JPS6299315A

JPS6299315A - Skin cosmetic

Info

Publication number: JPS6299315A
Application number: JP24031385A
Authority: JP
Inventors: Tadatake Ogawa; 小川　忠丈
Original assignee: Kanebo Ltd
Current assignee: Kanebo Ltd
Priority date: 1985-10-25
Filing date: 1985-10-25
Publication date: 1987-05-08

Abstract

PURPOSE:A skin cosmetic, obtained by incorporating at least one tetrapeptide in a skin cosmetic base and having improved humectant and skin beautifying effect, etc. CONSTITUTION:A skin cosmetic, obtained by incorporating at least one tetrapeptide expressed by the formula (Arg is arginine; Pro is proline; Phe is phenylalanine; n is 1-3; - is peptide bond) in a skin cosmetic base and having skin roughening improving, keratin improving and skin beautifying effect, etc. Mono- - trimers of the tetrapeptide are obtained by initially coupling phenylalanine to proline, eliminating N-terminal protecting group from the resultant product, further coupling the resultant product with arginine, eliminating the N-terminal protecting group from the product, hydrogenating the product and eliminating the C-terminal protecting group.

Description

【発明の詳細な説明】（発明の分野）本発明は皮膚化粧料に関する。更に詳しくは、保湿効果
（荒れ肌改善効果、角質改善効果）、美肌効果等の優れ
た皮膚化粧料に関する。DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to skin cosmetics. More specifically, the present invention relates to skin cosmetics that have excellent moisturizing effects (improving rough skin, improving keratin), beautifying skin, and the like.

（従来技術）従来皮ＩＮ化粧料に配合される生理活性物質は天然抽出
物が多く必要な量の生理活性物質を得る為に多量の動植
物が必要であった。近年ペプチドの合成技術が進歩し１
０個程度のアミノ酸からなるペプチドは９０％前後の高
い収率で合成が５ＪＤｅになった。しかしながら生理活
性を示すペプチドは数少なく、さらに皮膚化粧料に配合
して優れた効果を出現するものの探索は困難であった。(Prior Art) Conventionally, the physiologically active substances blended into skin-in cosmetics are mostly natural extracts, and in order to obtain the necessary amount of physiologically active substances, large amounts of plants and animals are required. In recent years, advances in peptide synthesis technology1
A peptide consisting of about 0 amino acids was synthesized into 5JDe with a high yield of around 90%. However, there are only a few peptides that exhibit physiological activity, and it has been difficult to find peptides that can be incorporated into skin cosmetics to produce excellent effects.

（発明の開示）本発明者は、多数のペプチドの生理活性を鋭意研究した
結果、皮膚化粧料基剤の中にアルギニン。(Disclosure of the Invention) As a result of intensive research on the physiological activities of a large number of peptides, the present inventor discovered arginine in a skin cosmetic base.

プロリン、フェニルアラニン、フェニルアラニンの順に
結合してなるテトラペプチドの１〜３喰体〔以下、（Ａ
ｒｇ−Ｐ　ｒｏ　−Ｐｈｅ　−Ｐｈｅ　）　１−Ｂと略
記する〕の少なくとも１つを配合することにより優れた
保湿効果（荒れ肌改善効果、角質改善効果）、美肌効果
等を発現する皮膚化粧料が得られることを見出し、本発
明を完成した。1 to 3 tetrapeptides formed by bonding proline, phenylalanine, and phenylalanine in this order [hereinafter referred to as (A
By blending at least one of rg-Pro-Phe-Phe) (abbreviated as 1-B), a skin cosmetic that exhibits excellent moisturizing effects (improving rough skin, keratin improving effects), beautifying skin, etc. can be obtained. The present invention was completed based on this discovery.

（発明の目的）即ち本発明は優れた保湿効果（荒れ肌改善効果、角質改
善効果）、美肌効果等を有する皮膚化粧料を提供するに
ある。(Objective of the Invention) That is, the present invention provides a skin cosmetic having excellent moisturizing effects (improving effects on rough skin and improving keratin), beautifying skin, and the like.

（発明の構成）本発明は、一般式（Ａｒｇ−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ　）Ｈ（式中、Ａｒ
ｇはアルギニン、Ｐｒｏ−Ｐｈｅはフェニルアラニン、
ｎは１〜３の整数、−はペプチド結合を表わす。）で表わされるテトラペプチドの少なくとも１つを皮膚化
粧料基剤に配合してなる皮膚化粧料である。(Structure of the Invention) The present invention provides a general formula (Arg-Pro-Phe-Phe)H (wherein Ar
g is arginine, Pro-Phe is phenylalanine,
n represents an integer of 1 to 3, and - represents a peptide bond. ) A skin cosmetic product comprising at least one of the tetrapeptides represented by:

（構成の具体的な説明）本発明に用いるテトラペプチドの１〜３量体の製法は例
えば以下の通りである。〔アグリカルチャラル・バイオ
ロジカル・ケミストリー第４９巻、１０１９〜１０２６
ページ、及び１８２９〜１８８７ページ（Ａｇｒｉｃ、
　Ｂｉｏｌ、　Ｃｈｅｍ、　Ｖｏ１４９．１０１９〜１
０２６゜１８２９〜１８３７　）参照〕実験例−１（第１表参照）（１）　　カップリング（プロリン）ｔ−ブトキシカルボニルプロリン（以下ｌ３ｏｃ　−Ｐ
ｒＯ−ＯＨのごとく略記する）　２　ｍｍｏｌ　、　　
０．３６　ｆをアセトニトリル１０ｇ／とＮ−メチルモ
ルフォリン（ＮＭＭ）　　２　ｍｍｏｌ　、　　０．２
２　ｙｘｌ中に溶解した溶液を一５°Ｃに冷して、エチ
ルクロロフォルメート（ＥＯＦ　）　２　ｍｍｏｌ　、
　　０．２　ｙｘｌを加えた。１０分後ジフェニルアラ
ニンのベンジルエステル塩酸塩（Ｈ−Ｐｈｅ−Ｐｈｅ−
ＯＢｚｌ　・ＨＣｌ）　２　ｍｍｏｌ　、　　０．８４
９と、ＮＭＭ　２　ｍｍｏｌ、　　０．２２ｍｌのＮ、
Ｎ−ジメチルホルムアマイド（ＤＭＦ）溶液１０ＩＩｌ
を添加した。反応液を水槽中にて１時間撹拌した後、１
夜室温に静置した。凍結乾燥後油性残渣を酢酸エチルに
溶解した。この溶液を順次、水、４％クエン酸水溶液、
４％炭酸水素ナトリウム水溶液、水によって洗浄し、無
水硫酸ナトリウムを用いて乾燥した。硫酸ナトリウムは
濾過により除去し、濾液を減圧蒸留し油性残渣のｔ−ブ
トキシカルボニルプロリンジフェニルアラニンのベンジ
ルエステル（Ｂｏａ−Ｐｒ。(Specific explanation of the structure) The method for producing the tetrapeptide mono-trimer used in the present invention is, for example, as follows. [Agricultural Biological Chemistry Volume 49, 1019-1026
Pages 1829-1887 (Agric,
Biol, Chem, Vo149.1019~1
026゜1829-1837)] Experimental example-1 (see Table 1) (1) Coupling (proline) t-butoxycarbonylproline (hereinafter l3oc -P
(abbreviated as rO-OH) 2 mmol,
0.36 f acetonitrile 10 g/and N-methylmorpholine (NMM) 2 mmol, 0.2
2 mmol of ethyl chloroformate (EOF), dissolved in 2 yxl and cooled to -5°C.
0.2 yxl was added. After 10 minutes, benzyl ester hydrochloride of diphenylalanine (H-Phe-Phe-
OBzl ・HCl) 2 mmol, 0.84
9, 2 mmol of NMM, 0.22 ml of N,
N-dimethylformamide (DMF) solution 10IIl
was added. After stirring the reaction solution in a water tank for 1 hour,
It was left to stand at room temperature overnight. The oily residue after lyophilization was dissolved in ethyl acetate. This solution was sequentially mixed with water, 4% citric acid aqueous solution,
It was washed with a 4% aqueous sodium bicarbonate solution and water, and dried using anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was distilled under reduced pressure to produce an oily residue, benzyl ester of t-butoxycarbonylproline diphenylalanine (Boa-Pr).

−Ｐｈｅ　−Ｐｈｅ　−０Ｂｚｌ　）を１．０６１Ｊた
（収率８８％）。-Phe -Phe -0Bzl) was 1.061 J (yield 88%).

（２）Ｎ末端保護基の脱離上記生成物１．５　ｍｍｏｌ、　　０．８２１をジオキ
サン１０ｊｔ／に溶解した溶液に４ＮＨＣ！ｌ含葡ジオ
キサン混合溶液１５耐を加えた。反応混液を室温にて１
．５時間静置後減圧蒸留した。油状残渣として、プロリ
ンジフェニルアラニンのベンジルエステル塩酸塩（Ｈ−
Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−ＯＥｚｌ・ＨＣｌ　）　０．
７２　ｆを寿た（収率９０％）。(2) Elimination of the N-terminal protecting group Add 4NHC! 15 ml of a grape dioxane mixed solution was added. The reaction mixture was mixed at room temperature for 1
．． After standing still for 5 hours, it was distilled under reduced pressure. The benzyl ester hydrochloride of proline diphenylalanine (H-
Pro-Phe-Phe-OEzl.HCl) 0.
72 f. (yield 90%).

（３）　　カップリング（アルギニン）を記生成物８　
ｍｍｏｌ、　　１．４４　ｆとＮ−（ｔ−ブトキシカル
ボニル）−Ｎ−ニトロ−アルギニン（Ｂｏａ−Ａｒｇ（
ＮＯ２）−０Ｈ）　８　ｍｍｏｌ　、　　０．９６１を
（１）と同様にカップリングさせて、Ｎ−（ｚ−ブトキ
シカルボニル）−Ｎ−ニトロ−アルギニンプロリンジフ
ェニルアラニンのベンジルエステル（Ｂｏｃ−Ａｒｇ　
（ＮＯ２）−Ｐｒｏ　−Ｐｈｅ　−Ｐｈｅ−ＯＢｚｌ　
）を１．８９　得た（収率７５％）。(3) Coupling (arginine) Product 8
mmol, 1.44 f and N-(t-butoxycarbonyl)-N-nitro-arginine (Boa-Arg(
NO2)-0H) 8 mmol, 0.961 was coupled in the same manner as in (1) to obtain the benzyl ester of N-(z-butoxycarbonyl)-N-nitro-arginine proline diphenylalanine (Boc-Arg
(NO2)-Pro-Phe-Phe-OBzl
) was obtained (yield 75%).

（４）Ｎ末端保ｍ基の脱離と記生成物２　ｍｍｏｌ、　　１．４９９を（２）と同
様に処置シて、Ｎ−ニトロ−アルキニンプロリンジフェ
ニルアラニンのベンジルエステルＮ　Ｍ　塩（Ｈ−Ａｒ
ｇ（Ｎ０２）−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−ＯＢｚ１４Ｈ
１３１Ｎ２０）を１．２５ｙ得た（収率８５％）。(4) Elimination of the N-terminal retaining group 2 mmol, 1.499 of the product was treated in the same manner as in (2) to obtain the benzyl ester N M salt of N-nitro-alkyne proline diphenylalanine (H- Ar
g(N02)-Pro-Phe-Phe-OBz14H
131N20) was obtained in an amount of 1.25y (yield: 85%).

（５）水素添加とＣ末端保４曖基の脱離と記生成物２ｍ
ｍｏｌ、　　１．４７１をメタノール８ｘｌと酢酸８　
ｍｌに溶解した溶液に、パラジウムブラック存在下、室
温にて４８時間水素添加した。触媒を濾別し、濾液を減
圧蒸留後油状残渣からエーテルを用いて結晶化させた。(5) Hydrogenation and elimination of the C-terminus group and the product 2m
mol, 1.471 with 8xl of methanol and 8xl of acetic acid
ml solution was hydrogenated for 48 hours at room temperature in the presence of palladium black. The catalyst was filtered off, and the filtrate was distilled under reduced pressure and the oily residue was crystallized using ether.

その後メタノール３−に溶解し、４．　Ｉ　Ｎ−ＨＣｌ
含有ジオキサン混合溶液１　ｍｌを加え、減圧蒸留後残
渣をアセトン・エーテルにて結晶化し、目的のテトラペ
プチド（Ｈ−Ａｒｇ　−Ｐ　ｒｏ　−Ｐｈｅ　−Ｐｈｅ
−ＯＨ−Ｎ２０　）　　を１．０２ｙ得た（収率９２％
）。Then dissolve in methanol 3-, 4. I N-HCl
After adding 1 ml of dioxane mixed solution containing dioxane and distilling under reduced pressure, the residue was crystallized with acetone/ether to obtain the desired tetrapeptide (H-Arg-Pro-Phe-Phe
-OH-N20) was obtained for 1.02y (yield 92%)
).

第１表Ｈ−Ｐｈｅ−Ｐｈｅ−ＯＢｚｌ−ＨＯＩ　＋　Ｂｏａ−
Ｐｒｏ−ＯＨ（１）↓ Ｂｏａ−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−ＯＢｚｌ（２）　↓
ＨＣ１／ｃｌｉｏｘａｎｅＨ−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−ＯＥｚｌ、ＨＯｌ（３）
↓＋Ｂｏａ−Ａｒｇ（ＮＯ２）−０ＨＢｏｃ　−Ａｒｇ
　（ＮＯ２）−Ｐｒｏ−Ｐｈｅ−Ｐｈ、ｅ　−０Ｂｚｌ
（４）↓Ｈｏｌ／ｄｉｏｘａｎｅＨ−Ａｒｇ−（ＮＯ２）Ｐｒｏ　−Ｐｈｅ−Ｐｈｅ−Ｏ
Ｂｚｌ、　ＨＣｌ（５）↓Ｈ２／Ｐａ、ＨＯＩ／ｄｉｏ
ｘａｎｅＡｒｇ−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−ＯＨ−Ｈ２
０実験例−２と記テトラペプチドの２祉体及びａ量体は実験例−１と
同様にして、例えば、以下の手順で合成される第２表Ｅ　ｏｃ　−Ｐｈｅ−Ｐｈｅ　−ＯＨ＋　Ｈ−Ａｒｇ　
（ＮＯ２）−Ｐｒｏ　−０Ｂｚｌ　・ＨｃＩカップリン
グ　↓ Ｂｏ　ｃ　−Ｐｈｅ　−Ｐｈｅ　−Ａｒｇ　（ＮＯ２）
−Ｐ　ｒｏ　−ＯＢｚｌＢｏａ−Ｐｈｅ−Ｐｈｅ−Ａｒ
ｇ（ＮＯ２）−Ｐｒｏ−ＯＨカップリング　↓＋Ｈ−Ｐ
ｈｅ−Ｐｈｅ−ＯＢｚｌ・ＨＯＩＢ　ｏｃ　−Ｐｈｅ　
−Ｐｈｅ　−Ａｒｇ　（ＮＯ２）−Ｐｒｏ　−Ｐｈｅ　
−Ｐｈｅ　−０Ｂｚｌ・ＨＯＩｆｔ−Ｐｈｅ　−Ｐｈｅ
　−Ａｒｇ　（ＮＯ２）　−Ｐｒｏ　−Ｐｈｅ　−Ｐｈ
ｅ−ＯＢｚｌ・ＨＯＩ→２量体（第８表）・カップリング　↓＋Ｂ　ｏ　ｃ　−Ｐｈｅ　−Ｐｈｅ
　−Ａｒｇ　（ＮＯ２）　−Ｐｒｏ　−０ＨＢＯＣ−Ｐ
ｈｅ　−Ｐｈｅ　−Ａｒｇ　（ＮＯ２）　−Ｐ　ｒｏ　
−Ｐｈ８−Ｐｈｅ　−Ａｒｇ（ＮＯ２）−Ｐｒｏ−Ｐｈ
ｅ−Ｐｈｅ−ＯＢｚｌＨ−Ｐｈｅ−Ｐｈｅ−Ａｒｇ（Ｎ
Ｏ２）−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−Ａｒｇ（ＮＯ２）”
Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−ＯＥｚｌ・Ｍｏｌカップリン
グ　↓＋Ｂｏｃ−Ａｒｇ（ＮＯ２）−Ｐｒｏ−ＯＨＢｏ
ａ　−Ａｒｇ　（ＮＯ２）−Ｐｒｏ　−Ｐｈｅ　−Ｐｈ
ｅ　−Ａｒｇ　（ＮＯｇ）−Ｐｒ。Table 1 H-Phe-Phe-OBzl-HOI + Boa-
Pro-OH (1) ↓ Boa-Pro-Phe-Phe-OBzl (2) ↓
HC1/clioxane H-Pro-Phe-Phe-OEzl, HOl (3)
↓+Boa-Arg(NO2)-0HBoc-Arg
(NO2)-Pro-Phe-Ph, e -0Bzl
(4)↓Hol/dioxane H-Arg-(NO2)Pro -Phe-Phe-O
Bzl, HCl(5)↓H2/Pa, HOI/dio
xaneArg-Pro-Phe-Phe-OH-H2
0 Experimental Example-2 The di-mer and a-mer of the tetrapeptides described in Table 2 are synthesized in the same manner as in Experimental Example-1, for example, by the following procedure.
(NO2)-Pro -0Bzl ・HcI coupling ↓ Bo c -Phe -Phe -Arg (NO2)
-Pro -OBzlBoa-Phe-Phe-Ar
g(NO2)-Pro-OH coupling ↓+H-P
he-Phe-OBzl・HOIB oc-Phe
-Phe -Arg (NO2)-Pro -Phe
-Phe -0Bzl・HOIft-Phe -Phe
-Arg (NO2) -Pro -Phe -Ph
e-OBzl・HOI→dimer (Table 8) ・Coupling ↓+B oc -Phe -Phe
-Arg (NO2) -Pro -0HBOC-P
he -Phe -Arg (NO2) -Pro
-Ph8-Phe -Arg(NO2)-Pro-Ph
e-Phe-OBzlH-Phe-Phe-Arg(N
O2)-Pro-Phe-Phe-Arg(NO2)”
Pro-Phe-Phe-OEzl/Mol coupling ↓+Boc-Arg(NO2)-Pro-OHBo
a -Arg (NO2)-Pro -Phe -Ph
e-Arg(NOg)-Pr.

−Ｐｈｅ−Ｐｈｅ−Ａｒｇ（ＮＯ２）−Ｐｒｏ−Ｐｈｅ
−Ｐｈｅ−ＯＢｚｌ・ＨＣＩＨ−Ａｒｇ（ＮＯ２）−Ｐ
ｒｏ−Ｐｈｅ−Ｐｈｅ−Ａｒｇ（ＮＯ２）−Ｐｒｏ−Ｐ
ｈｅ−Ｐｈｅ−Ａｒｇ（ＮＯｚ）−Ｐｒｏ−Ｐｈｅ−Ｐ
ｈｅ−ＯＢｚｌ、ＨＯ’Ｊ−Ｈ−Ａｒｇ−Ｐｒｏ−Ｐｈ
ｅ−Ｐｈｅ−Ａｒｇ−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−Ａｒｇ
−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−ＯＨ・５Ｈ２０（Ｂ　ｊａ
体）第８表Ｈ−Ｐｈｅ−Ｐｈｅ−Ａｒｇ（ＮＯ２）−Ｐｒｏ−Ｐｈ
ｅ−Ｐｈｅ−ＯＢｚｌ・Ｍｏｌカップリング　↓十Ｂｏ
ａ−Ｐｒｏ−ＯＨＢｏａ−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−Ａ
ｒｇ　（ＮＯ２）−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ　−０Ｂｚ
ｌゞ末端保護基　↓　ＨＯＩ／ＨＯＯＯＨの脱離Ｈ−Ｐ　ｒｏ−Ｐｈｅ−Ｐｈｅ−Ａｒｇ　（ＮＯ２）−
Ｐ　ｒ　ｏ−Ｐｈｅ−Ｐｈｅ　−０Ｂｚ　１ａＨＣｌカ
ップリング　↓＋Ｅｏｃ　−Ａｒｇ　（ＮＯ２）−０Ｈ
Ｂｏｃ−Ａｒｇ（ＮＯ２）−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−
Ａｒｇ（ＮＯ２）−Ｐｒｏ−Ｐｈｃ−Ｐｈｅ−ＯＢｚｌＨ−Ａｒｇ（ＮＯ２）−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−Ａｒ
ｇ（ＮＯ２）−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−ＯＢｚｌ　Ｈ
Ｏｌｌ：［−Ａｒｇ−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ−Ａｒｇ−Ｐ
ｒｏ−Ｐｈｅ−Ｐｈｅ−ＣＨ４・８Ｈ２０（２量体）Ｌ記テトラペプチドの１〜３飛体（Ａｒｇ−Ｐｒｃ−Ｐ
ｈｅ−Ｐｈｅ　）　ｒ〜８の各々の特性値を第４表に記
載す（Ａｒｇ−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ　）＋−ａの配
合量は、その単独或いは組合せの合計ｊｉｔに於いて、
本発明の皮膚化粧料の総量を基準として０．１〜１０．
０重世、好ましくは０．５〜５．（ｉｆｆ％（以下ｗｔ
％と略記する）であればよい。これらの各々の配合量の
と限を超えても、その超えた配合量に見合った効果は期
待出来ず、また、下限未満の配合量では本発明の目的を
達成することができない。-Phe-Phe-Arg(NO2)-Pro-Phe
-Phe-OBzl・HCIH-Arg(NO2)-P
ro-Phe-Phe-Arg(NO2)-Pro-P
he-Phe-Arg(NOz)-Pro-Phe-P
he-OBzl, HO'J-H-Arg-Pro-Ph
e-Phe-Arg-Pro-Phe-Phe-Arg
-Pro-Phe-Phe-OH・5H20(B ja
body) Table 8 H-Phe-Phe-Arg(NO2)-Pro-Ph
e-Phe-OBzl・Mol coupling ↓10Bo
a-Pro-OHBoa-Pro-Phe-Phe-A
rg (NO2)-Pro-Phe-Phe-0Bz
lゞTerminal protecting group ↓ Desorption of HOI/HOOOH H-Pro ro-Phe-Phe-Arg (NO2)-
P r o-Phe-Phe -0Bz 1aHCl coupling ↓+Eoc -Arg (NO2)-0H
Boc-Arg(NO2)-Pro-Phe-Phe-
Arg(NO2)-Pro-Phc-Phe-OBzl H-Arg(NO2)-Pro-Phe-Phe-Ar
g(NO2)-Pro-Phe-Phe-OBzl H
Ol l: [-Arg-Pro-Phe-Phe-Arg-P
ro-Phe-Phe-CH4・8H20 (dimer) 1 to 3 bodies of L tetrapeptide (Arg-Prc-P
The characteristic values of each of (Arg-Pro-Phe-Phe) r~8 are listed in Table 4.The compounding amount of (Arg-Pro-Phe-Phe)+-a, alone or in combination, is as follows:
0.1 to 10.0% based on the total amount of the skin cosmetic of the present invention.
0 times, preferably 0.5 to 5. (if% (hereinafter wt
(abbreviated as %) is sufficient. Even if these respective limits are exceeded, no effect commensurate with the exceeded amount can be expected, and if the amount is less than the lower limit, the object of the present invention cannot be achieved.

本発明の皮膚化粧料基剤には、ローシラン類、クリーム
類、乳液類、バンク類等々の通常の皮膚化粧料基剤を適
用することができろ。As the skin cosmetic base of the present invention, common skin cosmetic bases such as rhosilanes, creams, emulsions, banks, etc. can be used.

尚、本発明の皮膚化粧料には上記の他に色素、皮膚栄養
剤、香料、防腐剤、界面活性剤、顔料、抗酸化剤等を本
発明の目的を達成する範囲内で適宜配合することができ
る、１以下、実施例について説明する。In addition to the above, the skin cosmetics of the present invention may contain pigments, skin nutrients, fragrances, preservatives, surfactants, pigments, antioxidants, etc. as appropriate within the scope of achieving the purpose of the present invention. 1 Examples will be described below.

尚、実施例に記載の荒れ肌改善効果の測定試験法、角質
改善効果の測定試験法、官能テストは下記の通りである
。The test method for measuring the effect of improving rough skin, the test method for measuring the effect of improving keratin, and the sensory test described in the Examples are as follows.

（１）　　荒れ肌改善効果の測定試験法下脚に荒れ肌を
存する中高年被験者２０名を対象として４週間連続塗布
効果を調べた。被験者の左側下脚試験部位に１日２回約
１ｇの試料を塗布し、試験開始前および終了後の皮膚の
状態を下記の判定基準により判定した。右側下脚は試料
を塗布せず対照とした。(1) Test method for measuring the effect of improving rough skin The effect of continuous application for 4 weeks was investigated on 20 middle-aged and elderly subjects with rough skin on their lower legs. Approximately 1 g of the sample was applied to the test site of the left lower leg of the subject twice a day, and the condition of the skin before and after the test was judged according to the following criteria. No sample was applied to the right lower leg, which served as a control.

皮膚乾燥度の判定基準 −二正常 ±　：軽微乾燥、落屑なし、＋　：乾燥、落屑軽度＋＋：乾燥、落屑中等度＋＋＋：乾燥、落屑顕著試験前後の試験部位と対照部位の判定結果を比較し、皮
膚乾燥度が２段階以と改悟された場合（例えば＋−一、
＋＋→±）を「有効」、１段階改善された場合を「やや
有効」、変化がなかった場合を「無効」とした。試験結
果は「仔効」、「やや有効」となった被験者の人数で示
した。Judgment criteria for skin dryness - 2 Normal ±: Slight dryness, no flaking, +: Mild dryness, flaking ++: Moderate dryness, flaking +++: Significant dryness, flaking Compare the judgment results of the test site and control site before and after the test. , if the skin dryness is determined to be level 2 or higher (e.g. +-1,
++→±) was considered "effective," one level of improvement was considered "slightly effective," and no change was considered "ineffective." The test results are shown in terms of the number of subjects who found the drug to be "slightly effective" or "slightly effective."

（２）角質改善（角質細胞の抗剥離性増大）効果の測定
試験法前述の荒れ肌改善測定試験開始前および終了後の被験部
皮膚にスコッチテープにチバンメンディングテープ）を
接着し、これを剥離した時テープに付着した角質細胞の
状態を走査型電子顕微鏡によって詳細に調べ、下記の）
＆準によって皮膚角質細胞抗剥離性を分離し、角質改善
効果を求めた。(2) Test method for measuring the effect of improving keratin (increasing anti-peeling properties of keratinocytes) Apply Scotch tape (Tiban Mending Tape) to the test area skin before and after the start and end of the rough skin improvement measurement test described above, and peel it off. The condition of the corneocytes attached to the tape was examined in detail using a scanning electron microscope (see below).
The anti-exfoliation properties of skin keratinocytes were separated by the following methods, and the keratin improving effect was determined.

角質改善効果（角質細胞抗剥離性増大）の判定基準評価点１ニスケールを認めず〃　２：小スケール点在〃　３：小〜中スケール顕著／／　４：大スケール顕著評価は４週間連続塗布後の試験部位の評価点と対照部位
のそれとの差が２点以ｔの場合を「膏効」、１点の場合
を「やや有効」、０点の場合を「無効」とした。判定結
果は「可動」、「やや有効」となった被験者の人数で示
した。Judgment criteria for keratin improving effect (increased anti-desquamation property of keratinocytes) Evaluation points: 1.2 scales not observed〃 2: Small scales scattered〃 3: Small to medium scales noticeable // 4: Large scales markedly evaluated after 4 weeks of continuous application When the difference between the evaluation score of the test site and that of the control site was 2 points or more, it was considered "paste effective," when it was 1 point, "slightly effective," and when it was 0 points, it was "ineffective." Judgment results are shown in terms of the number of subjects who found it ``mobile'' or ``slightly effective.''

（３）官能テスト（美肌効果試験）荒れ肌、小じわ、乾燥肌等を訴える女子被試験者（３５
〜５５才）２０人に試料を１日２回（朝夕）連続３ケ月
間塗布して、３ケ月後の効果を評価した。評価結果は、
皮膚の湿潤性、平滑性、弾力性の各項目に対して、「皮
膚に潤いが生じた」。(3) Sensory test (skin beautification effect test) Female test subjects (35
The sample was applied to 20 people (up to 55 years old) twice a day (morning and evening) for 3 consecutive months, and the effects were evaluated after 3 months. The evaluation results are
"My skin felt moisturized" for each of the skin's wettability, smoothness, and elasticity items.

「皮膚が滑らかになった」、「皮膚に張りが生じた」と
回答した人数で示した。This is expressed by the number of people who answered that their skin became smoother and their skin became taut.

実施例１〜６．比較例１〔二層型スキンローシラン〕下記の組成のごとく、二層型スキンローションの基剤に
実験例−１，−２で得た（　Ａｒｇ−Ｐｒｏ　−Ｐｈｅ
−Ｐｈｅ　）　１〜８を第５表に記載の通りに配合して
、各々のスキンローシランを調製し、前記の諸試験を実
施した。Examples 1-6. Comparative Example 1 [Two-layered skin lotion] As shown in the following composition, Arg-Pro-Phe obtained in Experimental Examples-1 and -2 was added to the base of a two-layered skin lotion.
-Phe) 1 to 8 were blended as shown in Table 5 to prepare each skin low silane, and the various tests described above were conducted.

（１）組成以ｊ′下−戸（２）　　調製法 ■、　０３）成分を各々均一に溶解した後、（Ａ）成分
と［Ｆ］）成分をａ合撹拌分散し、次いで容器に充填す
る。(1) Composition (2) Preparation method ■, 03) After each component is dissolved uniformly, the (A) component and [F]) component are mixed and dispersed, and then filled into a container. .

使用時には内容物を均一に振盪分散して使用する。When using, shake and disperse the contents uniformly.

（３）特性各二１１゛４型スキンローションの諸試餉を実施した結
果を第５表右欄に記載した。(3) Characteristics The results of various tests of the 211゛4 type skin lotions are listed in the right column of Table 5.

第５表に示すごとく、二層型スキンローシラン基剤のみ
の比較例１に対して、本発明の皮膚化粧料である、（Ａ
ｒｇ−Ｐｒｏ−Ｐｈｅ−Ｐｈｅ　）　ｓ　〜ｇの少なく
とも１つを配合した実施例１〜６の二層型スキンローシ
ランは諸特性に於いて優れた効果を有することが認めら
れた。As shown in Table 5, in contrast to Comparative Example 1, which uses only a two-layer skin low silane base, the skin cosmetic of the present invention (A
It was found that the two-layer skin low silanes of Examples 1 to 6 containing at least one of rg-Pro-Phe-Phe)s to g had excellent effects in terms of various properties.

実施例７〜１１．比較例２〔スキンクリーム〕実施例１と同様に、下記の組成にて各々のスキンクリー
ムを調製し、諸特性の結果を第５表右欄に記載した。Examples 7-11. Comparative Example 2 [Skin Cream] In the same manner as in Example 1, skin creams were prepared with the following compositions, and the results of various properties are listed in the right column of Table 5.

（２）調製法（３）成分及び■成分を各々８０°Ｃに加熱溶解した後
混合して、撹拌しつつ３０°Ｃ迄冷却して各スキンクリ
ームを調製した。(2) Preparation method Component (3) and component (2) were heated and dissolved at 80°C, mixed, and cooled to 30°C with stirring to prepare each skin cream.

（３）特性第５表に示すごとく、比軟例２に対して本発明の皮膚化
粧料である実施例７〜１１のスキンクリームは諸特性に
於いて優れた効果を示し、（Ａｒｇ−Ｐｒｏ　−Ｐｈｅ
　−Ｐｈｅ　）　１−８の配合量は０．１〜１０゜Ｏｗ
ｔ％（発明の効果）以と記載のごとく、本発明は、保湿効果（荒れ肌改善効
果、角質改善効果）に優れると共に、顕著な美肌効果を
仔する皮膚化粧料を提供することは明らかである。(3) Properties As shown in Table 5, the skin creams of Examples 7 to 11, which are skin cosmetics of the present invention, exhibited superior effects in various properties compared to Ratio Example 2. -Phe
-Phe) The blending amount of 1-8 is 0.1 to 10°Ow
t% (Effect of the Invention) As described below, it is clear that the present invention provides a skin cosmetic that is excellent in moisturizing effects (improving rough skin and improving keratin) and has a remarkable skin beautifying effect. .

手続補正ＩＩ（自発）昭和６０年１２月ｑ日特許庁長官　宇　賀　道　部　殿１、事件の表示昭和６０年特許願第２４０３１３号２、発明の名称皮膚化粧料３、補正をする者事件との関係　　特許出願人住所　東京都墨田区墨田五丁目１７番４号〒５３４　大
阪市部島区友淵町１丁目５番９０号鐘紡株式会社特許部電話（０６）９２１−１２５１４、Ｍ正によシ増加する発明の数　　　　なし５・補正
０対象　　　　　　　　　　　　　　　／−＼明細書の
「発明の詳細な説明」の欄　　　ｎ　７ＣＦ？′６０．
１２．１１６、補正の内容（１）明細書、第７頁第１０行に記載の「Ｎ末端」を「
Ｃ末端」に補正します。Procedural amendment II (spontaneous) December q, 1985 Michibe Uga, Commissioner of the Patent Office1, Indication of the case 1985 Patent Application No. 2403132, Name of the invention Skin cosmetics3, Person making the amendment Case and Relationship Patent Applicant Address: 5-17-4 Sumida, Sumida-ku, Tokyo 5-90 Tomobuchi-cho, Bejima-ku, Osaka 534 Kanebo Co., Ltd. Patent Department Tel: (06) 921-1251 4, Masaru M. The number of inventions will increase as the number of inventions increases. None 5/Amended 0 /-\Detailed description of the invention column in the specification n 7CF? '60.
12.11 6. Contents of amendment (1) The “N-terminus” described in the specification, page 7, line 10, has been changed to “
Correct to "C-terminus".

（２）明細書、第１１頁第３行に記載の「重量、」を１
重量％、」に補正します。(2) "Weight" stated on page 11, line 3 of the specification is 1
Corrected to ``weight%''.

（３）明［醤、第１３頁第６行に記載の「分離」を「解
析」に補正します。(3) Ming [Soy] Correct “separation” to “analysis” on page 13, line 6.

Claims

[Claims] General formula (Arg-Pro-Phe-Phe)_n (wherein, Arg is arginine, Pro is proline, Ph
e represents phenylalanine, n represents an integer of 1 to 3, and - represents a peptide bond. ) A skin cosmetic comprising at least one of the tetrapeptides represented by the following formula incorporated into a skin cosmetic base.