigmentation in the treated area was visually determined according to the following criteria. The results are shown in Table 2 as an average value. (Judgment Criteria) 0: No pigmentation was observed 0.5: Weak pigmentation with unclear boundary 1.0: Mild pigmentation with clear boundary 2.0: Moderate pigmentation with clear boundary 3.0 : Clear and intense pigmentation

[0022]

[Table 2]

As shown in the results of Table 2, when applied to the skin, esculin at 0.1% or more obviously suppresses the production of melanin by ultraviolet rays, but with horse chestnut extract, the upper limit concentration practically compoundable. That is, no satisfactory effect was observed even in the case of 20% formulation.

Experimental Example 3. Stability test against ultraviolet rays A 0.5% solution of esculin or a 1% compounded ointment was prepared and comparatively examined for stability against ultraviolet rays.

(Experimental example 3-1) PH stability A 5% propylene glycol / ethanol (3: 1) solution of esculin was added to a previously prepared 0.1M phosphate buffer of each PH in an amount of 1/10. It was used as a test sample. 3 ml of this was put into a glass test tube with a stopper and left outdoors for one day on a sunny day. After the experiment was completed, the color tone of the solution was visually evaluated, and the residual rate of esculin was measured by high performance liquid chromatography. In preparing the phosphate buffer, pH 5 and 6 were adjusted with HCl, and PH 8 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 exhibits a yellow color immediately after dissolution in the alkaline region at pH 7 or higher, and is unstable to sunlight irradiation, whereas it is weakly acidic to acidic region. It turned out that it was kept stable at.

(Experimental Example 3-2) Effect of Addition of UV Protective Agent or Antioxidant A 5% propylene glycol / ethanol (3: 1) solution of esculin was added to a 50% ethanol aqueous solution at 1/10.
The test sample was added in an amount. Furthermore, an ultraviolet protection agent (4-
When (1,1-dimethylethyl) -4'-methoxydibenzoylmethane) or an antioxidant (butylhydroxytoluene) was added, a 5% ethanol solution of these substances was prepared and then added in 1/5 amount. 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 the experiment was completed, the color tone of the solution was visually evaluated, and the residual rate 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 esculin was suppressed from being colored and decomposed by adding an ultraviolet protective agent or an antioxidant.

(Experimental example 3-3) Effect of water-in-oil (W / O) type emulsification system Esculin was kneaded into a water-absorbing ointment and a hydrophilic ointment of the Japanese Pharmacopoeia so as to be 1%, and hair was removed in advance. Apply to the back skin of Hartley guinea pig, then FL40S ・ B
LB lamp as light source, 4 mW / cm ² / sec. Irradiation was performed for 2 hours with the energy intensity of. After the experiment was completed, the degree of coloring on the skin surface was visually evaluated. As a result, the hydrophilic ointment exhibited a yellowish tinge, but no change was observed in the water-in-oil (W / O) water-absorbing ointment.

Experimental Example 4. Actual use test of melanin inhibitory effect The cream of the product of the present invention shown in Example 1 below and a cream of a comparative product containing 5% horse chestnut extract instead of esculin were statistically equivalent to 40 people of black and white, stains, A group of women suffering from freckles was continuously used for 3 months to evaluate the melanin suppressing effect. The results are shown in Table 4.

[0033]

[Table 4]

As is clear from the results shown in Table 4, the product of the present invention containing esculin was proved to be much more effective than the comparative product containing 5% horse chestnut extract. still,
No unfavorable reaction on the skin was observed at the application site of the present invention.

[0035]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited thereto. The mixing ratio is parts by weight.

Example 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) Marvit 8.0 1,3-Butanediol 7.0 Esculin 2.0 Purified water 61.25 (Production Method) (A) at 80 ° C. Dissolve uniformly at 80 ℃ separately
(B) dissolved in (1) is added to (A) with stirring with a homomixer to emulsify and then cooled to 30 ° C.

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 2-hydroxy- 4-Methoxybenzophenone 0.5 Butylparaben 0.2 (B) Propylene glycol 10.0 Esculin 1.0 Purified water 57.24 (Production method) The components of (A) are combined and heated to 80 ° C.
The components of (B) are combined and heated to 80 ° C. The formulation of (A) is added with the formulation of (B), and the mixture is stirred to emulsify and then cooled.

Example 3. Emulsion (A) Synthetic Geiro 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 0.1 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 potassium 0.2 Esculin 1.0 Purified water 76.64 (Production method) (A) and (B) are dissolved with stirring at 70 ° C. (A) is added to (B) and pre-emulsified and homogenized with a homomixer. After emulsification, 30 ° C with stirring.
Cool down.

Example 4. 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) The components of (A) are combined and dissolved at room temperature.
On the other hand, each component of (B) also dissolves at room temperature,
Add to formulation and solubilize.

Example 5. Packing material (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)
Add to dissolve evenly.

[0041]

INDUSTRIAL APPLICABILITY According to the present invention, esculin exerts a strong melanin production-inhibiting effect on living pigment cells, and when blended in a base at a certain ratio or more, esculin exerts a markedly excellent whitening effect on the skin. As a result, it can be used for the improvement and treatment of locality such as spots, freckles, and dark skin due to sunburn, and systemic pigmentation diseases such as Addison's disease. Moreover, it has excellent safety and can be used for a long period of time.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 7/42 7252-4C 9/06 G 7329-4C 31/70 AED 8314-4C // C07H 17 / 075 (72) Koji Yokoyama, 27 Takashimadai, Kanagawa-ku, Kanagawa-ku, Kanagawa Prefecture Pora Kasei Kogyo Co., Ltd. Yokohama Research Institute (72) Keiko Onuki 27, Takashimadai, Kanagawa-ku, Yokohama, Kanagawa Polar Chemical Industry Co., Ltd. Company Yokohama Research Institute (72) Inventor Hiroyuki Nakano 27 Takashimadai, Kanagawa-ku, Yokohama, Kanagawa 1 Polar Chemical Industry Co., Ltd. Yokohama Research Laboratory

Claims (5)

[Claims] 1. An external preparation for skin, comprising esculin as an active ingredient in an amount of 0.1 to 10% by weight based on the whole base. 2. The external preparation for skin according to claim 1, which contains 0.01 to 5% by weight of an ultraviolet protective agent. 3. The external preparation for skin according to claim 1, which contains 0.01 to 5% by weight of an antioxidant. 4. The external preparation for skin according to claim 1, wherein the pH of the base is adjusted to an acidic range. 5. The emulsion according to claim 1, wherein the formulation is a water-in-oil type emulsion system.
The external preparation for skin according to any one of 1 to 4.