WO2012108410A1 - 皮膚コラーゲン産生促進剤 - Google Patents
皮膚コラーゲン産生促進剤 Download PDFInfo
- Publication number
- WO2012108410A1 WO2012108410A1 PCT/JP2012/052690 JP2012052690W WO2012108410A1 WO 2012108410 A1 WO2012108410 A1 WO 2012108410A1 JP 2012052690 W JP2012052690 W JP 2012052690W WO 2012108410 A1 WO2012108410 A1 WO 2012108410A1
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- WO
- WIPO (PCT)
- Prior art keywords
- tgf
- collagen production
- skin
- skin collagen
- degradation product
- Prior art date
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- A—HUMAN NECESSITIES
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K2800/74—Biological properties of particular ingredients
Definitions
- the present invention relates to a skin collagen production promoter useful for preventing skin deterioration such as roughening, wrinkles, and a decrease in elasticity, a food and drink for promoting skin collagen production, and a cosmetic for promoting skin collagen production. More specifically, the present invention relates to a skin collagen production promoter comprising as an active ingredient a TGF- ⁇ degradation product obtained by degrading transforming growth factor beta (TGF- ⁇ ) and / or TGF- ⁇ with a proteolytic enzyme. .
- TGF- ⁇ transforming growth factor beta
- Collagen can also retain moisture in its molecules, thereby helping to keep the skin moist, and when the collagen is destroyed by external factors, the skin becomes dry. And it becomes rough. From the above, it is possible to prevent skin wrinkles and sagging by promoting the biosynthesis of collagen, which is one of the main components of the dermis layer, and there is no problem in terms of safety. It was desired.
- TGF- ⁇ Transforming growth factor beta
- TGF- ⁇ Transforming growth factor beta
- Patent Document 1 An action of inducing differentiation in animal cells has been confirmed.
- Patent Document 1 In skin, it has been reported as a growth factor for fibroblasts (Non-patent Document 1).
- An object of the present invention is to provide a skin collagen production promoter having no problem in terms of safety. Moreover, this invention makes it a subject to provide the food-drinks for skin collagen production promotion which mix
- TGF- ⁇ or TGF- ⁇ thereof was It has been found that a TGF- ⁇ degradation product obtained by degradation increases the amount of collagen in the skin, and the present invention has been completed.
- the present invention includes the following aspects.
- a skin collagen production promoter comprising TGF- ⁇ and / or a TGF- ⁇ degradation product as an active ingredient.
- the proteolytic enzyme is any one or more selected from trypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8 protease. Collagen production promoter.
- TGF- ⁇ degradation product has an average molecular weight of 500 or more and 8000 or less.
- a food / beverage product for promoting skin collagen production comprising the TGF- ⁇ and / or TGF- ⁇ degradation product according to any one of (1) to (4).
- a cosmetic for promoting skin collagen production comprising the TGF- ⁇ and / or TGF- ⁇ degradation product according to any one of (1) to (4).
- proteolytic enzyme is any one or more selected from trypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8 protease.
- Method for promoting collagen production (12) The method for promoting skin collagen production according to any one of (9) to (11), wherein the TGF- ⁇ degradation product has an average molecular weight of 500 or more and 8000 or less.
- TGF- ⁇ degradation product is obtained by degrading TGF- ⁇ with a proteolytic enzyme.
- proteolytic enzyme is any one or more selected from trypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8 protease. Deterioration prevention or improvement method.
- TGF- ⁇ degradation product has an average molecular weight of 500 or more and 8000 or less.
- An agent for preventing or improving skin deterioration comprising TGF- ⁇ and / or a TGF- ⁇ degradation product as an active ingredient.
- the proteolytic enzyme is any one or more selected from trypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8 protease. Deterioration preventing or improving agent.
- a skin collagen production promoter a skin collagen production promoting food and drink, and a skin collagen production promoting cosmetic comprising TGF- ⁇ and / or a TGF- ⁇ degradation product as an active ingredient.
- the skin collagen production promoter, skin collagen production promoting food and drink, and skin collagen production promoting cosmetic of the present invention have an action of promoting skin collagen production and prevent skin wrinkles and sagging, dryness and rough skin. Useful for treatment.
- the skin collagen production promoter of the present invention is characterized in that TGF- ⁇ and / or TGF- ⁇ degradation product obtained by degrading TGF- ⁇ with a proteolytic enzyme is an active ingredient.
- the TGF- ⁇ of the present invention can be used from any origin.
- human and bovine-derived TGF- ⁇ has already been clarified in gene sequence and can be produced by gene recombination.
- TGF- ⁇ produced by genetic engineering techniques is also used. Is possible.
- TGF- ⁇ is contained in a relatively large amount in bovine colostrum and may be recovered from milk.
- TGF- ⁇ can be recovered from the culture medium of cell culture, and even those derived from such cells can be used.
- TGF- ⁇ derived from milk can be produced according to a known method (see, for example, J. Protein Chem., Vol.10, p565-575, 1991).
- Raw milk, powdered milk, skim milk, TGF- ⁇ is obtained from reduced milk or other processed milk by appropriately combining heat treatment, salting treatment, ethanol treatment, various chromatographic treatments such as ion exchange chromatography and gel filtration chromatography, and ultrafiltration treatment. be able to.
- the TGF- ⁇ degradation product was obtained by restricting TGF- ⁇ with a proteolytic enzyme such as trypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8 protease so that the average molecular weight was 8,000 or less. It is possible to use peptide mixtures. However, the lower limit of the average molecular weight is preferably 500 or more.
- the average molecular weight of the TGF- ⁇ degradation product is 500 to 8000, 1500 to 8000, 2500 to 8000, 3500 to 8000, 4500 to 8000, 5500 to 8000, 6500 to 8000, 7500 to 8000.
- the skin collagen production promoter of the present invention exhibits an effect of promoting skin collagen production by oral administration or application.
- the active ingredient TGF- ⁇ or a TGF- ⁇ degradation product can be used as it is, but according to conventional methods, powders, granules, tablets In addition, it can be formulated into oral preparations such as capsules and drinks.
- oral preparations such as powders, granules, tablets and capsules are formulated by conventional methods using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts. It becomes.
- binders such as starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, sodium carboxymethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, and polyvinylpyrrolidone.
- disintegrant examples include starch, hydroxypropyl starch, carboxymethylcellulose, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, and crystalline cellulose.
- TGF- ⁇ and TGF- ⁇ degradation products can be used as they are or after preparation, and then blended with nutrients, foods and drinks. Further, if TGF- ⁇ or a TGF- ⁇ degradation product is blended together with components such as vitamin C which are conventionally considered to have an effective action for collagen production, further skin collagen production promoting action can be expected. Since TGF- ⁇ or TGF- ⁇ degradation products are relatively stable to heat, it is possible to heat sterilize raw materials containing TGF- ⁇ or TGF- ⁇ degradation products under normal conditions. It is.
- the skin collagen production promoter of the present invention When applying the skin collagen production promoter of the present invention, it is prepared into various dosage forms such as a liquid agent, a solid agent, a semi-solid agent, etc., by blending with commonly used known components according to the purpose of use.
- Preferred compositions include ointments, gels, creams, sprays, patches, lotions, powders and the like.
- the skin collagen production promoter of the present invention is a hydrocarbon such as petrolatum, higher fatty acid lower alkyl esters such as stearyl alcohol, isopropyl myristate, animal fats such as lanolin, polyhydric alcohols such as glycerin, glycerin fatty acid esters, mono Cosmetics for promoting skin collagen production by mixing with surfactants such as stearic acid and polyethylene glycol, inorganic salts, waxes, resins, water and, if necessary, preservatives such as methyl paraoxybenzoate and butyl paraoxybenzoate And can produce medicines.
- surfactants such as stearic acid and polyethylene glycol
- inorganic salts such as stearic acid and polyethylene glycol
- waxes such as stearic acid and polyethylene glycol
- preservatives such as methyl paraoxybenzoate and butyl paraoxybenzoate And can produce medicines.
- the effective amount of the skin collagen production promoter of the present invention by oral administration is appropriately defined by the formulation form, administration method, purpose of use, and age, weight, and medical condition of the patient to which it is applied, but is not constant. According to the results of animal experiments, it was found that in order to show an action for promoting skin collagen production, an effect can be expected by ingesting 10 ⁇ g or more of TGF- ⁇ and / or TGF- ⁇ degradation product per 1 kg of rat body weight. Therefore, according to the extrapolation method, an effect can be expected by ingesting 10 ⁇ g or more of TGF- ⁇ and / or a TGF- ⁇ degradation product per adult per day. Or it may be administered as a medicine. The administration can be divided into several times a day as necessary.
- the effective amount by application of the skin collagen production promoter of the present invention varies depending on the dosage form, but is preferably 0.001 to 2% by weight based on the total amount of the composition to be applied, and TGF- ⁇ and / or Alternatively, a TGF- ⁇ degradation product may be blended. However, what is diluted at the time of use like a bath agent can increase a compounding quantity further.
- TGF- ⁇ was again fractionated by phenyl S Sepharose hydrophobic column chromatography. Further, this fraction was sequentially treated by C4 and C8 reverse phase chromatography and gel filtration chromatography using an HPLC system to obtain 412 mg of TGF- ⁇ (fraction A).
- the TGF- ⁇ thus obtained can be used as it is as a skin collagen production promoter.
- TGF- ⁇ degradation product Fraction A 25 mg obtained in Example 1 was suspended in 100 ml of water, pancreatin was added to a final concentration of 1%, and enzyme treatment was performed at 37 ° C. for 5 minutes to 6 hours. Then, the enzyme was inactivated by heat treatment at 90 ° C. for 5 minutes and then freeze-dried to obtain 24 mg of TGF- ⁇ degradation product (fractions B, C, D). The average molecular weight of the TGF- ⁇ degradation product thus obtained was about 8,000 for B, about 500 for C, and about 300 for D. Fractions B and C can be used as a skin collagen production promoter as they are.
- Example 1 For the fraction A obtained in Example 1 and the fractions B to D obtained in Example 2, the collagen production promoting action was examined by an animal experiment using rats. 7-week-old Wistar male rats were treated with a physiological saline administration group (control group), and the fraction A obtained in Example 1 was administered at 10 ⁇ g per kg body weight of the rat (Group A-1).
- the group in which 100 ⁇ g of the obtained fraction A was administered per kg body weight of the rat (group A-2), and the fractions B to D obtained in Example 2 were administered in the amount of 10 ⁇ g per kg of body weight of the rat (B-1 to D- 1 group), and fractions B to D obtained in Example 2 were divided into 9 test groups (n 6) in groups (B-2 to D-2 groups) administered with 100 ⁇ g / kg of rat body weight, Orally administered once with a sonde and reared for 10 weeks.
- the rat dermis was treated according to the method of Nimni et al. (See Arch. Biochem.
- hydroxyproline is a special amino acid contained only in collagen and accounts for about 10% of all amino acids constituting collagen, so that the amount of collagen can be estimated (see Takashi Asano et al., Bio Industry, p. 12, 2001). The results are shown in Table 1.
- TGF- ⁇ and a TGF- ⁇ degradation product having an average molecular weight of 500 or more and 8000 or less have a skin collagen production promoting action, and are shown to be useful as a skin collagen production promoter. It was. It was also revealed that this skin collagen production promoting action was observed when TGF- ⁇ or a TGF- ⁇ degradation product was administered at a minimum of 10 ⁇ g / kg rat body weight.
- Example 2 For the fraction A obtained in Example 1 and the fraction B obtained in Example 2, the skin was obtained by an experiment using a normal human fibroblast cell line [CCD45SK (ATCCRL 1506) collected from the skin of a white female]. Collagen production promoting action was examined. 10 volume% fetal bovine serum (hereinafter FBS hereinafter) containing modified Eagle's medium (MEM, 10-101, manufactured by Dainippon Pharmaceutical Co., Ltd.) using, 4 ⁇ 10 4 pieces of normal human fibroblast cell line / well / 0 After seeding in a 24-well plate so as to be 4 ml and culturing at 37 ° C.
- FBS fetal bovine serum
- MEM modified Eagle's medium
- TGF- ⁇ and the TGF- ⁇ degradation product were added was more than twice as effective in promoting collagen production as the group to which TGF- ⁇ and the TGF- ⁇ degradation product were not added (control). showed that. From this, it became clear that TGF- ⁇ and TGF- ⁇ degradation products act on skin fibroblasts and promote collagen production, indicating that they are useful as skin collagen production promoters. .
- a skin collagen production promoting beverage having the composition shown in Table 3 was produced by a conventional method.
- the flavor of the manufactured beverage was good, and the flavor did not deteriorate even after storage at room temperature for 1 year, and there was no problem such as precipitation.
- a dough having the composition shown in Table 4 was prepared and molded by a conventional method, and then baked to produce a biscuit for promoting skin collagen production.
- a skin collagen production promoter having the composition shown in Table 5 was produced by a conventional method.
- a lotion having the composition shown in Table 6 was produced by a conventional method.
- a cream having the composition shown in Table 7 was produced by a conventional method.
- Example 3 Using the lotion obtained in Example 6 and the cream obtained in Example 7, an actual use test was conducted.
- a comparative product the same formulation as in Examples 6 and 7 was used except that TGF- ⁇ and TGF- ⁇ degradation product were removed.
- 20 adult women with dry skin where facial sagging and fine wrinkles are recognized, 10 each at random, 2 groups (E, F group), 20 women with rough skin on the hands, respectively 10 people randomly divided into 2 groups (G, H group), 2g of the product of the present invention on the face of group E, 2g of the comparison product on the face of group F, and fingers of group G 2g of the cream of the present invention and 2g of the comparative cream were applied to the fingers of the H group twice a day for 10 days in the same manner as in normal use.
- the results are shown in Table 8.
Abstract
Description
(1)TGF-β及び/又はTGF-β分解物を有効成分とする皮膚コラーゲン産生促進剤。
(2)前記TGF-β分解物が、TGF-βをタンパク質分解酵素で分解して得られたものであることを特徴とする(1)記載の皮膚コラーゲン産生促進剤。
(3)前記タンパク質分解酵素が、トリプシン、パンクレアチン、キモトリプシン、ペプシン、パパイン、カリクレイン、カテプシン、サーモライシン、V8プロテアーゼから選択されるいずれか1種以上であることを特徴とする(2)記載の皮膚コラーゲン産生促進剤。
(4)前記TGF-β分解物が、平均分子量500以上、8000以下であることを特徴とする(1)~(3)のいずれかに記載の皮膚コラーゲン産生促進剤。
(5)(1)~(4)のいずれかに記載のTGF-β及び/またはTGF-β分解物を配合した皮膚コラーゲン産生促進用飲食品。
(6)(1)~(4)のいずれかに記載のTGF-β及び/またはTGF-β分解物を配合した皮膚コラーゲン産生促進用化粧料。
(7)TGF-β及び/又はTGF-β分解物を経口摂取又は塗布することによる肌質の改善方法。
(8)TGF-β及び/又はTGF-β分解物を1日あたり10μg以上経口摂取するか、又は0.001~2重量%になるよう塗布することによる肌質の改善方法。
(9)TGF-β及び/又はTGF-β分解物を投与することを含む皮膚コラーゲン産生促進方法。
(10)前記TGF-β分解物が、TGF-βをタンパク質分解酵素で分解して得られたものであることを特徴とする(9)記載の皮膚コラーゲン産生促進方法。
(11)前記タンパク質分解酵素が、トリプシン、パンクレアチン、キモトリプシン、ペプシン、パパイン、カリクレイン、カテプシン、サーモライシン、V8プロテアーゼから選択されるいずれか1種以上であることを特徴とする(10)記載の皮膚コラーゲン産生促進方法。
(12)前記TGF-β分解物が、平均分子量500以上、8000以下であることを特徴とする(9)~(11)のいずれかに記載の皮膚コラーゲン産生促進方法。
(13)TGF-β及び/又はTGF-β分解物を投与することを含む皮膚劣化防止又は改善方法。
(14)前記TGF-β分解物が、TGF-βをタンパク質分解酵素で分解して得られたものであることを特徴とする(13)記載の皮膚劣化防止又は改善方法。
(15)前記タンパク質分解酵素が、トリプシン、パンクレアチン、キモトリプシン、ペプシン、パパイン、カリクレイン、カテプシン、サーモライシン、V8プロテアーゼから選択されるいずれか1種以上であることを特徴とする(14)記載の皮膚劣化防止又は改善方法。
(16)前記TGF-β分解物が、平均分子量500以上、8000以下であることを特徴とする(13)~(15)のいずれかに記載の皮膚劣化防止又は改善方法。
(17)TGF-β及び/又はTGF-β分解物を有効成分とする皮膚劣化防止又は改善剤。
(18)前記TGF-β分解物が、TGF-βをタンパク質分解酵素で分解して得られたものであることを特徴とする(17)記載の皮膚劣化防止又は改善剤。
(19)前記タンパク質分解酵素が、トリプシン、パンクレアチン、キモトリプシン、ペプシン、パパイン、カリクレイン、カテプシン、サーモライシン、V8プロテアーゼから選択されるいずれか1種以上であることを特徴とする(18)記載の皮膚劣化防止又は改善剤。
(20)前記TGF-β分解物が、平均分子量500以上、8000以下であることを特徴とする(17)~(19)のいずれかに記載の皮膚劣化防止又は改善剤。
(21)(17)~(20)のいずれかに記載のTGF-β及び/またはTGF-β分解物を配合した皮膚劣化防止又は改善用飲食品。
(22)(17)~(20)のいずれかに記載のTGF-β及び/またはTGF-β分解物を配合した皮膚劣化防止又は改善用化粧料。
(23)TGF-β及び/又はTGF-β分解物を経口摂取又は塗布することによる純粋に美容目的の肌質の改善方法。
(24)TGF-β及び/又はTGF-β分解物を1日あたり10μg以上経口摂取するか、又は0.001~2重量%になるよう塗布することによる純粋に美容目的の肌質の改善方法。
さらには、これらのTGF-βやTGF-β分解物をそのままあるいは製剤化した後、これを栄養剤や飲食品等に配合することも可能である。また、ビタミンC等の従来からコラーゲン産生に有効な作用を持つと考えられている成分とともにTGF-βやTGF-β分解物を配合すれば、一層の皮膚コラーゲン産生促進作用が期待できる。なお、TGF-βあるいはTGF-β分解物は、比較的熱に対して安定であるので、TGF-βあるいはTGF-β分解物を含む原料を通常行われるような条件で加熱殺菌することも可能である。
実施例1で得られた画分A及び実施例2で得られた画分B乃至Dについて、ラットを用いた動物実験によりコラーゲン産生促進作用を調べた。7週齢のWistar系雄ラットを、生理食塩水投与群(コントロール群)、実施例1で得られた画分Aをラット体重1kg当たり10μg投与する群(A-1群)、実施例1で得られた画分Aをラット体重1kg当たり100μg投与する群(A-2群)、実施例2で得られた画分B乃至Dをラット体重1kg当たり10μg投与する群(B-1~D-1群)、実施例2で得られた画分B乃至Dをラット体重1kg当たり100μg投与する群(B-2~D-2群)の9試験群(n=6)に分け、それぞれを毎日1回ゾンデで経口投与して10週間飼育した。皮膚のコラーゲン量については、ラットの真皮をNimniらの方法(Arch. Biochem. Biophys., 292頁, 1967年 参照)に準じて処理した後、可溶性画分に含まれるヒドロキシプロリン量を測定した。ヒドロキシプロリンはコラーゲンのみに含まれる特殊なアミノ酸で、コラーゲンを構成する全アミノ酸の約10%を占めることからコラーゲン量の推定ができる(浅野隆司ら,Bio Industory,12頁, 2001年 参照)。その結果を表1に示す。
実施例1で得られた画分A及び実施例2で得られた画分Bについて、正常ヒト線維芽細胞株〔白人女性の皮膚より採取されたCCD45SK(ATCCRL 1506)〕を用いた実験により皮膚コラーゲン産生促進作用を調べた。10容量%ウシ胎児血清(以下FBSと略記)含有変法イーグル培地(MEM、10‐101、大日本製薬社製)を用いて、正常ヒト線維芽細胞株を4×104個/ウエル/0.4mlとなるように24ウエルプレートに播種して、5%炭酸ガス、飽和水蒸気下、37℃で24時間培養した後、0.6容量%FBS含有MEM培地に置換した。そして、実施例1で得られた画分A及び実施例2で得られた画分Bを、各ウエルに0.1容量%となるように添加(n=6)して、24時間培養した後、β-アミノプロピオニトリルを50μg/ml、トリチウム-L-プロリンを1μCi/mlとなるように添加して、さらに24時間培養して培養液を得た。このようにして得られた培養液より、Websterらの方法(Analytical Biochemistry,220頁,1979年 参照)に従いコラーゲン画分を分画し、コラーゲン画分に取り込まれた放射能を測定した。なお、対照として、TGF-β及びTGF-β分解物を添加しないで同様の試験を行った。その結果を表2に示す。
実施例6で得られた化粧水及び実施例7で得られたクリームを用いて、実使用テストを行った。比較品としては、TGF-β及びTGF-β分解物を除いた以外は実施例6及び7と同じ配合のものを用いた。顔面のたるみや小ジワが認められる乾燥肌を有する成人女性20人を、それぞれ10人ずつ無作為に2群(E、F群)に、また、手に肌荒れが認められる女性20人を、それぞれ10人ずつ無作為に2群(G、H群)に分け、E群の顔面には本発明品の化粧水2gを、F群の顔面には比較品の化粧水2gを、G群の手指には本発明品のクリーム2gを、H群の手指には比較品のクリーム2gを、それぞれ1日2回通常の使用状態と同様に10日間塗布した。結果を表8に示す。
Claims (8)
- TGF-β及び/又はTGF-β分解物を有効成分とする皮膚コラーゲン産生促進剤。
- 前記TGF-β分解物が、TGF-βをタンパク質分解酵素で分解して得られたものであることを特徴とする請求項1記載の皮膚コラーゲン産生促進剤。
- 前記タンパク質分解酵素が、トリプシン、パンクレアチン、キモトリプシン、ペプシン、パパイン、カリクレイン、カテプシン、サーモライシン、V8プロテアーゼから選択されるいずれか1種以上であることを特徴とする請求項2記載の皮膚コラーゲン産生促進剤。
- 前記TGF-β分解物が、平均分子量500以上、8000以下であることを特徴とする請求項1~3のいずれかに記載の皮膚コラーゲン産生促進剤。
- 請求項1~4のいずれかに記載のTGF-β及び/またはTGF-β分解物を配合した皮膚コラーゲン産生促進用飲食品。
- 請求項1~4のいずれかに記載のTGF-β及び/またはTGF-β分解物を配合した皮膚コラーゲン産生促進用化粧料。
- TGF-β及び/又はTGF-β分解物を経口摂取又は塗布することによる肌質の改善方法。
- TGF-β及び/又はTGF-β分解物を1日あたり10μg以上経口摂取するか、又は0.001~2重量%になるよう塗布することによる肌質の改善方法。
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JP2012188384A (ja) | 2011-03-10 | 2012-10-04 | Snow Brand Milk Products Co Ltd | 美肌剤 |
JP2013079216A (ja) | 2011-10-04 | 2013-05-02 | Snow Brand Milk Products Co Ltd | 感覚改善剤 |
KR102021764B1 (ko) * | 2013-05-03 | 2019-09-18 | (주)아모레퍼시픽 | 진세노사이드 Rh4를 함유하는 피부 외용제 조성물 |
JP6332941B2 (ja) * | 2013-11-01 | 2018-05-30 | 株式会社東洋発酵 | 美容健康用経口組成物 |
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