JP2006137705A - Melanogenesis inhibitor and skin care preparation for external use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a skin care preparation for external use having melanogenesis inhibitory activity and sufficient ameliorative and curative effects on dyspigmentation and having stability and safety as well. <P>SOLUTION: A melanogenesis inhibitor is provided, consisting of 13-oxo-14,15-dinor-8(17)-labdane of formula(I). The skin care preparation for external use contains 0.0001-10 mass% of the above melanogenesis inhibitor. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a melanin production inhibitor and a skin external preparation, and more particularly to a skin external preparation excellent in fairness effect using a specific diterpene compound as an active ingredient.

  Factors that determine human skin color include the amount of melanin in the epidermis, blood flow in capillaries, and the thickness of the stratum corneum. Among these, the most important factor is the amount of melanin in the epidermis. Is mentioned. So-called stains, buckwheat, and pigmentation after sunburn are the result of a marked increase in melanin production due to the activation of melanocytes present in the skin, and are one of the problems of the skin of middle-aged and elderly people.

  In general, melanin pigments are produced in melanosomes, which are organelles in melanocytes existing in the basal layer of the epidermis, the hair root, and the outer root sheath. In the melanin production process, tyrosine is oxidatively converted to dopa and dopaquinone by the action of tyrosinase in the melanocyte, further auto-oxidized, polymerized via dopachrome and 5,6-dihydroxyindole and finally polymerized. Becomes a melanin pigment. The melanin produced is secreted from the melanocyte dendrites to the basal cells, and the basal cells divide and become spiny cells, then rises, reaches the stratum corneum, and then drops off when the stratum corneum detaches. ing.

Therefore, in order to prevent and improve stains, buckwheat and skin darkness, it is conceivable to inhibit the melanin production process or to lighten already produced melanin. Based on such an idea, various whitening components have been conventionally proposed. Examples of those that inhibit tyrosinase activity and suppress melanin production include kojic acid and its derivatives, glutathione, arbutin, and placenta extract. In addition, zinc peroxide, ascorbic acid and its derivatives, tocopherol and its derivatives, etc. have been used to lightly bleach the produced melanin. Furthermore, it has been reported that some diterpene compounds also have a melanin production inhibitory effect (see, for example, Patent Document 1, Patent Document 2, and Patent Document 3).
Japanese Patent No. 3236130 JP 2003-63944 A Japanese translation of PCT publication No. 2003-500346

  However, these whitening ingredients described above have poor stability and solubility in the formulation system, point out the occurrence of off-flavors and coloring due to starch and decomposition, and are not sufficient in the living body level, and further to the skin. There was a problem in terms of safety, such as a rash, which was not satisfactory.

  The present invention has been made in view of such a situation, and provides an external preparation for skin having an inhibitory action on melanin production, a sufficient improvement / treatment effect on skin pigmentation, and has stability and safety. This is the issue.

As a result of intensive studies in order to solve the above problems, the present inventors have obtained 13-oxo-14 represented by the following formula (I), which is a diterpene compound similar to manure described in Patent Document 1. , 15-dinol-8 (17) -labdane (13-oxo-14,15-dinor-8 (17) -labdane)
Has a remarkable melanin production inhibitory effect and pigmentation inhibitory effect on pigment cells, compared to manur, and when the compound is added to a skin external preparation at a predetermined concentration, It has been found that a pigmentation improving effect (whitening effect) is exhibited, and the present invention has been achieved.

  That is, the present invention comprises 13-oxo-14,15-dinol-8 (17) -labdane (13-oxo-14,15-dinor-8 (17) -labdane) represented by the above formula (I). The present invention relates to a melanin production inhibitor.

  Moreover, this invention is skin external preparation, Comprising: 0.0001-10 mass% of said melanin production inhibitor is contained with respect to this skin external preparation whole quantity, It is characterized by the above-mentioned.

  INDUSTRIAL APPLICABILITY According to the present invention, a melanin production inhibitor and an external preparation for skin that are excellent in fairness effect and have high stability and safety can be provided. The external preparation for skin of the present invention can be used for the prevention, amelioration, and treatment of local pigmentation diseases such as darkness due to spots, buckwheat and sunburn, and systemic pigmentation diseases such as Addison's disease.

<1> Melanin production inhibitor of the present invention The melanin production inhibitor of the present invention is a 13-oxo-14,15-dinol-8 (17) -labdane (13-oxo-14) represented by the above formula (I). 15-dinor-8 (17) -labdane). Such 13-oxo-14,15-dinol-8 (17) -labdane (hereinafter referred to as X-keton) is described in the literature. Is a known compound (see, for example, HELVETICA CHIMICA ACTA Vol. 63, Fasc. 7 (1980), p1932-1946), and is one of diterpene compounds. However, the X-keton has never been used in a practical sense, and it has never been known that the compound has an excellent inhibitory action on melanin production.

  As long as there is a commercially available X-keton used for the melanin production inhibitor of the present invention, the commercially available product may be used. For example, starting from a manure described in Japanese Patent No. 3236130, etc. It is also possible to synthesize like this.

<2> Synthesis of X-keton (hereinafter, also simply referred to as X-keton) used in the melanin production inhibitor of the present invention (Synthesis Example 1)
Manul (trade name: Manool, distributor: Westchem Industries Inc.) 0.8 g (2.75 mmol) is dissolved in 80 mL of acetone, and 1.2 g of KMnO ₄ is added in small portions over 2 hours with stirring under ice cooling. . Added 1 hour after the KMnO _4, further adds a KMnO ₄ in 0.3 g, continued for 1 hour and a half stirring. After the temperature of the above mixture is brought to room temperature, 10 mL of methanol is added and stirred at 50 ° C. for 1 hour. The reaction product was removed of the insoluble material with Celite, and concentrated under reduced pressure.
Purification by silica gel column chromatography (hexane / ethyl acetate = 95/5 to 88/12) yields 165.7 mg of X-keton as a colorless oil. Yield 23%.

<3> External preparation for skin of the present invention The external preparation for skin of the present invention preferably contains the melanin production inhibitor in a range of 0.0001 to 10% by mass relative to the total amount of the external preparation for skin. More preferably, it mix | blends in 0.01-10 mass%. Among external preparations for skin, particularly those intended to suppress and / or improve pigmentation such as stains, buckwheat and dark black due to sunburn, the blending amount should be 0.01% by mass or more Is preferred. If the blending amount is less than 0.0001% by mass, the effect based on the melanin production inhibitory action is reduced, and even if an amount exceeding 10% by mass is used, the effect reaches a peak, so it is preferable to blend in the above range. .

  In addition to the above melanin production inhibitor, the skin external preparation of the present invention includes various components generally used in pharmaceuticals, cosmetics, and the like, that is, fats and oils, waxes, mineral oils, fatty acids, alcohols, polyhydric alcohols, Esters, metal soaps, gums, sugars and water-soluble polymer compounds, surfactants, vitamins, amino acids or other powder components, or coloring agents, fragrances, antioxidants, pH adjusters, chelating agents, Preservatives, UV protection agents, anti-inflammatory agents, and the like can be blended.

  The above fats and oils include avocado oil, almond oil, fennel oil, sesame oil, olive oil, orange oil, orange raffer oil, sesame oil, cocoa butter, chamomile oil, carrot oil, cucumber oil, beef tallow fatty acid, cucuin nut oil, safflower Oil, shea fat, soybean oil, camellia oil, corn oil, rapeseed oil, persic oil, castor oil, cottonseed oil, peanut oil, turtle oil, mink oil, egg yolk oil, cocoa butter, palm oil, palm kernel oil, owl, palm Examples thereof include oil, beef tallow, pork tallow, and hydrogenated products (hardened oil, etc.) of these fats and oils.

  Examples of the waxes include beeswax, carnauba wax, whale wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, candelilla wax, montan wax, shellac wax, and the like.

  Examples of the mineral oil include liquid paraffin, petrolatum, paraffin, ozokelide, ceresin, microcristan wax, squalene, squalane, and pristane.

  Examples of the fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, 12-hydroxystearic acid, undecylenic acid, tall oil, lanolin fatty acid and other natural fatty acids, isononanoic acid, caproic acid, 2 -Synthetic fatty acids such as ethylbutanoic acid, isopentanoic acid, 2-methylpentanoic acid, 2-ethylhexanoic acid and isopentanoic acid.

  Examples of the alcohols include natural alcohols such as ethanol, isopropyl alcohol, lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol, lanolin alcohol, cholesterol, phytosterol, and synthetic alcohols such as 2-hexyldecanol, isostearyl alcohol, and 2-octyldodecanol. Can be mentioned.

The polyhydric alcohols include ethylene oxide, ethylene glycol, diethylene glycol, triethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, polyethylene glycol, propylene oxide, propylene glycol, polypropylene. Examples include glycol, 1,3-butylene glycol, glycerin, pentaerythritol, sorbitol, and mannitol.

  Examples of the esters include isopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, oleyl oleate, decyl oleate, octyldodecyl myristate, hexyl decyl dimethyloctanoate, cetyl lactate, myristyl lactate , Diethyl phthalate, dibutyl phthalate, lanolin acetate, ethylene glycol monostearate, propylene glycol monostearate, propylene glycol dioleate, and the like.

  Examples of the metal soap include aluminum stearate, magnesium stearate, zinc stearate, calcium stearate, zinc palmitate, magnesium myristate, zinc laurate, and zinc undecylenate.

Examples of the gums, sugars and water-soluble polymer compounds include gum arabic, benzoin rubber, dammar gum, guaiac oil, Irish moss, karaya gum, tragacanth gum, carob gum, quince seed, agar, casein, lactose, fructose, sucrose and esters thereof. , Trehalose and derivatives thereof, dextrin, gelatin, pectin, starch, carrageenan, carboxymethyl chitin or chitosan, hydroxyalkyl (C ₂ -C ₄ ) chitin to which alkylene (C ₂ -C ₄ ) oxide such as ethylene oxide is added or Chitosan, low molecular chitin or chitosan, chitosan salt, sulfated chitin or chitosan, phosphorylated chitin or chitosan, alginic acid and its salt, hyaluronic acid and its salt, chondroitin sulfate and its salt, heparin, ethylcellulose, methyl Loose, carboxymethyl cellulose, carboxyethyl cellulose, sodium carboxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, nitrocellulose, crystalline cellulose, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone, polyvinyl methacrylate, polyacrylate, polyethylene oxide, polypropylene oxide, etc. Polyalkylene oxide or a crosslinked polymer thereof, carboxyvinyl polymer, polyethyleneimine and the like.

  Examples of the surfactant include an anionic surfactant (alkyl carboxylate, alkyl sulfonate, alkyl sulfate ester salt, alkyl phosphate ester salt), cationic surfactant (alkyl amine salt, alkyl quaternary ammonium salt), Amphoteric surfactant: Carboxylic acid type amphoteric surfactant (amino type, betaine type), sulfate ester type amphoteric surfactant, sulfonic acid type amphoteric surfactant, phosphate ester type amphoteric surfactant, nonionic surfactant (Ether type nonionic surfactant, ether ester type nonionic surfactant, ester type nonionic surfactant, block polymer type nonionic surfactant, nitrogen-containing type nonionic surfactant), other surfactants (Natural surfactants, protein hydrolysates, polymer surfactants, surfactants containing titanium and silicon Fluorocarbon surfactant), and the like.

  As the above vitamins, vitamin A group: retinol, retinal (vitamin A1), dehydroretinal (vitamin A2), carotene, lycopene (provitamin A), vitamin B group: thiamine hydrochloride, thiamine sulfate (vitamin B1), Riboflavin (vitamin B2), pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), folic acid, nicotinic acids, pantothenic acids, biotins, choline, inositols, vitamin C group: ascorbic acid and its derivatives, vitamin D group: ergo Calciferol (vitamin D2), cholecalciferol (vitamin D3), dihydrotaxosterol, vitamin E group: tocopherol and its derivatives, ubiquinones, vitamin K group: phytonadione (vitamin K1), menaquinone (vitamin) K2), menadione (vitamin K3), menadiol (vitamin K4), other essential fatty acids (vitamin F), carnitine, ferulic acid, γ-oryzanol, orotic acid, vitamin Ps (rutin, eriocitrin, hesperidin), vitamin U Etc.

  Examples of the amino acids include valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, asparagine, glutamine, serine, cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid, hydroxylysine. , Arginine, ornithine, histidine, and their amino acid derivatives such as sulfate, phosphate, nitrate, citrate, or pyrrolidone carboxylic acid.

  In addition, the external preparation for skin of the present invention may contain a melanin production inhibitor component other than X-keton used for the melanin production inhibitor of the present invention. For example, pantethein-s-sulfonic acid, isoferulic acid, ellag It is also possible to blend one or more of acid, arbutin, kojic acid, linoleic acid, methyl linoleate, 4-butylresorcinol and the like.

  The dosage form of the external preparation for skin of the present invention is not particularly limited, and is usually used in pharmaceuticals, quasi drugs, cosmetics, etc., such as ointments, creams, emulsions, lotions, packs, bath preparations, etc. The dosage form is mentioned.

The amount of the external preparation for skin use of the present invention is appropriately selected depending on the content of the melanin production inhibitor of the present invention, the user's weight, age, sex, symptoms, etc. For example, in the case of cream or ointment, It is preferable to use 5 mg to 50 mg per 1 cm ^{2 of the} layer surface, and it is more preferable to use 10 mg to 30 mg. In the case of a liquid preparation, it is preferable to use 2 mg to 30 mg, more preferably 5 mg to 20 mg per 1 cm ^{2 of} the skin surface.

  The preparation of the external preparation for skin of the present invention can be performed by a known preparation technique.

  EXAMPLES Next, although an Example is given and this invention is demonstrated further more concretely, this invention is not limited to these Examples.

Below, the effect | action of X-keton is demonstrated based on an Example. X-keton used below was synthesized by the method described in Synthesis Example 1 above. Fig. 1 shows the measurement results of the synthesized X-keton with ¹³ C-NMR (67.5 MHz, CDCl ₃ ), Fig. 2 shows the measurement results with ¹ H-NMR (270 MHz, CDCl ₃ ), and Fourier transform red Fig. 3 shows the measurement results with an external spectrophotometer (FT-IR).
In addition, commercially available manurs (trade name Manool, distributor Westchem Industries Inc.) were used.

<Example 1> X-keton suppresses melanin production on pigment cells 1) Preparation of sample solution X-keton and manur were dissolved in dimethyl sulfoxide to prepare a sample solution.
2) Inhibition of melanin production by X-keton 5 × 10 ⁴ B-16 melanoma cells (Dainippon Pharmaceutical Co., Ltd.) were seeded in a plastic culture flask (75 cm ² ) and contained eagle containing 10% serum. Using MEM medium, the cells were cultured at 37 ° C. in a CO ₂ incubator in the presence of 5% carbon dioxide (95% air, 5% carbon dioxide). Two days later, the samples shown in Table 2 were added at concentrations of 10 ⁻⁵ and 10 ⁻⁴ mass% in the medium, and further cultured for 4 days.

After completion of the culture, the medium was removed, washed with phosphate buffered saline (PBS), cells were detached from the flask using trypsin and EDTA-containing medium, and the cells were recovered from the cell suspension by centrifugation. The obtained cells were washed twice with PBS, and the whiteness of the sediment was visually observed. In addition, what added only the said solvent for a sample dissolution (dimethyl sulfoxide) was made into the control | contrast. The observation results were evaluated according to the criteria shown in Table 1 below, and the evaluation results are shown in Table 2.

Thereafter, 1N sodium hydroxide (2 ml) was further added to the precipitate and dissolved by heating. After cooling, chloroform (2 ml) was added and centrifuged again. The absorbance at 400 nm of the obtained supernatant was measured, and the amount of melanin (unit: μg) was determined from a calibration curve prepared in advance using synthetic melanin. The amount of melanin was determined as the amount per 10 ⁴ cells. The results are shown in Table 3.

  In addition, the suppression rate in a table | surface was calculated | required by the following formula 1.

(Formula 1) Inhibition rate (%) = <melanin amount of cells added with solvent for sample lysis (control) −melanin amount of cells added with each sample> × 100 / <cells added with solvent for sample lysis Melanin content (control)>

  As is clear from these results, X-keton showed an effect of remarkably suppressing melanin production in pigment cells as compared with control and manure.

<Example 2> Pigmentation inhibitory action of X-keton Brown guinea pig (Tokyo Experimental Animal Co., Ltd.) used for each experimental group (7 animals each, 21 animals in total)
The back skin of the hair was shaved and shaved with an electric hair clipper and a shaver, and this part was covered with a black cloth having a total of six 1.5 × 1.5 cm irradiation windows for left and right controls. Using a FL20S · E30 lamp (Toshiba Corporation) as a light source, ultraviolet rays of 1 mW / cm 2 / sec were irradiated for 4 minutes and 20 seconds from a position 30 cm from the object.

  This operation was performed once a day for 3 consecutive days. From the day after the completion of irradiation, 20 μl of the sample solution shown in Table 5 (dissolved in ethanol) was applied once a day until the end of the experiment. In addition, the same experiment was conducted using ethanol alone as a control. On the 21st day from the start of the experiment, the degree of pigmentation in the treated area was evaluated by visual observation according to the evaluation criteria shown in Table 4. The results are shown in Table 5 as average values (average values of 7 animals in each experimental group).

  As shown in Table 5, when applied to the skin, X-keton significantly suppressed the production of melanin by ultraviolet rays at a concentration of 0.5% by mass as compared with manur.

  As described above, X-keton used in the present invention has an action of suppressing melanin production and an action of suppressing pigment deposition. As a result, when a certain percentage or more of this is added to the skin external preparation base, it has a markedly excellent fairness effect on the skin. Local pigmentation such as spots, freckles, sunburn, etc., and Mr. Addison It can be used to improve and treat systemic pigmentation such as illness. Moreover, since it is excellent in safety, it can be used for a long time.

  Below, the skin external preparation of this invention is demonstrated based on an Example. In addition, the compounding quantity in a following example is a mass part.

<Example 3> Oil-in-water cream POE (30) cetostearyl ether 2.0 parts by weight Glycerol monostearate 10.0 parts by weight Liquid paraffin 10.0 parts by weight Vaseline 4.0 parts by weight Cetanol 5.0 parts by weight γ-tocopherol 0.05 parts by weight BHT 0 .01 parts by mass Butylparaben 0.1 parts by mass X-keton 0.2 parts by mass Propylene glycol 10.0 parts by weight Purified water 58.64 parts by weight

1) Manufacturing method of external preparation for skin of the present invention (oil-in-water cream) The components A and B were mixed and heated to 80 ° C. These were added, stirred and emulsified, and then cooled to obtain an oil-in-water cream.

2) Pigmentation improving effect of the external preparation for skin of the present invention The cream (Example 3) obtained above and Comparative Example 1 in which X-keton was replaced with Manur in Example 3 and X- in Example 3 A control group in which keton was replaced with water was used for 60 months in a statistically equivalent manner for a group of women suffering from black, dark spots, and freckles, and the pigmentation improving effect was evaluated. The results are shown in Table 6.

  As is apparent from these results, the external preparation for skin of the present invention is a pigment that is much more effective than Comparative Example 1 in which manure is blended instead of X-keton and the control in which water is blended in place of X-keton. It was shown to have an effect of improving deposition. In the application site of the cream of the present invention (Example 3), no undesirable reaction was observed on the skin.

<Example 4> Emulsion A. Synthetic gallow 2.0 parts by weight Cetanol 1.0 part by weight Squalane 4.0 parts by weight Stearic acid 1.0 part by weight POE (25) monostearic acid 2.2 parts by weight Glycerin monostearate 0.5 part by weight Butylparaben 0 .1 part by weight γ-tocopherol 0.05 part by weight BHT 0.01 part by weight X-keton 1.0 part by weight 1,3-butylene glycol 3.0 parts by mass Propylene glycol 7.0 parts by mass Caustic potash 0.2 parts by mass Purified water 77.44 parts by mass

1) Manufacturing method of skin external preparation (milky lotion) of this invention The component of A and B was melt | dissolved, stirring each at 70 degreeC. The component A was added to the component B, preliminarily emulsified, and uniformly emulsified with a homomixer. After emulsification, the mixture was cooled to 30 ° C. with stirring to obtain an emulsion.

<Example 5> Emulsion A. Synthetic gallows 2.5 parts by weight Cetanol 1.0 parts by weight Squalane 4.0 parts by weight Stearic acid 1.0 parts by weight POE (25) monostearic acid 2.2 parts by weight Glycerin monostearate 0.5 parts by weight Butylparaben 0 .1 part by weight γ-tocopherol 0.05 part by weight BHT 0.01 part by weight X-keton 0.5 part by weight 1,3-butylene glycol 3.0 parts by mass Propylene glycol 7.0 parts by mass Caustic potash 0.2 parts by mass Purified water 77.94 parts by mass

1) Manufacturing method of skin external preparation (milky lotion) of this invention The component of A and B was melt | dissolved, stirring each at 70 degreeC. The component A was added to the component B, preliminarily emulsified, and uniformly emulsified with a homomixer. After emulsification, the mixture was cooled to 30 ° C. with stirring to obtain an emulsion.

<Example 6> Lotion A. POE (20) sorbitan monolaurate 1.5 parts by mass POE (20) monolaurate 0.5 parts by mass Ethanol 10.0 parts by mass γ-tocopherol 0.02 parts by mass X-keton 0.1 parts by mass B. Glycerin 5.0 parts by mass Propylene glycol 4.0 parts by mass Citric acid 0.15 parts by mass Sodium citrate 0.1 parts by mass Purified water 78.63 parts by mass

1) Manufacturing method of external preparation for skin (skin lotion) of the present invention The components of A were combined and dissolved at room temperature. On the other hand, each component of B was also dissolved at room temperature, and this was added to the component A to solubilize to obtain a lotion.

<Example 7> Packing fee A.1. Polyvinyl alcohol 15.0 parts by mass Purified water 40.0 parts by mass Bisabolol 0.5 parts by mass γ-tocopherol 0.02 parts by mass Ethanol 4.0 parts by mass 1,3-butylene glycol 4.0 parts by mass POE (8) POP (55) 3.0 parts by mass X-keton 3.0 Parts by mass purified water 30.48 parts by mass

1) Manufacturing method of external preparation for skin (packing material) of the present invention The component A was dispersed and dissolved at room temperature. The component B was added thereto and dissolved uniformly to obtain a pack material.

<Example 8> Oil-in-water cream POE (30) cetyl ether 2.0 parts by mass Glycerin monostearate 10.0 parts by weight Liquid paraffin 10.0 parts by weight Vaseline 4.0 parts by weight Cetanol 5.0 parts by weight γ-tocopherol 0.05 parts by weight BHT 0. 01 parts by mass Butylparaben 0.1 parts by mass X-keton 0.01 parts by mass Propylene glycol 10.0 parts by weight Purified water 58.83 parts by weight

1) Manufacturing method of external preparation for skin of the present invention (oil-in-water cream) The components A and B were mixed and heated to 80 ° C. These were added, stirred and emulsified, and then cooled to obtain an oil-in-water cream.

The measurement result by ¹³ C-NMR (67.5 MHz, CDCl ₃ ) of X-keton synthesized by the method described in Synthesis Example 1. The measurement result by ¹ H-NMR (270 MHz, CDCl ₃ ) of X-keton synthesized by the method described in Synthesis Example 1. The measurement result by the Fourier-transform infrared spectrophotometer (FT-IR) of X-keton synthesize | combined by the method of the synthesis example 1. FIG.

Claims (2)

Melanin production inhibitor consisting of 13-oxo-14,15-dinol-8 (17) -labdane (13-oxo-14,15-dinor-8 (17) -labdane) represented by the following formula (I).

  It is a skin external preparation, Comprising: 0.0001-10 mass% of melanin production inhibitors of Claim 1 are contained with respect to the said skin external preparation whole quantity, The skin external preparation characterized by the above-mentioned.

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