CN105188727A - 美白促进剂或特应性皮炎改善剂 - Google Patents
美白促进剂或特应性皮炎改善剂 Download PDFInfo
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Abstract
选自由以下组成的组的肽:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp或其药学上可接受的盐作为美白促进剂或特应性皮炎改善剂是有用的。
Description
技术领域
本发明涉及一种美白促进剂或特应性皮炎改善剂,其包含肽等。
背景技术
紫外线辐射被认为是斑(斑疹)和皮肤的雀斑的一个原因。因紫外线照射形成色素沉着的过程,大致可分为三个阶段:黑素细胞的增殖,是黑素化限速酶的酪氨酸酶的合成和激活,和从黑素细胞到角化细胞的黑色素小体运输。特别是,UVB辐射后旁分泌地作用于来自表皮角化细胞的黑素细胞的细胞因子很大程度涉及前两个阶段,和迄今已经报道了内皮缩血管肽-1(ET-1),碱性成纤维细胞生长因子(bFGF),α-黑素细胞刺激素(αMSH),膜结合的干细胞生长因子(SCF),一氧化氮(NO)等。因此,可以通过抑制这些细胞因子,例如,通过抑制内皮缩血管肽-1(非专利文献1)的表达来抑制色素沉着。
皮肤是由表皮层和真皮层组成的,并且已经发现,除了表皮层细胞,conifered包膜(CE),其是一个边缘结构,还在屏障功能中具有重要作用。因为表皮角质分化,形成CE的前体蛋白出现在从棘层上层跨越到颗粒层的位置。然后,在到达角质层的过程中,这些蛋白质的赖氨酸残基和谷氨酰胺残基间形成异肽键,并因此发生交联和不溶化,从而完成CE。另外,经由多胺的谷氨酰胺残基之间形成的伪异肽键的存在也是已知的。这些键的形成是通过转谷氨酰胺酶(TGase)催化的,转谷氨酰胺酶是与表皮角化的分化相关联产生的酶。转谷氨酰胺酶包括几个同工酶,其中,存在于细胞质的TGase3和膜结合TGase1被推测为在形成CE中具有重要作用。转谷氨酰胺酶负责交联结构蛋白,但是在表皮在深空间仍然未分化的阶段不具有粘附蛋白的功能。然后,有一个巧妙的机制,其中当表皮成熟和分化,具有低活性的前体逐渐具有活性和开始运作。构成CE的前体蛋白的例子包括内披蛋白,兜甲蛋白,小的富含脯氨酸的蛋白质(SPR,角质蛋白),抑半胱氨酸蛋白酶蛋白A,弹性蛋白酶蛋白(elafin),聚丝蛋白,角蛋白,包斑蛋白(envoplakin),桥粒组成蛋白(desmosomeconstitutingprotein),squireline,膜联蛋白I和PAI-2。当这些前体蛋白增加,CE也增加,因此,屏障功能改进。聚丝蛋白是在表皮的颗粒细胞中产生的碱性蛋白之一,并且具有通过形成角质层,从而改善屏障功能,抑制对异物的免疫应答的作用,角质层是用于改善特应性皮炎的功能所必需的。在被生物合成为前体聚丝蛋白原,形成角质层的阶段,磷酸聚丝蛋白原经受去磷酸化和有限的水解而分解以形成聚丝蛋白。此外,聚丝蛋白被降解,形成天然保湿因子(NMF)。干燥也是使特应性皮炎恶化的一个因素。可以想象的是,为NMF源的聚丝蛋白的增加和表皮透明质酸的产生的促进也提高了保水性和与NMF同样地改善皮肤干燥,从而改善特应性皮炎。
因此,转谷氨酰胺酶1(TGM1),内披蛋白(ivl),角蛋白10(K10)和聚丝蛋白(FLG)的表达为分化过程的最后阶段的一个标识。通过促进转谷氨酰胺酶1,内披蛋白,角蛋白10和聚丝蛋白的表达,表皮代谢,即表皮角化细胞的代谢被促进,使得表皮角化细胞也不会在皮肤表面作为斑(斑疹)或雀斑而被保留,能促进从皮肤释放黑色素颗粒。此外,由于特应性皮炎与聚丝蛋白的蛋白质减少和保湿性能力的恶化相关联,聚丝蛋白基因表达的增强和透明质酸合酶2基因的表达增强有助于特应性皮炎的改善。
非专利文献2描述了,当胶原口服给予胶原合成被抑制到正常的小鼠的40%的伪老龄小鼠时,所述胶原合成量恢复到98%,并且皮肤周转被促进了约20%。据文献报道,本实验结果被归因于促进支承皮肤的基底层的真皮层的胶原合成,和与这相关的表皮代谢的活化。然而,非专利文献2缺少关于胶原肽混合物等的说明,并没有显示促进美白的效果,因为实验使用了伪老龄小鼠,其中胶原的合成被异常降低。
非专利文献3描述了,从水母来源的胶原肽混合物具有抗氧化作用,并减少黑色素的量。但是,由于非专利文献3的实验系统不同于本说明书的实验系统,并不能进行与本发明的效果的比较,我们制备了非专利文献3的胶原肽混合物,如在后述的比较例24所述,并做了评价试验。其结果是,得以揭示的是,非专利文献3的胶原肽混合物效果显著劣于本发明的效果。
非专利文献4描述了鹿角胶有聚丝蛋白表达促进能力。然而,如从后述的比较例26可知,使用商购的鹿角胶进行的评价试验,其显示,该鹿角胶效果显著劣于本发明的效果。
非专利文献5报告,来源于鲑鱼皮的胶原肽可改善特应性皮炎,如颈背部得分所示的。然而,通过使用购买的海洋胶原肽以在如后述的比较例27中描述的方式进行的评价试验显示,该海洋胶原肽效果显著劣于本发明的效果。
专利文献1描述,用于通过三肽改善特应性皮炎引起的皮肤瘙痒感的外用制剂。专利文献1的肽不同于本发明的肽序列,专利文献1的肽的预期的用途是改善特应性皮炎引起的皮肤瘙痒感,不同于通过本发明实质改善特应性皮炎本身。专利文献2中报告,当使用相似于专利文献1胶原肽的胶原肽时,在所有测量的项目中没有观察到显著差异,所有测量的项目包括特应性皮炎引起的皮肤瘙痒感,在血液中总IgE量的测定值,经表皮水份丢失(TEWL),和在皮肤中嗜酸细胞计数和肥大细胞计数。此外,购买了这些胶原肽和同时相比这些胶原肽,如在后述的比较例25中所述,并且证实这些胶原肽效果显著劣于本发明的效果。
引用列表
专利文献
专利文献1:特开2003-137807
专利文献2:WO2011/070767
非专利文献
非专利文献1:J.Invest.Dermatology,105:32-37(1995)
非专利文献2:FragranceJournal,1997-7:58-64
非专利文献3:J.Sci.FoodAgric.,89:1722-1727(2009)
非专利文献4:Int.J.Cosmet.Sci.,35(3):281-285(2013)
非专利文献5:NorthernAdvancementCenterforScience&Technology,ReportsofResearch&Developmentsubsidizingprojects2005(于2004获得认可)(財財法人北海道科学技術術合振興センター平成17年(平成16年度採採分)研究開開助成事業業告書),第161-174页
发明内容
技术问题
要由本发明解决的问题是提供一种优良的美白促进剂或特应性皮炎改善剂。
解决问题的方案
通过大量的努力,本发明人发现选自由Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp组成的组的肽具有优良的内皮缩血管肽-1表达的抑制效果,并且还具有促进转谷氨酰胺酶1,内披蛋白,角蛋白10,聚丝蛋白和透明质酸合酶2的表达的效果,终于完成了本发明。具体地说,本发明如下。
[1]一种美白促进剂或特应性皮炎改善剂,其含有选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp。
[2]根据[1]记载的美白促进剂或特应性皮炎改善剂,含有胶原肽混合物,所述胶原肽混合物含有选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp,使得所述肽或其药物学上可接受的盐的总含量为1.6重量%或更多。
[3]根据[1]记载的美白促进剂或特应性皮炎改善剂,含有胶原肽混合物,所述胶原肽混合物含有选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp,使得所述肽或其药物学上可接受的盐的总含量为1.6重量%或更多。
[4]根据[1]至[3]中的任一项的美白促进剂或特应性皮炎改善剂,其通过口服或经皮给药。
[5]一种内皮缩血管肽-1表达抑制剂,包括选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp。
[6]一种聚丝蛋白表达促进剂,其含有选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp。
[7]一种促进美白的方法或改善特应性皮炎的方法,包括应用选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp至需要其的对象。
[8]一种抑制内皮缩血管肽-1表达的方法或促进聚丝蛋白的表达的方法,包括应用选自由以下组成的组的肽或其药学上可接受的盐至需要其的对象:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp。
发明的效果
选自由以下组成的组的肽:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp抑制内皮缩血管肽-1的表达,并因此抑制由黑素细胞生成黑色素色素,并抑制色素沉着。此外,这些肽促进转谷氨酰胺酶1,内披蛋白,角蛋白10和聚丝蛋白的表达,从而促进表皮代谢以促进皮肤的周转,使在皮肤中的黑色素色素(斑(斑疹))更迅速地排出。这两种效果促进美白。
此外,选自由以下组成的组的肽:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp通过促进聚丝蛋白基因表达改善皮肤屏障功能。此外,存在作为产生的聚丝蛋白的降解的结果的天然保湿因子(NMF),由此可改善皮肤的干燥。还通过在角质形成细胞中促进透明质酸的产生,能够提高表皮的保湿性和改善皮肤干燥,如同采用NMF的情况。而体内免疫力低下是特应性皮炎的原因之一,体内的IgE值被显著抑制,并且当胶原肽混合物被摄取时观察到变应性免疫力低下,胶原肽混合物含有高浓度的这些肽。这两种效果改善特应性皮炎。
具体实施方式
以下,对本发明进行详细说明。
1.肽
本发明中使用的肽是Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp(以下,也称为本发明的肽),和本发明的肽可以是药学上可接受的盐。优选的肽包括:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5和(Pro-Hyp-Gly)2,并且更优选的肽包括Hyp-Gly和Pro-Ala-Gly。本发明的肽可以是两种或多种肽的组合。另外包括这些肽或其药学上可接受的盐的胶原肽混合物可以被使用。在这种情况下,这些肽或其药学上可接受的盐的总含量是1.6重量%或更多,优选1.8重量%或更多,更优选2.0重量%或更多,进一步优选为2.3重量%或更多,和尤其优选为2.6重量%或更多。还优选的是,一种胶原肽混合物,其包括选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp,使得的这些肽或其药学上可接受的盐的总含量为1.6重量%或更多,优选1.8重量%或更多,更优选为2.0重量%或更多,进一步优选为2.3重量%或更多,特别优选为2.6重量%或更多。优选的例子包括,例如,胶原肽混合物“S型”(获自新田明胶公司(新田ゼラチン製)),其含有2.94重量%的这些肽。
“药学上可接受的盐”的实例包括无机酸盐如盐酸盐,硫酸盐,磷酸盐和氢溴酸盐,有机酸盐如乙酸盐,甲磺酸盐,苯磺酸盐,对甲苯磺酸盐,琥珀酸盐,草酸盐,富马酸盐,和马来酸盐,无机碱性盐例如钠盐,钾盐,和钙盐,和有机碱盐,如三乙基铵盐。根据通常的方法,特定肽可被制成药学上可接受的盐。
本发明的肽可通过使用,例如,固相合成法或液相合成法(例如,日本特开2003-183298号公报)从氨基酸合成。在固相合成法的情况下,Fmoc法和Boc法是已知的,和本发明的肽可以通过任何一种方法来合成。固相合成方法的例子将被如下进行具体说明。具有约0.1mm直径、在其表面上采用氨基修饰的聚苯乙烯高分子凝胶的珠用作固相,和二异丙基碳二亚胺被用作缩合剂。首先,在C末端的氨基酸氨基被用Fmoc基团或Boc基团保护,并使其与上述的聚苯乙烯高分子凝胶的氨基形成肽键。将固相用溶剂充分洗涤,剩下的试剂和氨基酸通过洗涤除去,然后结合于固相的氨基酸氨基的保护基被除去。然后,通过使用氨基被保护的氨基酸依次重复上述反应,在固相合成肽。最后,用三氟乙酸浸渍固相,以从固相分离肽,从而肽可以被合成。
也可以通过结合两种或更多种的内切型蛋白酶和外切型蛋白酶水解明胶产生本发明的肽。另外,在本发明中,上面提到的水解胶原肽混合物或通过部分纯化上面提到的水解胶原肽混合物获得的混合物也可以被使用。例如,通过参照在WO2012/081531,WO2012/102308等中描述的方法,可以进行,组合前述两种或更多种的水解,和其纯化等。
另外,在本发明中,本发明的肽可被化学修饰。化学修饰可以对每个氨基酸单元进行,例如,羟基羟脯氨酸的羟基,N-末端氨基酸的氨基和C末端氨基酸的羧基。这种化学修饰允许在弱酸性至中性条件溶解,使得可以提高与后述的其它活性成分的相容性。
具体地说,羟脯氨酸的羟基的化学修饰包括,例如,O-乙酰化。N末端氨基酸的氨基的化学修饰包括,例如,多肽基化,琥珀酰化,马来酰化,乙酰化,脱氨基化,苯甲酰化,烷基磺酰化,烯丙基磺酰化,二硝基苯基化,三硝基苯基化,氨甲酰化,苯基氨甲酰化,和硫醇化。C-末端氨基酸的羧基的化学修饰包括,例如,酯化和酰胺化。此外,在阳离子化本发明的肽的情况下,可以进行乙二胺化,精胺化等。
作为化学修饰的具体的手段和处理条件,可应用用于普通的肽的化学修饰技术。例如,羟基脯氨酸的羟基的O-乙酰化可以通过采用乙酸酐在水性溶剂或非水溶剂中反应来进行。例如,C-末端氨基酸的羧基的酯化,可以如下进行,例如,通过采用干燥的氯化氢气体通气于在甲醇中的悬浮液,以及可以通过与碳二亚胺或类似物反应来进行酰胺化。此外,作为化学修饰的其他具体例,在日本专利公开号昭62-44522和日本专利公开号平5-79046等中描述的化学修饰技术可以应用。
2.美白促进剂或特应性皮炎改善剂
如将在后述的试验例所进行的说明,本发明肽具有内皮缩血管肽-1的表达抑制效果。它也具有促进表皮转谷氨酰胺酶1,内披蛋白,角蛋白10,聚丝蛋白和透明质酸合酶2表达的效果。这两种效果抑制黑色素色素的生成,并导致在皮肤中的黑色素色素被更迅速地排出,因此提供用作美白促进剂或特应性皮炎改善剂。具体应用包括医药品,化妆品,用于特定保健用的食品,保健食品,和以被包含在各种食品材料的状态给予对象如人类和哺乳动物。
本发明的美白促进剂或特应性皮炎改善剂可以以各种形式口服或非口服给药。用于口服给药的形式实例包括片剂,颗粒剂,胶囊剂,粉剂,液剂,混悬剂,和乳剂,以及饮料或食品中的混合物。用于非口服给药的形式实例包括涂覆到皮肤,注射剂,经皮剂,栓剂,滴鼻剂和吸入剂。优选的实例包括片剂,颗粒剂,胶囊剂,直接涂覆到皮肤的液体,薄膜剂,软膏,乳膏,和泥敷剂。本发明的肽是适合通过口服给药摄取,因为它在消化道被少量消化成氨基酸,并且在肠道被迅速吸收。还优选的是,本发明肽以在膳食或饮料中被混合的状态而被摄取。
本发明肽的剂量取决于对象的状况和体重,化合物种类,给药途径等等而不同,并且在口服给药的情况下是,例如,约0.1至2000毫克,优选约1至1000mg,更优选约5至500毫克,特别优选为约10至200毫克每位成人。当肽被直接施用到皮肤上,本发明的肽在整个经皮剂的含量为,例如约0.00001~20重量%,优选约0.0001~10重量%,更优选约0.001至5重量%。关于其它形式的制剂,剂量可适当地参照这些剂量确定。这些制剂可以在每天一次至数次给药,或每一至数天给药一次。当制剂被以胶原肽混合物的形式使用时,可调整,使得包含在其中的本发明肽具有如上所述的剂量或含量。
本发明的美白促进剂或特应性皮炎的改善剂可以含有适宜的其它活性成分和用于制剂的成分,只要本发明的效果不被干扰。其它活性成分的实例包括,例如,透明质酸。其它活性成分的混合量可以根据各个效果进行适当变更。
用于配制成药物制剂的药学上可接受的载体实例包括稀释剂,粘合剂(糖浆,阿拉伯胶,明胶,山梨醇,黄蓍胶,或聚乙烯吡咯烷酮),赋形剂(乳糖,蔗糖,玉米淀粉,磷酸钾,山梨糖醇,或甘氨酸),润滑剂(硬脂酸镁,滑石,聚乙二醇或二氧化硅),崩解剂(马铃薯淀粉)和润湿剂(月桂基硫酸钠)。本申请药物制剂可通过将本发明肽,其它活性成分,药学上可接受的载体等按照公知的方法来制造。
实施例
在下面,本发明将被更具体地通过实施例,比较例,和试验例来描述,但是,要注意的是,本发明不受这些的任何限制。
实施例1~11
通过如上所述的肽固相合成方法合成了下列肽。
(实施例1)(Pro-Hyp-Gly)5[(POG)5]
(实施例2)(Pro-Hyp-Gly)2[(POG)2]
(实施例3)Gly-Pro[GP]
(实施例4)Pro-Ala-Gly[PAG]
(实施例5)Pro-Hyp-Gly[POG]
(实施例6)Glu-Hyp[EO]
(实施例7)Ala-Hyp-Gly[AOG]
(实施例8)Glu-Hyp-Gly[EOG]
(实施例9)Hyp-Gly[OG]
(实施例10)Ser-Hyp-Gly[SOG]
(实施例11)Phe-Hyp[FO]
实施例12
胶原肽混合物“S型”(获自新田明胶公司)。
通过LC-MS/MS的分析发现,此胶原肽混合物含有下列肽。
GP:672ppm,PAG:12520ppm,POG:340ppm,EO:58ppm,AOG:331ppm,EOG:308ppm,OG:14581ppm,SOG:283ppm,FO:283ppm。
实施例13
胶原肽的混合物“LCP”(获自新田明胶公司)。
通过LC-MS/MS分析发现,此胶原肽混合物含有下列肽。
GP:249ppm,PAG:15568ppm,POG:没有检出,EO:14ppm,AOG:29ppm,EOG:126ppm,OG:545ppm,SOG:3ppm,FO:未检出。
比较例1~6
通过如上所述的肽固相合成方法合成了下列肽。
(比较例1)Gly-Pro-Hyp[GPO]
(比较例2)Ala-Hyp[AO]
(比较例3)Leu-Hyp[LO]
(比较例4)Pro-Gly[PG]
(比较例5)Pro-Pro[PP]
(比较例6)Pro-Ala[PA]
比较例7至23
(比较例7)L-脯氨酸(可以获自WakoPureChemicalIndustries,Ltd.)
(比较例8)L-羟基脯氨酸(可以获自TOKYOCHEMICALINDUSTRYCO.,LTD.)
(比较例9)L-甘氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例10)L-亮氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例11)L-谷氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例12)L-丙氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例13)L-丝氨酸(可以获自WakoPureChemicalIndustries,Ltd.)
(比较例14)L-苯基丙氨酸(可以获自WakoPureChemicalIndustries,Ltd.)
(比较例15)L-甘氨酸(可以获自KANTOCHEMICALCO.,INC.)+羟基脯氨酸(可以获自TOKYOCHEMICALINDUSTRYCO.,LTD.)
(比较例16)L-脯氨酸(可以获自WakoPureChemicalIndustries,Ltd.)+L-丙氨酸(可以获自KANTOCHEMICALCO.,INC.)+L-甘氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例17)L-脯氨酸(可以获自WakoPureChemicalIndustries,Ltd.)+L-羟基脯氨酸(可以获自TOKYOCHEMICALINDUSTRYCO.,LTD.)+L-甘氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例18)L-谷氨酸(可以获自KANTOCHEMICALCO.,INC.)+L-羟基脯氨酸(可以获自TOKYOCHEMICALINDUSTRYCO.,LTD.)
(比较例19)L-丙氨酸(可以获自KANTOCHEMICALCO.,INC.)+L-羟基脯氨酸(可以获自TOKYOCHEMICALINDUSTRYCO.,LTD.)+L-甘氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例20)L-谷氨酸(可以获自KANTOCHEMICALCO.,INC.)+L-羟基脯氨酸(可以获自TOKYOCHEMICALINDUSTRYCO.,LTD.)+L-甘氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例21)L-羟基脯氨酸(可以获自TOKYOCHEMICALINDUSTRYCO.,LTD.)+L-甘氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例22)L-丝氨酸(可以获自WakoPureChemicalIndustries,Ltd.)+L-羟基脯氨酸(可以获自TOKYOCHEMICALINDUSTRYCO.,LTD.)+L-甘氨酸(可以获自KANTOCHEMICALCO.,INC.)
(比较例23)L-苯基丙氨酸(可以获自WakoPureChemicalIndustries,Ltd.)+L-羟基脯氨酸(可以获自TOKYOCHEMICALINDUSTRYCO.,LTD.)
比较例24
从水母衍生的胶原肽混合物根据在非专利文献3描述的方法制备。具体地说,明胶是按照通常的方法从水母中通过加热提取,胰蛋白酶(获自Sigma)以1/100的比例加入到底物,并且将混合物在45℃反应3小时(pH为7.0)。此外,ProperaseE(可得自GenencorKYOWA)以1/50的比率加入到底物,并且将混合物在50℃反应3小时(pH为7.5)。将反应保温在95℃5分钟使酶失活。然后,进行离心分离(5000克×15分钟),并收集上清液,得到胶原肽混合物。通过LC-MS/MS分析发现,此胶原肽混合物含有下列肽。
GP:5ppm,PAG:2ppm,POG:7ppm,EO:未检出,AOG:2ppm,EOG:2ppm,OG:10ppm,SOG:1ppm,FO:未检出。
比较例25
胶原肽的混合物“HACP(猪来源)”(可以获自JELLICE)。
通过LC-MS/MS分析发现,此胶原肽混合物含有下列肽。
GP:359ppm,PAG:761ppm,POG:14ppm,EO:271ppm,AOG:25ppm,EOG:没有检出,OG:75ppm,SOG:没有检出,FO:未检出。
对比实施例26
鹿角胶从SiwonHerbalMedicineCo购买。LC-MS/MS分析表明,在比较例26的鹿角胶中没有检测到任何本发明的肽。
比较例27
海洋胶原肽购买自IHARA&CO.,LTD。
通过LC-MS/MS分析发现,下列肽被包含在比较例27的胶原肽混合物中。
GP:没有检出,PAG:58ppm,POG:15ppm,EO:128ppm,AOG:34ppm,EOG:104ppm,OG:378ppm,SOG:没有检出,FO:未检出。
试验例1
ET-1的表达抑制试验/K10,TGM1,ivl,FLG和HAS2表达促进试验
正常人表皮角质形成细胞NHEK(NB)(获自KURABOINDUSTRIESLTD。)被使用。将细胞在HuMedia-KG2(获自KURABOINDUSTRIESLTD)中预培养,和1.5×104细胞/mL×5毫升(7.5×104个细胞/皿)在60毫米培养皿中培养2天。确认细胞汇合后,将培养基替换为5毫升HuMedia-KB2(获自KURABOINDUSTRIESLTD。)。样品以各自浓度添加,并使其反应24小时(ET-1,K10),48小时(TGM1,ivl,HAS2)和72小时(FLG)。总RNA从细胞中提取,逆转录,并进行实时PCR。在实时PCR中,作为靶基因,内皮缩血管肽-1(ET-1;Hs00174961_m1),角蛋白10(K10;Hs01043114_g1),转谷氨酰胺酶-1(TGM1;Hs01070310_m1),内披蛋白(ivl;Hs00846307_s1),聚丝蛋白(FLG;Hs00856927_g1)和透明质酸合酶2(HAS2;Hs00193435_m1)被测定。GAPDH用作校正基因。计算是通过使用校准曲线法进行,并且引物和探针使用TaqMan基因表达的FAM色素。
对于实施例1至13和比较例1至27中的每种肽等,内皮缩血管肽-1(ET-1),角蛋白10(K10),转谷氨酰胺酶1(TGM1),内披蛋白(ivl),聚丝蛋白(FLG)和透明质酸合酶2(HAS2)的RNA表达量被测定。结果示于表1~12。各表中的值是平均值±标准偏差,并且*,**和***分别表示,相对于配对t检验的对照,它们分别以P<0.05,P<0.01,和P<0.001显著。
[表1]
[表2]
[表3]
[表4]
[表5]
[表6]
[表7]
[表8]
浓度 | 角蛋白10 |
RNA表达量 | ||
对照 | - | 1.00±0.00 |
实施例12 | 0.10% | 2.35±0.02** |
实施例13 | 0.10% | 1.51±0.03** |
比较例24 | 0.10% | 1.02±0.01 |
比较例25 | 0.10% | 0.95±0.03 |
比较例26 | 0.10% | 0.99±0.08 |
比较例27 | 0.10% | 0.82±0.05 |
[表9]
[表10]
[表11]
[表12]
试验例2
干性皮肤模型小鼠试验
5周龄的雄性无毛小鼠(HOS:HR-1)分成三组,和提供的是,采用正常饲料喂养的一组(N组),采用诱导干性皮肤的专用饲料饲(HR-AD,获自日本农业工业株式公司(NosanCorporation))喂养的对照组(C组),和采用通过混合1重量%的胶原肽入HR-AD而成的饲料喂养的一组(CP组)。从饲料的给予开始5个星期后,使用Corneometer测定在背部的皮肤水含量。结果示于表13。与此同时,用Tewameter测定经表皮失水量(TWEL)。结果示于表14。各表中的值是平均值±标准偏差,并且*、**和***在配对t检验中相对于对照组(C组),分别表示它们是以P<0.05和P<0.01显著的。
[表13]
Corneometer得分 | |
N组 | 57.69±5.63** |
C组 | 46.92±3.69 |
CP组(实施例12) | 56.99±5.22** |
CP组(实施例13) | 53.85±4.95** |
CP组(比较例24) | 46.62±3.99 |
CP组(比较例25) | 47.35±3.67 |
CP组(比较例26) | 46.98±4.28 |
CP组(比较例27) | 49.88±4.33 |
[表14]
TWEL(g/hr/m2) | |
N组 | 4.60±0.23 |
C组 | 21.72±1.89 |
CP组(实施例12) | 7.51±0.34** |
CP组(实施例13) | 10.13±1.12* |
CP组(比较例24) | 20.90±1.75 |
CP组(比较例25) | 17.33±1.99 |
CP组(比较例26) | 20.99±1.77 |
CP组(比较例27) | 18.92±1.56 |
试验例3
在卵清蛋白(OVA)致敏小鼠中测定血中IgE浓度
通过腹膜内给药20μg/小鼠的OVA致敏6周龄的BALB/c雄性小鼠。致敏后,将小鼠分为7组,给予对照样品和实验样品,分别通过将实施例12,13,比较例24,25,26或27混合入对照样品使得胶原肽为1重量%而制备实验样品。通过ELISA试剂盒(E99-115获自Funakoshi有限公司),检测血中IgE的量。该程序遵循方案。结果示于表15。各表中的值是平均值±标准偏差,并且*、**和***在配对t检验中相对于对照组,分别表示它们是以P<0.05和P<0.01显著的。
[表15]
IgE数值(ng/mL) | |
对照 | 7.51±0.61 |
实施例12 | 3.22±0.19** |
实施例13 | 4.31±0.44** |
比较例24 | 7.34±0.43 |
比较例25 | 7.58±0.83 |
比较例26 | 7.49±0.48 |
比较例27 | 6.99±0.40 |
如从表1可以看出,本发明的肽抑制内皮缩血管肽-1的表达。因此,从黑素细胞的黑色素色素的产生被抑制,色素沉着可被抑制。如从表中2至5可以看出,这些肽促进转谷氨酰胺酶1,内披蛋白,角蛋白10,聚丝蛋白和透明质酸合酶2的表达。因此,可以促进表皮的代谢,促进皮肤的周转,并且使在皮肤中的黑色素色素(斑(斑疹))能够更迅速地排出。此外,通过促进转谷氨酰胺酶1,内披蛋白,角蛋白10,聚丝蛋白和透明质酸合酶2的表达,改善皮肤屏障功能和保湿性,并且通过减少血中IgE的量,可改善特应性皮炎。
如从表7到15中可以看出,在非专利文献3(比较例24)中所述的水母来源的胶原肽混合物,仅含有0.15重量%的本发明的肽的胶原肽混合物(比较例25),在非专利文献4中所述鹿角胶(比较例26)和非专利文献5中描述的仅包括0.07重量%本发明的肽的胶原肽(比较例27)没有显示出,抑制内皮缩血管肽-1的表达的效果和促进转谷氨酰胺酶1,内披蛋白,角蛋白10,聚丝蛋白和透明质酸合成酶2的表达的效果。与此相反,包括1.65重量%本发明的肽的胶原肽混合物“LCP”(获自新田明胶公司:实施例13)可靠地显示出前述这两个效果,并且包括2.94重量%本发明肽的胶原肽混合物“S型”(获自新田明胶公司:实施例12)显著地显示出,抑制内皮缩血管肽-1的表达的效果,和促进转谷氨酰胺酶1,内披蛋白,角蛋白10,聚丝蛋白和透明质酸的表达的效果合酶2。
如可从表14中看出,实施例13中的“LCP”和实施例12中的“S型”,使得TWEL值被改善到正常的值。同样,表15表明,实施例12和实施例13使得血中IgE值显著降低,和过敏性反应被抑制。这些表明,包含1.6重量%以上的选自由以下组成的组的肽的胶原肽通过改善皮肤屏障功能,并减少过敏反应而改善特应性皮炎:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp。
总之,本发明的肽等作为美白促进剂或特应性皮炎改善剂是有用的。
工业实用性
本发明可以提供一种优良的美白促进剂或特应性皮炎改善剂,其包含肽等。
Claims (6)
1.一种美白促进剂或特应性皮炎改善剂,其含有选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp。
2.根据权利要求1的美白促进剂或特应性皮炎改善剂,含有胶原肽混合物,所述胶原肽混合物含有选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp,使得所述肽或其药物学上可接受的盐的总含量为1.6重量%或更多。
3.根据权利要求1的美白促进剂或特应性皮炎改善剂,含有胶原肽混合物,所述胶原肽混合物含有选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp,使得所述肽或其药物学上可接受的盐的总含量为1.6重量%或更多。
4.根据权利要求1至3中的任一项的美白促进剂或特应性皮炎改善剂,其通过口服或经皮给药。
5.一种内皮缩血管肽-1表达抑制剂,包括选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp。
6.一种聚丝蛋白表达促进剂,其含有选自由以下组成的组的肽或其药学上可接受的盐:Hyp-Gly,Pro-Ala-Gly,Gly-Pro,Glu-Hyp-Gly,(Pro-Hyp-Gly)5,(Pro-Hyp-Gly)2,Pro-Hyp-Gly,Glu-Hyp,Ala-Hyp-Gly,Ser-Hyp-Gly和Phe-Hyp。
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PCT/JP2014/059408 WO2014175001A1 (ja) | 2013-04-26 | 2014-03-31 | 美白促進剤またはアトピー性皮膚炎改善剤 |
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JPWO2016129174A1 (ja) * | 2015-02-09 | 2017-11-16 | 株式会社ファーマフーズ | ヒアルロン酸産生促進剤 |
JP6826359B2 (ja) * | 2015-02-25 | 2021-02-03 | 株式会社ニッピ | 環状ジペプチドの製造方法 |
JP6473024B2 (ja) * | 2015-03-27 | 2019-02-20 | 株式会社ファンケル | メラニン産生抑制剤 |
JP6486745B2 (ja) * | 2015-03-27 | 2019-03-20 | 株式会社ファンケル | 美白用組成物 |
EP3366273A4 (en) | 2015-10-19 | 2019-06-12 | Ajinomoto Co., Inc. | MOISTURIZER AND COSMETIC PRODUCT CONTAINING THE SAME |
JP6809848B2 (ja) * | 2016-09-05 | 2021-01-06 | 株式会社ファンケル | キマーゼ阻害用組成物 |
WO2018174286A1 (ja) | 2017-03-24 | 2018-09-27 | 味の素株式会社 | 角層機能改善剤 |
JP7187781B2 (ja) * | 2017-04-04 | 2022-12-13 | 味の素株式会社 | 保湿剤 |
JP6779851B2 (ja) * | 2017-11-09 | 2020-11-04 | 株式会社ファーマフーズ | ヒアルロン酸産生促進剤 |
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