200826969 (1) 九、發明說明 【發明所屬之技術領域】 本發明係關於含維生素A類及四羥反式丨，2二苯乙烯 及其衍生物之化妝品組成物，可用於期望無刺激地改善膠 原蛋白的合成之護膚處理。 【先前技術】 維生素A醇（維生素A)爲人體中天然存在之內因性物 質，在上皮細胞分化中爲必須的。天然及合成之維生素A 衍生物以抗皺作用物質爲人所熟知，對於皺紋、乾裂、多 毛孔、粗糙、乾燥、斑（色素過度沉澱）等皮下老化作用有 減輕之效果。（對於Kingman，參考專利文獻1及2)。維生 素A類，對於引起表皮之肥厚（棘細胞症、皮膚肥厚症）之 炎症，及局部細胞內浮腫所造成之表皮剝落有減輕之作用 ，此作用已爲人熟知。 含維生素A類製劑組成處方時’ 一方面需注意維生 素A在角質層有最適當之釋出濃度’另一方面需留意其 體循環吸收程度爲最小。進一步對於使用者慢性使用之對 應也是重要的。但是，現有之含維生素A類製劑會造成 乾燥及刺激而引起過度之皮膚剝離。這樣的組成份，使用 者說不定不得不停用能得到最好之效果之頻繁及足量地使 用維生素A類製劑。 [專利文獻1]美國專利4.603.1 4 6號 [專利文獻2]美國專利4.877.805號 200826969 (2) 【發明內容】 [發明所欲解決之課題] 本發明係由天然或合成之維生素 A類與作爲抗炎劑 之四羥反式1，2二苯乙烯搭配所組成，部份基於可抑制皮 膚之乾燥及/或刺激，且邊利用維生素A類之優點邊釋放 於皮膚之未預期的知識。這樣的組成可改善使用者之耐受 性，如此一來，同時在皮膚調整效果全面改善，同時對使 用者來說可促進其順從性。 四羥反式1，2二苯乙烯（反式-3,4,3’，5’-四羥-1,2-二苯 乙烯）爲多種植物中的成份，常常也有其相關構造成份之 白黎蘆醇（Resveratrol)(反式-4,3’，5’_三羥基-1,2 -二苯乙；(：希 )° 兩成份係對黴菌及其他環境壓力反應而在植物體中所 合成，被分類爲植物抗毒素（phytoalexin)。四經反式1，2二 苯乙嫌被定爲學名 Melaleuca leucadendron(白千層）之有 效成份。文獻爲 Tsuruga，T.,Chun，Y.T.，Ebizawa，Y.& Sankawa ，U.(1991)「Melaleuca leucadendron 之生物學有效組成份 :大鼠肥胖細胞而來之誘發組織氨釋放之抑制物質」 Chem Pharm.Bull.(Tokyo)3 9:3276-3 278。 又，發現爲 Cassia garretiana，（Asian legume)之有效 作用物質。文獻爲 Inamori,Y.，Kato,Y.，Kubo，M.，Yasuda， M.，Baba，K.，&Kozawa，M.(l 984)「由 Cassia garretiana(CRAIB) 心材所純化之3,3’，4,5’-四羥-1，2-二苯乙烯之生理學作用」 200826969 ⑶200826969 (1) IX. Description of the invention [Technical field to which the invention pertains] The present invention relates to a cosmetic composition containing vitamin A and tetrahydroxytranspurin, stilbene and derivatives thereof, which can be used for improvement without stimulation Skin care treatment of collagen synthesis. [Prior Art] Vitamin A alcohol (vitamin A) is an endogenous substance naturally present in the human body and is essential for epithelial cell differentiation. Natural and synthetic vitamin A derivatives are well known for their anti-wrinkle substances and have a reduced effect on subcutaneous aging such as wrinkles, chapped, multi-pores, roughness, dryness, and plaque (hyperpigmentation). (For Kingman, refer to Patent Documents 1 and 2). The vitamin A class has a role in alleviating the epidermal exfoliation caused by hypertrophy of the epidermis (echinocytosis, cutaneous hypertrophy) and local intracellular edema. This effect is well known. When formulating a vitamin A-containing preparation, it is necessary to pay attention to the fact that vitamin A has the most appropriate release concentration in the stratum corneum. On the other hand, it is necessary to note that the degree of systemic circulation is minimal. Further important for the user's chronic use is also important. However, existing vitamin A-containing preparations cause dryness and irritation which cause excessive skin peeling. With such a component, the user may have to discontinue the frequent and sufficient use of the vitamin A preparation for the best results. [Patent Document 1] U.S. Patent No. 4.603.1 4 6 [Patent Document 2] U.S. Patent No. 4.877.805 No. 200826969 (2) [Disclosed] [Problems to be Solved by the Invention] The present invention is a natural or synthetic vitamin A. It is composed of a combination of tetrahydroxytrans stilbene as an anti-inflammatory agent, based in part on the undesired release of the skin by inhibiting the dryness and/or irritation of the skin while utilizing the advantages of vitamin A. Knowledge. Such a composition improves the tolerance of the user, and at the same time, the skin conditioning effect is comprehensively improved while facilitating compliance for the user. Tetrahydroxytrans stilbene (trans-3,4,3',5'-tetrahydroxy-1,2-stilbene) is a component of many plants, often with white related structural components. Resveratrol (trans-4,3',5'-trihydroxy-1,2-diphenylethyl; (: Greek) ° two components reacted to mold and other environmental stresses in plants Synthetic, classified as phytoalexin. The trans-type 1,2 diphenylethyl is identified as the active ingredient of the scientific name Melaleuca leucadendron (Taiwan). The literature is Tsuruga, T., Chun, YT, Ebizawa, Y.& Sankawa, U. (1991) "Biologically effective component of Melaleuca leucadendron: inhibitory substance that induces tissue ammonia release from rat obese cells" Chem Pharm.Bull.(Tokyo)3 9:3276-3 278. Also found as an effective substance of Cassia garretiana, (Asian legume). The literature is Inamori, Y., Kato, Y., Kubo, M., Yasuda, M., Baba, K., & Kozawa, M (l 984) "Physiological effects of 3,3',4,5'-tetrahydroxy-1,2-stilbene purified by Cassia garretiana (CRAIB) heartwood 200826969 (3)
Chem Pharm.Bull.(Tokyo)32 ： 3 2 1 3 -3 2 1 8。 又，發現爲Rheum undulatum(朝鮮大黃）之有效成份 。文獻爲 Ko，S.K.，lee，S.M.，&Whang，W.K.(1 999)「由 Rheum undulatum得到之1，2-二苯乙烯衍生物之抗血小板凝集作 用」Arch · Pharm . Re s · 2 2 : 4 0 1 - 4 0 3，及 Mat suda，Η ·，Kageur a ,T.， Toguchida，I.，Harima，S.&Yoshikawa，M.(2000) 「脂多 醣類活化之巨嗜細胞中，由大黃得到之1，2-二苯乙烯成份 對於一氧化氮之作用」Bioorg.Med.Chem.Lett.10 : 323-3 27。這些被用於傳統之漢方藥。 又，爲Euphorbia lagascar(大戟）種子之抗白血病成 份，用於癌、腫瘤及瘤之民間治療。文獻爲 Ferrigni， N.R.，McLaughin ，J.L·，Powell，R.G.,&Smith，C.R.( 1 984)「 大戟種子作爲抗白血病作用因子之四羥反式1，2二苯乙烯 之純化及檢驗其作用爲目的之馬鈴薯板及豐年蝦生物檢測 之使用」J.N at.Prod.47 ·· 347-352。Chem Pharm.Bull.(Tokyo)32 : 3 2 1 3 -3 2 1 8. Also, it was found to be an effective ingredient of Rheum undulatum (North Korean Rhubarb). The literature is Ko, SK, lee, SM, & Whang, WK (1 999) "Antiplatelet aggregation of stilbene derivatives obtained from Rheum undulatum" Arch · Pharm . Re s · 2 2 : 4 0 1 - 4 0 3, and Mat suda, Η ·, Kageur a, T., Toguchida, I., Harima, S. & Yoshikawa, M. (2000) "Lipopolysaccharide-activated macrophages The effect of the 1,2-stilbene component obtained from rhubarb on nitric oxide. Bioorg. Med. Chem. Lett. 10: 323-3 27. These are used in traditional Chinese medicine. In addition, it is an anti-leukemia component of Euphoria lagascar seeds, which is used for folk treatment of cancer, tumors and tumors. The literature is Ferrigni, NR, McLaughin, JL·, Powell, RG, & Smith, CR (1 984). Purification and testing of tetrahydro-trans- stilbene as an anti-leukemia effect factor For the purpose of the potato board and the use of biological detection of brine shrimp" JN at.Prod.47 ·· 347-352.
Teguo硏究者們在Vitis venifera(葡萄、紅酒用葡萄 的一種）之細胞懸浮液中測出含四羥反式1，2二苯乙烯。文 獻爲 Teguo，P.W.，Decendit.S.，Krisa，S.，Deff*ieux，G·，Vercauteren ，J.&Merillon，J.M.(200 1 )「Vitis venifera 之細胞懸浮液中 之蒸餾糖苷之蓄積」J.Nat.Prod.59: 1 1 89- 1 1 9 1。 含有白藜蘆醇之化妝品組成全部被記載著。如， Pezzuto硏究者們（美國專利編號第64 1 403 7號）提出藉由含 白藜蘆醇之組成物作爲皮膚狀況之預防或處置之方法， PiUai硏究者們（美國專利編號第63 5 8 5 1 7號）提出含白藜蘆 200826969 (4) 醇與所選擇之維生素A類之搭配而成之護膚化妝品組成 份。以四羥反式1,2二苯乙烯爲有效成份之化妝品組成物 目前並無記載。科學證據已證實四羥反式丨，2二苯乙烯之 獨特性及四羥反式1，2二苯乙烯上追加羥基並非係單純地 在白藜蘆醇的延長線上之者。 如，參考 Ashikawa 硏究者們之 J.Immunol.2002 Dec 1;1 69( 1 1 ): 6490-7。因四羥反式1，2二苯乙烯及其衍生物 爲酚類，可作爲強力之抗氧化劑。 [欲解決課題之手段] 本發明之主要發明，係提出含有在皮膚適應性大幅改 善的含維生素A類之皮膚調整劑用組成物，其含有： (a) 維生素A醇、維生素A酯類、維生素A醛、維生 素A酸、維生素A酸鹽、這些的衍生物或類似物、及與 這些任一種搭配所成之群中選出之單一維生素A，其濃度 約0.001重量％到5重量％之者； (b) 四羥反式1，2二苯乙烯、皮膚學上可容許之鹽類、 酯類、醯胺類、這些之前驅藥及類似物、及與這些任一種 之搭配，其濃度約爲0.000 1重量％〜1〇重量％之者； (c) 可允許作爲化妝品之媒劑 文中使用的“調整劑”之意義爲對於乾燥肌、光敏感 肌、皺紋的產生、老化斑、老化肌、青春痘、白斑、乾癣 、異位性皮膚炎之預防及治療、軟化角質層、抑制皮脂分 泌、及改善一般膚質。該組成份亦可用於皮膚脫屑及細胞 (5) (5)200826969 增殖之改善。 本發明藉由四羥反式1，2二苯乙烯之存在，實質提高 了維生素A醇及維生素A酯之作用。且四羥反式1，2二苯 乙烯實質地提高了維生素A醇及維生素A酯之細胞增殖 作用。在哺乳類，四羥反式1，2二苯乙烯（分子層面的目標 不明）發揮了干渉細胞激素之產生與機能之抗氧化和抗發 炎作用。 但是，在皮膚效用的實際改善上，在四羥反式1，2二 苯乙烯與維生素A醇或維生素A酯搭配使用時實現。也 就是說本發明，至少有部份是基於維生素A醇或維生素A 酯與四羥反式1，2二苯乙烯間之相乘作用而得。 根據本發明，藉由在含維生素A醇或維生素A酯之 組成物中，添加有效量之四羥反式1，2二苯乙烯，可實質 改善該組成之作用。 本發明中，包含對於乾燥肌、光敏感肌、皺紋的產生 、老化斑、老化肌、青春痘、白斑、乾癬、異位性皮膚炎 之預防及治療、軟化角質層、抑制皮脂分泌、及改善一般 膚質等之調整劑的改善及預防其之方法，該方法亦包含將 該發明組成塗佈於皮膚之方法。 本發明之組成物雖然以在乾燥、脫皮、有皺紋、老化 、光敏感之哺乳類動物之皮膚上塗佈爲目的，但該發明之 組成物用於防止或減輕健康肌膚之退化，作爲預防目的而 塗佈亦可。 本發明更含有抑制因維生素A類引起之皮膚刺激、 -8- 200826969 (6) 刺痛感或發炎之化妝方法。基於此點，該發明亦包含含有 四經反式1，2二苯乙燒與維生素a類搭配之化妝品組成物 〇 [槪要及定義] “四經反式1，2二苯乙烯，，之用語，係指四羥反式ι，2二 苯乙烯之順式異構物、四羥反式1，2二苯乙烯之反式異構 物、或兩異構物之混合物之任一種。又此用語，包括指天 然之有效成份及經硏究室化學合成之化合物。又於文中之 四羥反式1,2二苯乙烯，更包含四羥反式丨，2二苯乙烯之皮 膚學上可容許之鹽類、酯類、醯胺類、前驅藥及類似物質 〇 “作皮膚狀況之處置”等之”處置（treat)”之用語中，包 含（1)狀況之防止，也就是說臨床症狀的預防、（2)狀況之 抑制，也就是說阻止臨床症狀的進展或進行及/或（3)狀況 ' 之緩和，也就是說消除臨床症狀。 “皮膚學上可容許的”係指，在生物學上或其他方面爲 適切的物質。也就是說這物質，其與所選擇之有效成份一 . 起用時，在個體投與時不會引起不期望之生物學作用，或 與含其之藥劑組成份中之任何成份都不會發生有害之交互 作用之物質。同樣地，文中之有效成份的”皮膚學上可容 許的”鹽，或”皮膚學上可容許的”酯爲，在生物學上或其 他方面爲適切之鹽或酯。 “選擇的”或”選擇性地”指’後述狀況發生或不發皆可 -9- 200826969 (7) 的情況。然而，其狀況係包含發生與不發生之兩種情況。 如，處方中之某種添加物係”選擇性地存在”之敘述時，其 包含含該添加物處方及不含該添加物之處方兩種。 [爲了處置之有效成份] 上述之該發明，係包含爲了預防或處置伴隨使用維生 素A類而來之皮膚狀況的四羥反式1，2二苯乙烯的使用。 四羥反式1，2二苯乙烯可使用天然的、也就是葡萄皮 、紅酒、或由其他植物成分純化而來的，或在硏究室化學 合成的、或市售品、如，BIOMOL Research Laboratories Inc.(Plymouth Meeting市，賓州）亦可使用。由天然資源 抽提四羥反式1，2二苯乙烯之方法偏好爲，由德國唐檜樹 皮抽出該成份。 該有效成份爲皮膚學上可容許之鹽、酯、醯胺、前驅 藥或類似物或與其搭配使用也可。四羥反式1，2二苯乙烯 之鹽類、酯、醯胺、前驅藥或類似物，可藉由有機化學合 成及醫藥品製劑熟練者用周知之標準步驟製造。酯類之製 造中，包含該藥物分子構造中之羥基的機能化。酯類係游 離醇基之典型醯基取代衍生物。 也就是說，化學式RCOOH(R爲烷基，以低分子量之 院基爲佳）之殘酸衍生物的一部份。酯類，依其必要性， 通常經由氫化分解或水解轉化爲游離酸類。在醯胺與前驅 藥的製造上，也可用類似之方法。有效成份之其它衍生物 及類似物之製造，可藉由有機化學合成熟練業者用周知之 -10- (8) (8)200826969 標準步驟或參考文獻推論得知。 四羥反式1，2二苯乙烯之順式及反式所偏好之衍生物 ，其成份之羥基典型上爲3-羥基，之一或其以上’係單糖 或雙糖、一般爲與單糖第1位置所結合之物。可與四羥反 式1，2二苯乙烯接合之糖類有葡萄糖、半乳糖、麥芽糖、 蔗糖等，但並不限這些。特別以順式四羥反式1，2二苯乙 烯葡糖苷及反式四羥反式1,2二苯乙烯葡糖苷（Astringine) 爲佳。 [化妝品用處方] 所偏好劑型之實施例爲，於含局部適用的適當載體及 技術上爲人熟知之物質之局部用處方中添加有效成份。局 部用的載體方面選用可提供該組成所希望之形態之載體。 如，軟膏劑、洗劑、乳霜、微乳劑、凝膠劑、油、溶 液劑等，含天然來源物質或合成物質皆可。所選擇之載體 必須對有效成分及該局部用組成中之其他成分無不良影響 〇 作爲局部用載體，適合的有，水、醇類·乙二醇類及 其他之無毒性有機溶劑、甘油、礦油、聚矽氧烷、凡士林 、綿羊油、脂肪酸、植物油、蠟等。 特別偏好之局部用載體爲，無色無臭之溶液、洗劑、 乳霜、微乳劑、及凝膠劑。 爲該領域之技術熟練者所習知之種種添加物’可包含 於本發明之局部用處方中。其添加物舉例如，溶解輔助劑 -11 - 200826969 (9) 、皮膚滲透性增強劑、漂白劑、防腐劑（如，抗氧化劑）、 凝膠化劑、緩衝劑、界面活性劑（特別是非離子兩性界面 活性劑）、乳化劑、皮膚軟化劑、增稠劑、安定劑、濕潤 劑、著色劑、香料等，但並不限定於此等。添加乳化劑、 皮膚軟化劑及防腐劑時，以同時添加溶解輔助劑及/或皮 膚滲透性增強劑爲佳。 皮膚滲透性增強劑可使有效成份在治療濃度下於非損 傷皮膚範圍大之部位容易地通過。適當的增強劑在此領域 爲被充分習知的，如，包含2-丙醇及二甲基異山梨醇。 溶解輔助劑的例子有以下者，但並不被其限定，如， 1，3-丁二醇、二丙二醇。 於處方中包含其他有效成份亦可。也就是，其他之抗 發炎劑、鎭痛劑、抗菌劑、抗真菌劑、抗生素、維生素、 抗氧化劑及防曬劑，於防曬劑中所共同使用之成份有二氧 化鈦、氧化鋅、蒽基酸鹽、二苯甲酮（特別是二苯甲酮-3) 、樟腦衍生物、桂皮酸鹽（如，辛基甲氧基桂皮酸鹽）、二 苯醯甲烷（如，丁基甲氧基二苯醯甲烷）、P -氨基安息香酸 (PΑΒΑ)及此等之衍生物、及水楊酸鹽（如，辛基水楊酸鹽） 〇 於本發明所期望之局部用處方中，有效成份爲處方中 之0 · 0 0 5重量％至1 〇重量％之範圍，以0 · 0 1重量％至5重量％ 爲佳，0 · 1重量％至5重量％更佳，〇 . 1重量％至2重量％最佳 -12- (10) 200826969 [發明之效果] [使用] 基於本發明之組成，主要爲適合人體皮膚局部使用之 化妝品，特別爲期望能作爲皮膚之護膚、保濕化、平滑化 及皺紋及老化肌之預防與抑制的製品。 處方品方面，如前所述，軟膏劑、洗劑、乳霜、微乳 劑、凝膠劑、溶液劑等，爲得到期望之結果於有效之用量 範圍內，用於皮膚局部。有效成份之一次投與量以 1〜1 0 0ml之範圍爲佳，一般，其投與計劃包含至少一日一 次的局部投與。 關於本發明，雖然記載了具體之劑型名稱，但前述例 及後述者係爲了作爲發明之目的的例證，期望能理解並不 被其所限定。其他的特徵、優點及改良，該發明相關領域 之技術者能明瞭。 全部之專利、專利資料及於本說明書所引用之文獻， 直接以參考文獻記載於本說明書。 【實施方式】 [實施例1 ] 基於本發明之處方的製作方式爲了完全揭示於一般之 技術熟練者，用以下之實施例揭示，但發明者並不意指該 發明之範圍會被此限制。在關於數字方面（如，份量、溫 度等）儘可能地努力確保其正確性，但多少可能有錯誤與 誤差。 -13- 200826969 (11) 在未特別說明的部分，比率爲重量比，溫度爲攝氏及 氣壓爲常壓。全部的溶劑、試藥、添加物爲藥品等級。 [實施例2] 此實施例中，四羥反式1，2二苯乙烯之溶液證實了其 可抑制維生素A類所誘發之刺激，及改善皮膚外觀。 實施例1及比較實施例1與2之組成，使用如表1所示之 成分調製而成。 [表1] 成分 實施例1 (重量％) 比較實施例1 (重量％) 比較實施例2 (重量％) 二甲基異山梨醇 25.0 25.0 25.0 二丙二醇 74.4 74.6 74.8 d- α -生育醇 0.2 0.2 0.2 維生素Α棕櫚酸酯(1.7m.IU/g) 0.2 0.2 0 反式-四羥反式1，2二苯乙烯 0.2 0 0 該組成如以下調製：d- α -生育醇、維生素A棕櫚酸 酯（1.7m.IU/g)及反式-四羥反式1，2二苯乙烯，於30°C下溶 於二甲基異山梨醇，成爲澄清溶液時同樣於3 0 °C添加二丙 二醇。操作於氮氣層下進行，全部之溶液於氮氣下保存。 關於實施例1及比較實施例1與2之組成作爲化妝品的 刺激強度，以人4-h貼膚試驗（Basketter D.A.，Food Chem Toxocl 1 997,35··845·8 52)之變向操作方法檢驗。實驗爲於 附有Webril墊片（Hilltop公司，CINCINNATI，俄亥俄州） -14· (12) 200826969 之25mm的Hill Top Chambers上承載0.2ml之被試驗溶液 ，用於1 6名自願者之外上部手挽之皮膚。使用被試驗者之 兩挽，均衡且隨機地貼附貼片。 24小時後除去貼片，於被試驗部位用麥克筆作記號。 於經過24、48、72小時後，觀察被試驗部位有無刺激，於 除去貼片之24、48、72小時之時間點，以4評分法（表2)判 定。 [表2] 反應評估 評分 反應程度 0 無反應 + 弱陽性反應 (通常以輕度紅疹或塗佈部位之大範圍乾燥爲特徵） ++ 中度陽性反應 (通常超越塗佈部位有明顯紅疹） +++ 重度陽性反應(強，廣範圍之紅疹常伴隨浮腫） 結果如表3所示。 [表3] 實施例1及比較實施例1及2組成之皮膚刺激度 組成 實施例1 比較實施例1 比較實施例2 評分(16人平均） 0 + 0 於添加四羥反式1，2二苯乙烯的情況，明顯可抑制維 生素A棕櫚酸酯之刺激。 -15- 200826969 (13) 將關於實施例1及比較實施例1與2之組成用作化妝品 之對皮膚皺紋的改善效果，以電腦化之雷射側面計測定。 試驗在3 0歲以上的1 6位女性中進行，將實施例1及比較實 — · 一 .—. —·. — •細. ... — - - - _ .·_· ·· -··_ - - -" 施例1與2的組成，在受試者之臉部（面積2x2cm2)l日1次’ 1次0.0 5 g塗9週。 接著以塑膠矽之精密構造物複製皮膚之皺紋（複製品） 。用視覺皮膚測定器（德國’ Couage&Khazaka electronic G m b Η公司製之 S k i η V i s i o m e t e r )檢測其複製皮膚之皺紋 變化。以CCD相機分析複製之三次元影像。皮膚皺紋之 改善效果，遵從下列方程式1，算出皺紋之平均粗度（Rz) 〇Teguo researchers measured tetrahydroxytrans stilbene in a cell suspension of Vitis venifera (a grape, a grape for wine). The literature is Teguo, PW, Decendit. S., Krisa, S., Deff*ieux, G., Vercauteren, J. & Merillon, JM (200 1 ) "Accumulation of Distilled Glycosides in Cell Suspensions of Vitis venifera" J. Nat. Prod. 59: 1 1 89- 1 1 9 1. All cosmetic ingredients containing resveratrol are recorded. For example, Pezzuto Researchers (US Patent No. 64 1 403 7) proposes a method for preventing or treating skin conditions by using a composition containing resveratrol, PiUai Researchers (US Patent No. 63) 5 8 5 1 7) A composition of skin care cosmetics containing white cucurbits 200826969 (4) Alcohol and selected vitamin A. A cosmetic composition containing tetrahydroxytrans pentadiene as an active ingredient is not currently described. Scientific evidence has confirmed that the uniqueness of tetrahydroxytrans hydrazine, stilbene and the addition of hydroxyl groups on tetrahydroxytrans stilbene are not simply on the extension of resveratrol. For example, refer to Ashikawa's researcher J.Immunol.2002 Dec 1;1 69( 1 1 ): 6490-7. Since tetrahydroxytrans pentadiene and its derivatives are phenols, they can be used as powerful antioxidants. [Means for Solving the Problem] The main invention of the present invention provides a composition for a skin conditioner containing vitamin A which is greatly improved in skin adaptability, and contains: (a) vitamin A alcohol, vitamin A ester, a vitamin A aldehyde, a vitamin A acid, a vitamin A acid salt, a derivative or the like thereof, and a single vitamin A selected from the group consisting of any one of them, in a concentration of about 0.001% by weight to 5% by weight (b) tetrahydroxytrans stilbene, dermatologically acceptable salts, esters, guanamines, these prodrugs and analogues, and combinations with any of these, 0.000 1% by weight to 1% by weight; (c) Allowable as a cosmetic agent The meaning of "adjusting agent" used in the text is for dry muscle, light-sensitive muscles, wrinkles, aging spots, aging muscles. , acne, leukoplakia, dryness, prevention and treatment of atopic dermatitis, softening the stratum corneum, inhibiting sebum secretion, and improving general skin texture. This component can also be used for skin desquamation and cell (5) (5) 200826969 proliferation improvement. The present invention substantially enhances the action of vitamin A alcohol and vitamin A ester by the presence of tetrahydroxytrans stilbene. Moreover, tetrahydroxytrans 1,2 diphenylethylene substantially enhances the cell proliferation of vitamin A alcohol and vitamin A ester. In mammals, tetrahydroxytrans pentadiene (the target at the molecular level is unknown) exerts the anti-oxidant and anti-inflammatory effects of dry cell cytokines production and function. However, in the actual improvement of the skin effect, it is achieved when tetrahydroxytrans stilbene is used in combination with vitamin A alcohol or vitamin A ester. That is, the present invention is based, at least in part, on the multiplication of vitamin A or vitamin A esters with tetrahydroxytrans stilbene. According to the present invention, the effect of the composition can be substantially improved by adding an effective amount of tetrahydroxytrans stilbene to the composition containing vitamin A or vitamin A ester. In the present invention, it comprises the prevention and treatment of dry muscle, light-sensitive muscle, wrinkles, aging spots, aging muscles, acne, leukoplakia, dry phlegm, atopic dermatitis, softening the stratum corneum, inhibiting sebum secretion, and improving The method of improving the skin conditioner and the like, and the method for preventing the same, the method also includes a method of applying the composition of the invention to the skin. Although the composition of the present invention is intended to be applied to the skin of a mammal which is dry, peeled, wrinkled, aged, and light-sensitive, the composition of the present invention is for preventing or reducing the deterioration of healthy skin, and for prevention purposes. Can also be applied. The present invention further comprises a cosmetic method for inhibiting skin irritation caused by vitamin A, -8-200826969 (6) tingling or inflammation. Based on this, the invention also includes a cosmetic composition containing four trans-type 1,2 diphenylethane and vitamin A. [Minor and definition] "Four trans-trans pentadiene," The term means any of the cis isomer of tetrahydroxy-trans-methane, stilbene, the trans isomer of tetrahydro-trans stilbene, or a mixture of two isomers. This term includes natural active ingredients and compounds chemically synthesized by the research laboratory. Also in the text, tetrahydroxytrans stilbene, including tetrahydroxytrans hydrazine, stilbene dermatological The term "treat" of allowable salts, esters, guanamines, prodrugs and the like, "treatment for skin conditions", etc., includes (1) prevention of conditions, that is, clinical Prevention of symptoms, (2) inhibition of the condition, that is, prevention of progression or progression of clinical symptoms and/or (3) mitigation of the condition, that is, elimination of clinical symptoms. "dermatologically permissible" means a substance that is biologically or otherwise suitable. That is to say, this substance, its Selective Active Ingredients 1. A substance that does not cause an undesirable biological effect when administered by an individual, or that does not adversely interact with any of the components of the pharmaceutical composition containing the same. A "dermatologically acceptable" salt, or a "dermatologically acceptable" ester of an active ingredient herein, is a salt or ester which is biologically or otherwise suitable. "Selected" or "optionally" "refers to the situation in which the following conditions occur or are not issued -9-200826969 (7). However, the condition includes both occurrence and non-occurrence. For example, an additive in the prescription" In the case of "presentation", it includes both the prescription containing the additive and the absence of the additive. [Active ingredient for disposal] The invention described above includes the use of vitamin A for prevention or treatment. The use of tetrahydroxytrans stilbene in the skin condition. Tetrahydroxytrans stilbene can be purified from natural, ie grape skin, red wine, or other plant ingredients, or Research room chemistry Synthetic or commercial products such as BIOMOL Research Laboratories Inc. (Plymouth Meeting, Penn State) may also be used. The method of extracting tetrahydroxy-trans-pyrylene from natural resources is preferred by German Don This ingredient is extracted from the bark of the bark. The active ingredient is a dermatologically acceptable salt, ester, guanamine, prodrug or the like. Alternatively, the salt or ester of tetrahydroxytrans stilbene may be used. A guanamine, a prodrug or the like can be produced by a person skilled in the art of organic chemical synthesis and pharmaceutical preparation by a well-known standard procedure. The manufacture of an ester includes the functionalization of a hydroxyl group in the molecular structure of the drug. A typical thiol-substituted derivative of a free alcohol group. That is, a portion of a residual acid derivative of the formula RCOOH (R is an alkyl group, preferably a low molecular weight hospital base). Esters, depending on their necessity, are usually converted to the free acids via hydrogenation or hydrolysis. A similar approach can be used in the manufacture of guanamine and prodrugs. The manufacture of other derivatives and analogs of the active ingredient can be inferred by the skilled person in organic chemical synthesis using the well-known -10-(8) (8)200826969 standard procedure or reference. a preferred derivative of cis and trans of tetrahydroxytrans stilbene, the hydroxyl group of which is typically 3-hydroxy, one or more of which is a monosaccharide or a disaccharide, generally a single The combination of the sugar position 1 position. The sugar which can be bonded to the tetrahydroxytrans stilbene has glucose, galactose, maltose, sucrose, etc., but is not limited thereto. In particular, cis tetrahydroxytrans 1,2 diphenylethylene glucoside and transtetrahydrol 1,2 stilbene glucoside (Astringine) are preferred. [Preparation for Cosmetics] An example of a preferred dosage form is the addition of an active ingredient to a topical formulation containing a suitable carrier and a technically well-known substance. The carrier used in the local aspect is selected from a carrier which provides the desired form of the composition. For example, ointments, lotions, creams, microemulsions, gels, oils, solutions, etc., may contain natural sources or synthetic substances. The selected carrier must have no adverse effect on the active ingredient and other ingredients in the topical composition. As a topical carrier, water, alcohols, glycols and other non-toxic organic solvents, glycerin, ore are suitable. Oil, polyoxyalkylene, petrolatum, lanolin, fatty acids, vegetable oils, waxes, etc. Partially preferred topical carriers are colorless, odorless solutions, lotions, creams, microemulsions, and gels. Various additives known to those skilled in the art can be included in the topical formulations of the present invention. Examples of such additives are dissolution aids -11 - 200826969 (9), skin permeability enhancers, bleaches, preservatives (eg, antioxidants), gelling agents, buffers, surfactants (especially nonionics). An amphoteric surfactant), an emulsifier, a skin softener, a thickener, a stabilizer, a wetting agent, a coloring agent, a perfume, etc., but are not limited thereto. When an emulsifier, a skin softener, and a preservative are added, it is preferred to add a dissolution aid and/or a skin permeability enhancer at the same time. The skin permeability enhancer allows the active ingredient to be easily passed through the non-injured skin at a therapeutic concentration. Suitable enhancers are well known in the art, for example, comprising 2-propanol and dimethyl isosorbide. Examples of the dissolution aid are as follows, but are not limited thereto, for example, 1,3-butanediol or dipropylene glycol. Other active ingredients may also be included in the prescription. That is, other anti-inflammatory agents, analgesics, antibacterial agents, antifungal agents, antibiotics, vitamins, antioxidants, and sunscreens, which are commonly used in sunscreens, are titanium dioxide, zinc oxide, and decyl sulfate. Benzophenone (especially benzophenone-3), camphor derivatives, cinnamate (eg, octylmethoxycinnamate), diphenylmethane (eg, butyl methoxydiphenylmethane) , P-aminobenzoic acid (PΑΒΑ) and derivatives thereof, and salicylates (eg, octyl salicylate) are used in the topical formulation desired in the present invention, and the active ingredient is 0 in the prescription. · 0 0 5 wt% to 1 〇 wt%, preferably from 0. 01% by weight to 5% by weight, more preferably from 0. 1% by weight to 5% by weight, 〇. 1% by weight to 2% by weight佳-12- (10) 200826969 [Effects of the Invention] [Use] Based on the composition of the present invention, it is mainly a cosmetic suitable for topical use on human skin, especially for skin care, moisturization, smoothing, wrinkles and aging A product for the prevention and suppression of muscles. As for the prescription, as described above, ointments, lotions, creams, microemulsions, gels, solutions, and the like are used for the skin part in order to obtain a desired result within an effective amount. The amount of one-time administration of the active ingredient is preferably in the range of 1 to 100 ml. Generally, the investment plan includes at least one partial administration per day. In the present invention, the specific formulation name is described, but the above examples and the following description are intended to be illustrative and not intended to be limiting. Other features, advantages, and modifications will become apparent to those skilled in the art of the invention. All patents, patents, and documents cited in this specification are incorporated herein by reference in their entirety. [Embodiment] [Embodiment 1] The production method based on the present invention is disclosed in the following embodiments in order to fully disclose the present invention, but the inventors do not intend to limit the scope of the invention. Try to make sure that it is correct in terms of numbers (eg, weight, temperature, etc.), but there may be errors and errors. -13- 200826969 (11) In the parts not specified, the ratio is the weight ratio, and the temperature is Celsius and the pressure is normal pressure. All solvents, reagents, and additives are pharmaceutical grades. [Example 2] In this example, a solution of tetrahydroxytrans stilbene was confirmed to inhibit the stimulation induced by vitamin A and to improve the appearance of the skin. The compositions of Example 1 and Comparative Examples 1 and 2 were prepared by using the components shown in Table 1. [Table 1] Ingredient Example 1 (% by weight) Comparative Example 1 (% by weight) Comparative Example 2 (% by weight) Dimethylisosorbide 25.0 25.0 25.0 Dipropylene glycol 74.4 74.6 74.8 d-α-tocopherol 0.2 0.2 0.2 Vitamin Α palmitate (1.7 m. IU / g) 0.2 0.2 0 trans-tetrahydroxytrans stilbene 0.2 0 0 The composition is as follows: d-α-tocopherol, vitamin A palmitic acid Ester (1.7m.IU/g) and trans-tetrahydroxytrans stilbene were dissolved in dimethyl isosorbide at 30 ° C, and added to the same at 30 ° C as a clear solution. Propylene glycol. The operation was carried out under a nitrogen blanket and all the solutions were stored under nitrogen. Regarding the composition of Example 1 and Comparative Examples 1 and 2 as a stimulus intensity of a cosmetic, a human 4-h skin test (Basketter DA, Food Chem Toxocl 1 997, 35··845·8 52) test. The experiment was carried on a 25 mm Hill Top Chambers with a Webril gasket (Hilltop, Inc., CINCINNATI, OH) -14 (12) 200826969 to carry 0.2 ml of the test solution for the upper hand of 16 volunteers. Pull the skin. The patch was attached in a balanced and random manner using the two strokes of the subject. After 24 hours, the patch was removed, and a mark was used to mark the portion to be tested. After 24, 48, and 72 hours, the presence or absence of irritation was observed at the test site, and the time of 24, 48, and 72 hours after removal of the patch was determined by the 4-score method (Table 2). [Table 2] Reaction evaluation Scoring reaction degree 0 No reaction + weak positive reaction (usually characterized by mild rash or extensive drying of the coated area) ++ Moderately positive reaction (usually there is a significant rash over the application site) +++ Severe positive reaction (strong, wide range of rashes often accompanied by edema) The results are shown in Table 3. [Table 3] Skin irritation composition of Example 1 and Comparative Examples 1 and 2 Example 1 Comparative Example 1 Comparative Example 2 Score (16 person average) 0 + 0 Addition of tetrahydroxy-trans 1, 2 In the case of styrene, it is apparent that the stimulation of vitamin A palmitate can be inhibited. -15- 200826969 (13) The effects of the composition of Example 1 and Comparative Examples 1 and 2 on the skin wrinkles of cosmetics were measured by a computerized laser side meter. The test was carried out in 16 women over the age of 30, and the example 1 and the comparison - - a. -. -.. - • fine. ... - - - - _ .·_· ·· -· · _ - - -" The composition of the examples 1 and 2 was applied to the face of the subject (area 2x2 cm2) once a day for 1 time 0.0 5 g for 9 weeks. Then copy the wrinkles (replica) of the skin with the precision structure of the plastic enamel. The wrinkle change of the replicated skin was examined using a visual skin tester (S k i η V i s i o m e t e r manufactured by Couage & Khazaka electronic G m b Η). The replicated three-dimensional image was analyzed with a CCD camera. For the improvement of skin wrinkles, calculate the average roughness (Rz) of wrinkles according to Equation 1 below.
Rz = (Ri+R2+.........+Rn-i+Rn)/皺紋數（η) (1) 此方程式中，Rn表示各皺紋之粗度而η爲皺紋之數 目。結果如表4所示。 [表4] 皮膚皺紋之改善效果（9週） 皴紋之平均粗度(Rz，單位μ ) 實施例1 比較實施例 11 比較實施例 12 T0 T9 Δ% T0 T9 Δ% T0 T9 Δ% 125 37 -70 133 59 •56 129 124 -4 由上表可知，皺紋之高度（粗度）以實施例1之組成9週 投與，有之減少，以比較實施例1之組成投與 -16- (14) 200826969 9週後有5 6 % (p < 0 · 0 1)之減少。因此’實施例1及比較實施 例1與安慰劑（比較實施例2)相比，顯示在統計上有意義地 可改善皮膚皺紋之粗度。此結果顯示四羥反式1，2二苯乙 烯對於改善皺紋之retinol(維生素A)之作用可使其實際增 強。此結果還顯示出作爲該發明之化妝品組成，在短期內 對皺紋改善就有可見之效果。 [實施例3] 此例中，反式（3,5,3’，4’-四羥二苯乙烯）-3-〇冲61&-(1-葡 萄糖苷（反式-astringine)可抑制溶液處方中維生素A類所 誘發之刺激，證實能改善皮膚之外觀。 實施例2之組成依表5所示之成分調製。 [表5] 成份名 實施例2(重量％) 二甲基異山梨醇 25.0 二丙二醇 74.4 d-α-生育醇 0.2 維生素A棕櫚酸酯(1.7m.IU/g) 0.2 反式 astringine 0.2 此組成爲依照實例1之操作方式調整而成。 用與實施例1所述之相同試驗方法，比較實施例2之組 成與比較實施例1及2組成的皮膚刺激強度。 結果如表6所不。 -17- (15) 200826969 [表6] 實施例2及比較實施例1及2之組成的皮膚刺激強度。 組成 實施例2 比較實施例1 比較實施例2 評分(16人平均） 0 + 0 藉由四羥反式1，2二苯乙烯-葡萄糖苷（astringine)之添 加，抑制了維生素A棕櫚酸酯的刺激。 實施例2之組成對於皮膚皺紋之改善效果’用與實施 例1所述之相同方法檢驗。其結果如表7所示。 [表7] 皮膚皺紋之改善效果（9週） 皺紋之平均粗度（Rz，單位// ) 實施例2 比較實施例 U 比較實施例 12 T0 T9 Δ% T0 T9 △% T0 T9 △% 129 43 -67 133 59 -56 129 124 -4 由上表可知，皺紋之高度（粗度）以實施例2之組成9週 投與，有67%(ρ<0·01)之減少。因此，實施例1及比較實施 例1與安慰劑（比較實施例2)相比’顯示在統計上有意義地 可改善皮膚皺紋之粗度。此結果顯示astringine對於改善 皴紋之retinol(維生素A)之作用可實際增強。此結果還顯 示出作爲該發明之化妝品組成’在對皺紋之改善於短期內 就有可見之效果。 -18- (16) 200826969 [實施例4] 此例中證實四羥反式1，2二苯乙烯，可抑制乳劑（洗劑） 型處方中維生素A類所誘發之刺激，改善皮膚之外觀。 實施例3與比較實施例3及4之組成，以表8所示之成分 調製。 [表8] 成分名 實施例3 (重量％) 比較實施例3 (重量％) 比較實施例4 (重量％) 液體石蠟 3.20 3.20 3.20 3_甲基葡萄糖倍半硬脂酸酯 1.20 1.20 1.20 PEG20甲基葡萄糖倍半硬脂酸酯 1.80 1.80 1.80 硬脂酸甘油酯（及）PEG100硬脂酸鹽 1.80 1.80 L80 硬脂酸 1.60 1.60 1.60 十六烷醇 1.20 1.20 1.20 環甲矽脂 2.40 2.40 2.40 水（純水） 76.53 76.73 76.93 羧基乙烯基聚合物 0.30 0.30 0.30 甘油 2.40 2.40 2.40 丙二醇 3.00 3.00 3.00 二甲矽酯/矽靈 1.60 1.60 1.60 氫氧化鈉（18%) 1.97 1.97 1.97 保存劑 0.40 0.40 0.40 d- α -生育醇 0.20 0.20 0.20 維生素Α棕櫚酸酯 0.20 0.20 0.00 四羥反式1，2二苯乙烯 0.20 0.00 0.00 該洗劑以化妝品用洗劑之標準操作法調製。 用與實施例1所述之相同方法’比較討論實施例3之組 -19- (17) 200826969 成與比較實施例3及4的組成之皮膚刺激強度。 結果如表9所示。 [表9] 實施例3與比較實施例3及4的組成之皮膚刺激度。 組成 實施例3 比較實施例3 比較實施例4 評分(16人平均） 0 + 0 藉由四羥反式1，2二苯乙烯之添加，明顯地抑制了洗 劑中維生素A棕櫚酸酯的刺激。 實施例3之組成對於皮膚皺紋之改善效果，用與實施 例1所述之相同方法檢驗。其結果如表1 〇所示。 [表 10] 皮膚皺紋之改善效果（9週） 皺紋之平均粗度（Rz，單位ju ) 實施例3 比較實施例 [3 比較實施例 (4 一 Τ0 T9 △% T0 T9 △% T0 T9 △%一 131 59 -55 128 88 -31 127 112 -12 一 由上表可知，皺紋之高度（粗度）以實施例3之組成9週 投與，有55%(p<0.01)之減少。比較實施例3之組成在9週 後有31%(ρ<0·01)之減少。 因此，實施例3及比較實施例3與安慰劑（比較實施例 4)相比，顯示在統計上有意義地可改善皮膚皺紋之粗度。 -20- (18) 200826969 此結果顯示四羥反式1，2二苯乙烯對於改善皺紋之retinol( 維生素A)之作用可實際增強。 此結果還顯示出作爲該發明之化妝品組成’在對皺紋 之改善於短期內就有可見之效果。 此例中證實四羥反式1，2二苯乙烯-葡萄糖苷（astringine) ，可抑制乳劑（洗劑）型處方中維生素A類所誘發之刺激， 改善皮膚之外觀。 實施例4之組成，以表1 1所示之成分調製。 [表 11] 成分名 實施例4 (重量％) 液體石蠘 3.20 3-甲基葡萄糖倍半硬脂酸酯 1.20 PEG20甲基葡萄糖倍半硬脂酸酯 1.80 硬脂酸甘油酯（及）PEG100硬脂酸鹽 1.80 硬脂酸 1.60 十六烷醇 1.20 環甲矽脂 2.40 水（純水） 76.53 羧基乙烯基聚合物 0.30 甘油 2.40 丙二醇 3.00 二甲矽酯/砂靈 1.60 氫氧化鈉（18%) 1.97 保存劑 0.40 d- α -生育醇 0.20 維生素Α棕櫚酸酯 0.20 Astringine 0.20 -21 - (19) 200826969 該洗劑以化妝品用洗劑之標準操作法調製。 用與實施例1所述之相同方法，比較討論實施例4組成 與比較實施例3及4組成的皮膚刺激強度。結果如表1 2所示 m 12] 實施例4與比較實施例3及4的組成之皮膚刺激度。 組成 實施例4 比較實施例3 比較實施例4 評分(16人平均） 0 + 0 藉由添加astringine，明顯地抑制了洗劑中維生素A 棕櫚酸酯的刺激。 實施例4之組成對於皮膚皺紋之改善效果，用與實施 例1所述之相同方法檢驗。其結果如表1 3所示。 im 13] 皮膚皺紋之改善效果（9週） 皺紋之平均粗度（Rz，單位/Ο 實施例4 比較實施例 |3 比較實施例 [4 T0 T9 Δ% T0 T9 Δ% T0 T9 △% 135 47 -65 128 88 -31 127 112 -12 由上表可知，皺紋之高度（粗度）以實施例4之組成9週 投與，有6 5 % (p < 0 · 〇 1 )之減少。因此，實施例4與安慰劑（ -22- (20) 200826969 比較實施例4)相比，顯示在統計上有意義地可改善皮膚皺 紋之粗度。 此結果顯示astringine對於改善皺紋之retinol(維生 素A)之作用可實際增強，及astringine在乳劑型化妝品中 有比四羥反式1,2二苯乙烯更好之效果。 此結果還顯示出作爲該發明之化妝品組成，在對皺紋 之改善於短期內就有可見之效果。 -23-Rz = (Ri + R2 + ... ... + Rn - i + Rn) / number of wrinkles (η) (1) In the equation, Rn represents the thickness of each wrinkle and η is the number of wrinkles. The results are shown in Table 4. [Table 4] Skin wrinkle improvement effect (9 weeks) Mean grain thickness (Rz, unit μ) Example 1 Comparative Example 11 Comparative Example 12 T0 T9 Δ% T0 T9 Δ% T0 T9 Δ% 125 37 -70 133 59 •56 129 124 -4 As can be seen from the above table, the height (thickness) of the wrinkles was administered by the composition of Example 1 for 9 weeks, and was reduced, and the composition of Comparative Example 1 was administered -16- ( 14) 200826969 There is a decrease of 5 6 % (p < 0 · 0 1) after 9 weeks. Therefore, Example 1 and Comparative Example 1 showed statistically significant improvement in the thickness of skin wrinkles as compared with placebo (Comparative Example 2). This result shows that the effect of tetrahydroxytrans 1,2-diphenylethylene on the improvement of wrinkle retinol (vitamin A) can actually increase it. This result also shows that as a cosmetic composition of the invention, there is a visible effect on wrinkle improvement in a short period of time. [Example 3] In this example, trans (3,5,3',4'-tetrahydroxystilbene)-3-indole 61 &-(1-glucoside (trans-astringine) inhibiting solution The stimulation induced by vitamin A in the prescription was confirmed to improve the appearance of the skin. The composition of Example 2 was prepared according to the components shown in Table 5. [Table 5] Ingredient name Example 2 (% by weight) Dimethylisosorbide 25.0 Dipropylene glycol 74.4 d-α-tocopherol 0.2 Vitamin A palmitate (1.7 m. IU/g) 0.2 trans astringine 0.2 This composition was adjusted in accordance with the procedure of Example 1. The same test method was used to compare the skin irritation intensity of the composition of Example 2 with the compositions of Comparative Examples 1 and 2. The results are shown in Table 6. -17- (15) 200826969 [Table 6] Example 2 and Comparative Example 1 and Skin irritation intensity of composition 2. Composition Example 2 Comparative Example 1 Comparative Example 2 Score (16 person average) 0 + 0 by addition of tetrahydroxytrans stilbene-glucoside (astringine), Stimulation of vitamin A palmitate was inhibited. The effect of the composition of Example 2 on the improvement of skin wrinkles The results were the same as those described in Example 1. The results are shown in Table 7. [Table 7] Skin wrinkle improvement effect (9 weeks) Wrinkle average roughness (Rz, unit / /) Example 2 Comparative Example U Comparative Example 12 T0 T9 Δ% T0 T9 Δ% T0 T9 Δ% 129 43 -67 133 59 -56 129 124 -4 As can be seen from the above table, the height (thickness) of wrinkles was administered by the composition of Example 2 for 9 weeks. There was a decrease of 67% (ρ < 0·01). Therefore, Example 1 and Comparative Example 1 showed a statistically significant improvement in the thickness of skin wrinkles as compared with placebo (Comparative Example 2). This result shows that astringine can actually enhance the effect of retinol (vitamin A) for improving crepe. This result also shows that the cosmetic composition of the invention has a visible effect on the improvement of wrinkles in a short period of time. -18- ( 16) 200826969 [Example 4] In this example, tetrahydroxytrans stilbene was confirmed to suppress the stimulation induced by vitamin A in the emulsion (lotion) type prescription, and to improve the appearance of the skin. The compositions of Comparative Examples 3 and 4 were prepared and prepared by the components shown in Table 8. [Table 8] Composition Example 3 (% by weight) Comparative Example 3 (% by weight) Comparative Example 4 (% by weight) Liquid paraffin 3.20 3.20 3.20 3_methylglucose sesquistearate 1.20 1.20 1.20 PEG20 methyl glucose sesqui-semi-hard Fatty acid ester 1.80 1.80 1.80 Glyceryl stearate (and) PEG100 stearate 1.80 1.80 L80 Stearic acid 1.60 1.60 1.60 Cetyl alcohol 1.20 1.20 1.20 Cyclomethate 2.40 2.40 2.40 Water (pure water) 76.53 76.73 76.93 Carboxyvinyl polymer 0.30 0.30 0.30 Glycerol 2.40 2.40 2.40 Propylene glycol 3.00 3.00 3.00 Dimethyl ester / 矽 1.60 1.60 1.60 Sodium hydroxide (18%) 1.97 1.97 1.97 Preservative 0.40 0.40 0.40 d- α - Tocopherol 0.20 0.20 0.20 Vitamin Α palmitate 0.20 0.20 0.00 Tetrahydroxytrans 1,2 stilbene 0.20 0.00 0.00 This lotion is prepared by standard operation method of cosmetic lotion. The skin irritation intensity of the composition of Comparative Example 3 and 4 was compared with the group of Examples -19-(17) 200826969 in the same manner as described in Example 1. The results are shown in Table 9. [Table 9] Skin irritation of the compositions of Example 3 and Comparative Examples 3 and 4. Composition Example 3 Comparative Example 3 Comparative Example 4 Score (16 person average) 0 + 0 By the addition of tetrahydroxytrans stilbene, the stimulation of vitamin A palmitate in the lotion was remarkably suppressed . The effect of the composition of Example 3 on the skin wrinkles was examined in the same manner as described in Example 1. The results are shown in Table 1. [Table 10] Skin wrinkle improvement effect (9 weeks) Wrinkle average roughness (Rz, unit ju) Example 3 Comparative Example [3 Comparative Example (4 Τ0 T9 Δ% T0 T9 △% T0 T9 △% A 131 59 -55 128 88 -31 127 112 -12 As can be seen from the above table, the height (thickness) of the wrinkles was administered by the composition of Example 3 for 9 weeks, with a decrease of 55% (p < 0.01). The composition of Example 3 had a decrease of 31% (ρ < 0·01) after 9 weeks. Therefore, Example 3 and Comparative Example 3 showed statistically significant compared with placebo (Comparative Example 4). Improves the thickness of skin wrinkles. -20- (18) 200826969 This result shows that tetrahydroxytrans stilbene can actually enhance the effect of wrinkle retinol (vitamin A). This result is also shown as the invention The cosmetic composition 'has a visible effect on the improvement of wrinkles in a short period of time. In this case, it is confirmed that the tetrahydrol stilbene-glucoside (astringine) can inhibit the vitamins in the emulsion (lotion) type prescription. The stimulation induced by class A improves the appearance of the skin. The composition of Example 4 is shown in Table 11. Ingredient composition. [Table 11] Ingredient name Example 4 (% by weight) Liquid Dendrobium 3.20 3-methylglucose sesquistearate 1.20 PEG20 methyl glucose sesquistearate 1.80 Stearic acid glyceride (and ) PEG100 stearate 1.80 stearic acid 1.60 cetyl alcohol 1.20 cyclomethicone 2.40 water (pure water) 76.53 carboxyvinyl polymer 0.30 glycerol 2.40 propylene glycol 3.00 dimethyl oxime ester / sand saponin 1.60 sodium hydroxide (18 %) 1.97 Preservative 0.40 d-α-tocopherol 0.20 Vitamin Α palmitate 0.20 Astringine 0.20 -21 - (19) 200826969 This lotion is prepared by the standard method of cosmetic lotion. In the same manner, the skin irritation intensity of the composition of Example 4 and the compositions of Comparative Examples 3 and 4 was compared and compared. The results are shown in Table 12 for the skin irritation of the composition of Example 4 and Comparative Examples 3 and 4. Composition Example 4 Comparative Example 3 Comparative Example 4 Score (16 person average) 0 + 0 The stimulation of vitamin A palmitate in the lotion was significantly inhibited by the addition of astringine. The composition of Example 4 was changed for skin wrinkles. The effect was tested by the same method as described in Example 1. The results are shown in Table 13. im 13] Skin wrinkle improvement effect (9 weeks) Wrinkle average thickness (Rz, unit / 实施 Example 4 Comparative Example | 3 Comparative Example [4 T0 T9 Δ% T0 T9 Δ% T0 T9 Δ% 135 47 -65 128 88 -31 127 112 -12 As can be seen from the above table, the height (thickness) of wrinkles is as in Example 4. The composition was administered for 9 weeks, with a decrease of 65% (p < 0 · 〇1). Thus, Example 4 showed a statistically significant improvement in the thickness of skin wrinkles compared to placebo (-22-(20) 200826969 Comparative Example 4). This result shows that astringine can actually enhance the effect of retinol (vitamin A) for improving wrinkles, and astringine has a better effect than tetrahydroxytrans stilbene in emulsion cosmetics. This result also shows that as a cosmetic composition of the invention, there is a visible effect in the improvement of wrinkles in a short period of time. -twenty three-