CN107106652A - 肽及其在皮肤处理中的用途 - Google Patents
肽及其在皮肤处理中的用途 Download PDFInfo
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- CN107106652A CN107106652A CN201580070540.XA CN201580070540A CN107106652A CN 107106652 A CN107106652 A CN 107106652A CN 201580070540 A CN201580070540 A CN 201580070540A CN 107106652 A CN107106652 A CN 107106652A
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- Prior art keywords
- peptide
- skin
- leu
- artificial sequence
- lys
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Abstract
本发明的实施例总体上涉及减轻人类体被,如皮肤的衰老迹象和/或改善人类体被健康的方法,并且涉及组合物,该组合物包括用于该方法的肽。根据本发明的组合物在局部可接受的媒介物中可以包含衍生自生长因子,例如生长分化因子11(GDF11)的一种或多种肽或其片段或衍生物。
Description
相关申请的交叉引用
本申请要求2014年12月23日提交的美国临时专利申请序列号62/095,873的优先权,出于所有目的将其全文结合在此。
序列表
本申请包含一份已经以ASCII格式电子递交的序列表并且该序列表通过引用以其全文结合在此。创建于2014年12月19日的所述ASCII副本名称为SC179P-US_SL.txt并且大小是28,919字节。
发明领域
本发明总体上涉及包括与某些人生长因子的片段同源的序列的肽以及其在配置品中的用途以及用于改进人皮肤健康和/或减轻人皮肤衰老的皮肤病学迹象的相关方法。特别地,本发明涉及衍生自人生长因子的肽。这些活性肽可促进人皮肤中胶原和/或透明质酸的生产。
背景
生长因子是充当细胞之间的信号分子的天然存在的物质,通常是蛋白质。其主要功能是促进细胞分化和成熟。它们在刺激细胞生长、增殖和伤口愈合方面起重要作用。相关生长因子的许多大类或超家族是已知的。
生长分化因子11(GDF11)是属于转化生长因子(TGF)超家族的蛋白质。最近发现血源性GDF11参与恢复小鼠衰老表型,该衰老表型包括心脏肥大(参见罗福利多(Loffredo)等人,细胞(Cell),2013,153,828-839),衰老相关的肌肉减少症(参见辛哈(Sinha)等人,科学(Science),2014,344:649-52)和认知功能下降(参见维莱达(Villeda)等人,自然医学(Nat.Med.)2014;20:659-63)。转化生长因子β(TGFβ)是TGF家族的另一个成员。它在大多数细胞中控制增殖、细胞分化和其他功能。结缔组织生长因子(CTGF)是细胞外基质相关肝素结合蛋白的CCN家族的蛋白质。CTGF在许多生物过程中具有重要作用,包括细胞粘附、迁移、增殖、血管生成、骨骼发育和组织伤口修复。认为CTGF可以与TGFβ配合,尽管途径仍然在很大程度上未知。最后,已知血小板源性生长因子(PDGF)在血管生成(来自已有血管组织的血管生长)方面起着重要作用。
由于生长因子在保持健康组织方面起许多重要作用,因此引起了人们对在皮肤病学配置品中使用它们的兴趣。然而,存在与在局部用配置品中使用生长因子相关的缺点。
因此,本发明的目的是提供衍生自生长因子的新肽和包含它们的局部用组合物。本发明的另一个目的是提供用于改进皮肤健康和/或外观、抵抗内在衰老和光衰老的迹象和/或处理皮肤障碍的方法。本发明的另一个目的是提供用于用包含有效量的本发明的肽的化妆品组合物处理、逆转、阻止和/或改善皮肤皱纹和细纹的组合物和方法。
给出上述讨论仅仅是提供对现有技术遇到的问题性质的更好理解,而不应以任何方式理解为对于现有技术的承认。
发明概述
根据上述目的和其他目的,本发明提供了活性肽及其局部用配置品,这些活性肽及其局部用配置品当局部施用于人类体被(皮肤、嘴唇、指甲、头发等),特别是皮肤时,对于改进一种或多种皮肤病学衰老迹象是有用的。本发明的肽衍生自人生长因子。在一些实施例中,肽能够增加皮肤细胞内的胶原蛋白和/或HA的产生,并且因此将对减少皮肤衰老的外观具有有益的作用(例如减轻皱纹和/或细纹的外观,紧致下垂的皮肤,增厚变薄的皮肤,使肤色均匀等)。
由于使用全长生长因子(例如,GDF11、或TGFβ、或CTGF、或PDFT)蛋白可能存在挑战,已经设计了衍生自全长蛋白的序列的肽序列(例如3-15、或3-12、或3-10、或3-8、或3-6、或3-4个氨基酸)。这些肽,特别是与蛋白质的推定功能区类似的肽,被认为会给皮肤上带来抗衰老益处。
本发明的一个方面提供在生理上可接受的载体中包含本发明的一种或多种GDF11衍生肽或其片段或衍生物(例如具有从约3至约12个氨基酸)的局部用组合物。还提供了改善和/或预防人皮肤光衰老和内在衰老迹象的方法,该方法包括将包含本发明的一种或多种GDF11衍生肽的组合物局部施用于皮肤。
本发明的另一个方面提供在生理上可接受的载体中包含本发明的一种或多种TGFβ衍生肽或其片段或衍生物(例如具有从约3至约12个氨基酸)的局部用组合物。还提供了改善和/或预防人皮肤光衰老和内在衰老迹象的方法,该方法包括将包含本发明的一种或多种TGFβ衍生肽的组合物局部施用于皮肤。
本发明的又另一个方面提供在生理上可接受的载体中包含本发明的一种或多种CTGF衍生肽或其片段或衍生物(例如具有从约3至约15个氨基酸)的局部用组合物。还提供了改善和/或预防人皮肤光衰老和内在衰老迹象的方法,该方法包括将包含本发明的一种或多种CTGF衍生肽的组合物局部施用于皮肤。
本发明的又另一个方面提供在生理上可接受的载体中包含本发明的一种或多种PDGF衍生肽或其片段或衍生物(例如具有从约3至约12个氨基酸)的局部用组合物。还提供了改善和/或预防人皮肤光衰老和内在衰老迹象的方法,该方法包括将包含本发明的一种或多种PDGF衍生肽的组合物局部施用于皮肤。
在阅读了包括说明性实施例和实例的本发明的以下详细说明之后,本发明的这些和其他方面对于本领域技术人员将变得显而易见。
发明详述
在此披露了本发明的详细实施例;然而,应当理解,所披露的实施例仅仅是可以以各种形式实施的本发明的说明。此外,所给出的与本发明各种实施例相关的每个实例旨在是说明性的,而不是限制性的。因此,在此披露的特定结构和功能细节不应被解释为限制性的,而是仅作为教导本领域技术人员以不同方式应用本发明的代表性基础。
在此给出的所有百分数均是指特定组分相对于整个组合物(包括媒介物)的重量百分数,除非另有说明。应当理解,组合物中各组分的所有重量%的总和不超过100%。
除非另有规定,在此中使用的所有术语旨在具有其普通含义。短语“生理上可接受的”、“局部可接受的”和“皮肤病学可接受的”可互换使用,并且旨在意指特定组分以所使用的水平施用于人类体被(例如皮肤)时通常被认为是安全和无毒的。如在此所使用的术语“预防”包括延缓、减缓或阻止特定皮肤衰老迹象的发生或进展。短语“对其有需要的个体”是指可以从改进的皮肤外观或健康中获益的人(包括男性或女性)。在一些实施例中,对其有需要的个体是女性。术语“皮肤”包括但不限于嘴唇、脸部、手、手臂、颈部、头皮和胸部的皮肤。术语“薄”皮肤包括过早变薄的皮肤,并且可以由皮肤科医生作出如此诊断。在一些实施例中,薄皮肤是40岁以下的女性的皮肤或绝经前女性的皮肤。如在此所使用的,如从本说明书的阅读可以理解的,术语“基本上由...组成”旨在将本发明限制在指定的材料或步骤以及不会实质上影响要求保护的发明的基本和新特征的那些。
如在此所使用的,除非特别定义,否则所有术语都旨在具有本领域的普通含义。术语“氨基酸”旨在包括天然发生的氨基酸以及非天然存在的氨基酸,并且包括具有能够形成肽键的至少一个羧基基团和至少一个伯或仲胺基团的任何小分子(MW<1,000道耳顿)。术语“肽”旨在包括包含通过肽键连接的至少两个氨基酸的任何分子,并且因此包括二肽、三肽、寡肽、和具有多达约20个氨基酸残基的多肽。术语“肽”还包括具有一个或多个不是氨基酸的接头、间隔子或末端基团的结构。
肽
本发明的肽包括衍生自生长分化因子11(GDF11)蛋白或相关蛋白(如TGFβ、CTGF和/或PDGF)或两个或更多个蛋白的同源区域(例如,GDF11和TGFβ的同源区)的序列,基本上由其组成或由其组成。如在此所使用的,基本上由...构成,旨在意指另外的氨基酸可以存在于任一末端,条件是它们不会实质上损害肽的活性。
在一个实施例中,本发明包括衍生自表1中所示的生长分化因子11(GDF11)前体[智人](NCBI参照序列登录号:NP_005802.1)的序列(SEQ ID NO:1)的任何3或4个连续氨基酸。
表1.GDF11前体[智人]的序列
在一些实施例中,本发明的肽包括来自表1中提供的GDF11的序列的三个或四个连续氨基酸,基本上由其组成或由其组成。例如,本发明的肽可以包括来自表1中提供的GDF11的序列的氨基酸1-10、或11-20、或21-30、或31-40、或41-50、或51-60、或61-70、或71-80、或81-90、或91-100、或101-110、或111-120、或121-130、或131-140、或141-150、或151-160、或161-170、或171-180、或181-190、或191-200、或201-210、或211-220、或221-230、或231-240、或241-250、或251-260、或261-270、或271-280、或281-290、或291-300、或301-310、或311-320、或321-330、或331-340、或341-350、或351-360、或361-370、或371-380、或381-390、或391-400、或401-407的三个或四个连续氨基酸。在其他实施例中,本发明的肽可以包括来自表1中提供的GDF11的序列的氨基酸5-14、或15-24、或25-34、或35-44、或45-54、或55-64、或65-74、或75-84、或85-94、或95-104、或105-114、或115-124、或125-134、或135-144、或145-154、或155-164、或165-174、或175-184、或185-194、或195-204、或205-214、或215-224、或225-234、或235-244、或245-254、或255-264、或265-274、或275-284、或285-294、或295-304、或305-314、或315-324、或325-334、或335-344、或345-354、或355-364、365-374、或375-384、或385-394、或395-407的三个或四个连续氨基酸,基本上由其组成或由其组成。
在一个实施例中,本发明包括衍生自表2中所示的结缔组织生长因子(CTGF)[智人](NCBI基因库登录号:AAA91279.1)的序列(SEQ ID NO:2)的任何3或4个连续氨基酸。
表2.CTGF[智人]的序列
在一些实施例中,本发明的肽包括来自表2中提供的CTGF的序列的三个或四个连续氨基酸,基本上由其组成或由其组成。例如,本发明的肽可以包括来自表2中提供的CTGF的序列的氨基酸1-10、或11-20、或21-30、或31-40、或41-50、或51-60、或61-70、或71-80、或81-90、或91-100、或101-110、或111-120、或121-130、或131-140、或141-150、或151-160、或161-170、或171-180、或181-190、或191-200、或201-210、或211-220、或221-230、或231-240、或241-250、或251-260、或261-270、或271-280、或281-290、或291-300、或301-310、或311-320、或321-330、或331-340、或341-349的三个或四个连续氨基酸。在其他实施例中,本发明的肽可以包括来自表2中提供的CTGF的序列的氨基酸5-14、或15-24、或25-34、或35-44、或45-54、或55-64、或65-74、或75-84、或85-94、或95-104、或105-114、或115-124、或125-134、或135-144、或145-154、或155-164、或165-174、或175-184、或185-194、或195-204、或205-214、或215-224、或225-234、或235-244、或245-254、或255-264、或265-274、或275-284、或285-294、或295-304、或305-314、或315-324、或325-334、或335-344、或345-349的三个或四个连续氨基酸,基本上由其组成或由其组成。
在一个实施例中,本发明包括衍生自表3中所示的转化生长因子-β(TGFβ)[智人](NCBI基因库登录号:AAA36738.1)的序列(SEQ ID NO:3)的任何3或4个连续氨基酸。
表3.TGFβ[智人]的序列
在一些实施例中,本发明的肽包括来自表3中提供的TGFβ的序列的三个或四个连续氨基酸,基本上由其组成或由其组成。例如,本发明的肽可以包括来自表3中提供的TGFβ的序列的氨基酸1-10、或11-20、或21-30、或31-40、或41-50、或51-60、或61-70、或71-80、或81-90、或91-100、或101-110、或111-120、或121-130、或131-140、或141-150、或151-160、或161-170、或171-180、或181-190、或191-200、或201-210、或211-220、或221-230、或231-240、或241-250、或251-260、或261-270、或271-280、或281-290、或291-300、或301-310、或311-320、或321-330、或331-340、或341-350、或351-360、或361-370、或371-380、或381-390、或391-400、或401-410、或411-420、或421-431的三个或四个连续氨基酸。在其他实施例中,本发明的肽可以包括来自表3中提供的TGFβ的序列的氨基酸5-14、或15-24、或25-34、或35-44、或45-54、或55-64、或65-74、或75-84、或85-94、或95-104、或105-114、或115-124、或125-134、或135-144、或145-154、或155-164、或165-174、或175-184、或185-194、或195-204、或205-214、或215-224、或225-234、或235-244、或245-254、或255-264、或265-274、或275-284、或285-294、或295-304、或305-314、或315-324、或325-334、或335-344、或345-354、或355-364、或365-374、或375-384、或385-394、或395-404、或405-414、或415-424、或425-431的三个或四个连续氨基酸,基本上由其组成或由其组成。
在一个实施例中,本发明包括衍生自表4中所示的血小板源性生长因子(PDGF)[智人](NCBI基因库登录号:AAA60552.1)的序列(SEQ ID NO:4)的任何3或4个连续氨基酸。
表4.PDGF[智人]的序列
在一些实施例中,本发明的肽包括来自表4中提供的PDGF的序列的三个或四个连续氨基酸,基本上由其组成或由其组成。例如,本发明的肽可以包括来自表4中提供的PDGF的序列的氨基酸1-10、或11-20、或21-30、或31-40、或41-50、或51-60、或61-70、或71-80、或81-90、或91-100、或101-110、或111-120、或121-130、或131-140、或141-150、或151-160、或161-170、或171-180、或181-190、或191-200、或201-210、或211-220、或221-230、或231-241的三个或四个连续氨基酸。在其他实施例中,本发明的肽可以包括来自表4中提供的PDGF的序列的氨基酸5-14、或15-24、或25-34、或35-44、或45-54、或55-64、或65-74、或75-84、或85-94、或95-104、或105-114、或115-124、或125-134、或135-144、或145-154、或155-164、或165-174、或175-184、或185-194、或195-204、或205-214、或215-224、或225-234、或235-241的三个或四个连续氨基酸,基本上由其组成或由其组成。
在一些实施例中,本发明的肽衍生自在GDF11、TGFb、CTGF、和PDGF中任何两个之间的同源区域。在一些实施例中,同源区域可以跨序列中的3-16个或3-12个或3-8个或3-6个连续氨基酸。在一些实施例中,同源区域可以跨序列中的4-16个或4-12个或4-8个或4-6个连续氨基酸。这些区域可以是至少50%、或至少60%、或至少70%、或至少80%、或至少90%同源的。
在一些实施例中,根据本发明的肽不包括具有序列ID NO 5-86的肽。在另一个实施例中,不包括具有序列ID NO 87-92的肽。
本发明的一方面提供了衍生自GDF11的、具有以下序列的肽:QILSKLRL(Gln-Ile-Leu-Ser-Lys-Leu-Arg-Leu)(SEQ ID NO:5)、LRLK(Leu-Arg-Leu-Lys)(SEQ ID NO:6)、和MVV(Met-Val-Val)(SEQ ID NO:7)。
本发明的另一方面提供了衍生自TGFβ的具有以下序列的肽:QILSKLRL(Gln-Ile-Leu-Ser-Lys-Leu-Arg-Leu)(SEQ ID NO:5)、LRLK(Leu-Arg-Leu-Lys)(SEQ ID NO:6)。
本发明的另一方面提供了衍生自CTGF的具有以下序列的肽:TAKDGAP(Thr-Ala-Lys-Asp-Gly-Ala-Pro)(SEQ ID NO:8)、IFGGTVYRS(Ile-Phe-Gly-Gly-Thr-Val-Tyr-Arg-Ser)(SEQ ID NO:9)、和RTPKISKPIKFELSG(Arg-Thr-Pro-Lys-Ile-Ser-Lys-Pro-Ile-Lys-Phe-Glu-Leu-Ser-Gly)(SEQ ID NO:10)。
本发明的又另一方面提供了衍生自PDGF的具有以下序列的肽:AECK(Ala-Glu-Cys-Lys)(SEQ ID NO:11)。
本发明的肽可以具有通过肽键连接到氨基和/或羧基末端的一个或多个另外的氨基酸。在一些实施例中,肽将在氨基和/或羧基末端包括烃链,包括但不限于可以是直链或支链或环状的C1-24、或C6-18、或C12-18脂肪烃。在一些实施例中,肽包括肽与脂肪酸或脂肪醇的反应产物。例如,N末端可以与C6-24脂肪酸(例如棕榈酸)反应以形成酰胺键。羧基末端可与C6-24脂肪醇(例如鲸蜡醇)反应以形成酯。这些脂肪衍生物可以改进肽的亲油性。如在此所使用的,短语“基本上由...组成”旨在意指在肽和/或侧链的任一末端可以存在另外的氨基酸或其他残基,条件是它们不会实质上害肽的活性以刺激胶原蛋白和/或HA生产。
本发明的肽的局部可接受的盐、酯和前药(统称为“衍生物”)也是合适的。酯可以包括羧基末端和/或羧基侧链的C1-24脂肪烃酯,包括C1-24、或C1-18、或C1-16、或C1-12、或C1-6烷基酯。盐通常是通过肽与无机或有机酸反应形成的酸加成盐。无机酸包括矿物酸如HCl和H2SO4等。有机酸包括柠檬酸、苯甲酸、酒石酸、苹果酸、马来酸、琥珀酸、乙酸、和丙酸。前药包括在体内水解产生具有化学式(I)的肽的任何酯或酰胺。合适的前药的实例可以在威力-VCH出版公司(WILEY-VCH Verlag&Co)出版的标题为“前药和靶向递送:达到更好的ADME性质(Prodrugs and Targeted Delivery:Towards Better ADME Properties)”的书的第47卷(2011)中找到,将其以其全部内容通过引用结合在此。在一个实施例中,前药通过使肽与乙醛酸反应而形成,以产生具有改进的稳定性的肽基-α-羟基甘氨酸衍生物。在其他实施例中,前药可以包括其N-末端和/或侧链的末端N-乙酰基衍生物、侧链N-乙酰基衍生物、N-羟基甲基化或N-苯酞化。在一些实施例中,任一末端可以用H2N-(CH2)n-CO2形式的氨基酸官能化,其中“n”是从1-10的整数,包括氨基戊酸。在一些实施例中,通过肽键在任一末端添加赖氨酸-氨基戊酸基团。
还考虑了本发明的肽的片段。如在此所用,片段被定义为具有从其衍生的肽序列的至少3个氨基酸。
在一个方面,考虑了衍生自GDF11并具有序列QILSKLRL(SEQ ID NO:5)的肽的以下三肽片段:QIL(Gln-Ile-Leu)(SEQ ID NO:12)、ILS(Ile-Leu-Ser)(SEQ ID NO:13)、LSK(Leu-Ser-Lys)(SEQ ID NO:14)、SKL(Ser-Lys-Leu)(SEQ ID NO:15)、KLR(Lys-Leu-Arg)(SEQ ID NO:16)、和LRL(Leu-Arg-Leu)(SEQ ID NO:17)。四肽片段包括以下序列:QILS(Gln-Ile-Leu-Ser)(SEQ ID NO:18)、ILSK(Ile-Leu-Ser-Lys)(SEQ ID NO:19)、LSKL(Leu-Ser-Lys-Leu)(SEQ ID NO:20)、SKLR(Ser-Lys-Leu-Arg)(SEQ ID NO:21)、和KLRL(Lys-Leu-Arg-Leu)(SEQ ID NO:22)或这些肽的衍生物。
在另一方面,考虑了衍生自GDF11并具有序列LRLK(SEQ ID NO:6)的肽的以下三肽片段:LRL(Leu-Arg-Leu)(SEQ ID NO:23)和RLK(Arg-Leu-Lys)(SEQ ID NO:24)、以及这些肽的衍生物。
在又另一个方面,考虑了衍生自CTGF并具有序列TAKDGAP(SEQ ID NO:8)的肽的以下三肽片段:TAK(Thr-Ala-Lys)(SEQ ID NO:25)、AKD(Ala-Lys-Asp)(SEQ ID NO:26)、KDG(Lys-Asp-Gly)(SEQ ID NO:27)、DGA(Asp-Gly-Ala)(SEQ ID NO:28)、和GAP(Gly-Ala-Pro)(SEQ ID NO:29)或其衍生物。四肽片段包括以下序列:TAKD(Thr-Ala-Lys-Asp)(SEQ IDNO:30)、AKDG(Ala-Lys-Asp-Gly)(SEQ ID NO:31)、KDGA(Lys-Asp-Gly-Ala)(SEQ ID NO:32)、和DGAP(Asp-Gly-Ala-Pro)(SEQ ID NO:33)或其衍生物。
在又另一方面,考虑了衍生自CTGF并具有序列IFGGTVYRS(SEQ ID NO:9)的肽的以下三肽片段:IFG(SEQ ID NO:34)、FGG(SEQ ID NO:35)、GGT(SEQ ID NO:36)、GTV(SEQ IDNO:37)、TVY(SEQ ID NO:38)、VYR(SEQ ID NO:39)、和YRS(SEQ ID NO:40)或其衍生物。四肽片段包括以下序列:IFGG(SEQ ID NO:41)、FGGT(SEQ ID NO:42)、GGTV(SEQ ID NO:43)、GTVY(SEQ ID NO:44)、TVYR(SEQ ID NO:45)、和VYRS(SEQ ID NO:46)或其衍生物。
在又另一方面,考虑了衍生自CTGF并具有序列RTPKISKPIKFELSG(SEQ ID NO:10)的肽的以下三肽片段:RTP(SEQ ID NO:47)、TPK(SEQ ID NO:48)、PKI(SEQ ID NO:49)、KIS(SEQ ID NO:50)、ISK(SEQ ID NO:51)、SKP(SEQ ID NO:52)、KPI(SEQ ID NO:53)、PIK(SEQID NO:54)、IKF(SEQ ID NO:55)、KFE(SEQ ID NO:56)、FEL(SEQ ID NO:57)、ELS(SEQ IDNO:58)、和LSG(SEQ ID NO:59)或其衍生物。四肽片段包括以下序列:RTPK(SEQ ID NO:60)、TPKI(SEQ ID NO:61)、PKIS(SEQ ID NO:62)、KISK(SEQ ID NO:63)、ISKP(SEQ ID NO:64)、SKPI(SEQ ID NO:65)、KPIK(SEQ ID NO:66)、PIKF(SEQ ID NO:67)、IKFE(SEQ ID NO:68)、KFEL(SEQ ID NO:69)、FELS(SEQ ID NO:70)、和ELSG(SEQ ID NO:71)或其衍生物。
在又另一方面,考虑了衍生自CTGF并具有序列IFGGTVYRS(SEQ ID NO:9)的肽的以下三肽片段:IFG(SEQ ID NO:72)、FGG(SEQ ID NO:73)、GGT(SEQ ID NO:74)、GTV(SEQ IDNO:75)、TVY(SEQ ID NO:76)、VYR(SEQ ID NO:77)、和YRS(SEQ ID NO:78)或其衍生物。四肽片段包括以下序列:IFGG(SEQ ID NO:79)、FGGT(SEQ ID NO:80)、GGTV(SEQ ID NO:81)、GTVY(SEQ ID NO:82)、TVYR(SEQ ID NO:83)、和VYRS(SEQ ID NO:84)或其衍生物。
在另一方面,考虑了衍生自PDGF并具有序列AECK(SEQ ID NO:11)的肽的以下三肽片段:AEC(SEQ ID NO:85)和ECK(SEQ ID NO:86)或其衍生物。
包括本发明肽(例如SEQ ID NO:5-86)或其片段或衍生物的肽可以具有一个或多个通过肽键连接到氨基和/或羧基末端的另外的氨基酸。在一些实施例中,肽或其片段(SEQID NO:5-86)将具有从3至20、或从3至16、或从3至12、或从3至10、或从3-9、或从3-8、或从3-7、或从3-6个氨基酸。在一些实施例中,肽将在氨基和/或羧基末端包括烃链,包括但不限于可以是直链或支链或环状的C1-24、或C6-18、或C12-18脂肪烃。在一些实施例中,肽包括肽与脂肪酸或脂肪醇的反应产物。例如,N末端可以与C6-24脂肪酸(例如棕榈酸)反应以形成酰胺键。羧基末端可与C6-24脂肪醇(例如鲸蜡醇)反应以形成酯。这些脂肪衍生物可以改进肽的亲油性。如在此所使用的,短语“基本上由...组成”旨在意指在肽和/或侧链的任一末端可以存在另外的氨基酸或其他残基,条件是它们不会实质上损害肽的活性以刺激胶原蛋白生产。
使用例如常规保护和活化化学来制备肽是在本领域的技术之内。通常,用可除去的氨基保护基团保护第一氨基酸的氨基官能度,并用可除去的羧基保护基团保护第二氨基酸的羧基官能度。合适的胺保护基团包括但不限于苯甲酰氧基羰基(Cbz)、叔丁氧基羰基(t-Boc)和9-芴基甲氧基羰基(FMOC)。可以通过形成酸或碱不稳定酯如甲基、乙基、苄基或三甲基甲硅烷基酯来保护羧基基团。保护后,第一和第二氨基酸在合适的溶剂如水或DMF中,在原位活化剂如N,N′-二环己基碳二亚胺(DCCI)、二异丙基碳二亚胺(DIPCDI)或1-乙基-3-(3′-二甲基氨基丙基)碳二亚胺(EDCI)的存在下发生反应,以实现肽键形成。将任何氨基酸侧链上的反应性部分用保护基团保护,这些保护基团如针对OH和SH为叔丁基或苄基;针对羧基基团为甲基、乙基、叔丁基或苄基,以及针对Arg的-NHC(NH2)═NH官能度为2,2,5,7,8-五甲基色满-6-磺酰基。偶联反应后,在不除去第二氨基酸的羧基保护基团的条件下通过酸水解实现第一氨基酸的氨基基团的选择性脱保护。用另外的氨基保护的氨基酸重复该过程。固相合成,如众所周知的梅里菲尔德(Merrifield)方法,对于合成本发明的肽是特别有用的。赖氨酸-氨基戊酸(K-ava)衍生物描述于美国专利号8,551,956中,其披露内容通过引用结合在此。
局部用组合物
根据本发明的组合物可以以多种形式配制用于局部施用,并且通常包括按重量计约0.000001%至按重量计约20%的肽。更典型地,肽将包括从按重量计约0.00001%至按重量计约10%,并且更优选地从按重量计约0.00001%至按重量计约5%的组合物。在一个实施例中,活性肽或其片段或衍生物将包括从按重量计约0.00001%至按重量计约0.0001%、或至按重量计约0.001%、或至按重量计约0.1%的组合物。这些组合物可以包括有效量的肽,该有效量意指足以刺激皮肤中胶原蛋白生产的量。在其他实施例中,当每天局部施用于给定的皮肤区域持续至少8周的时间时,肽或其片段或衍生物的量足以减轻给定皮肤区域的衰老的皮肤病学迹象的外观。
本发明的肽(例如,SEQ ID NO:5-86)是在生理上可接受的媒介物或载体中提供。该媒介物可以是疏水性的或亲水性的。合适的疏水性载体包括例如通常用于化妆品中的蜡状非离子物质,如脂肪醇和脂肪酸的酯和醚,其中碳链长度为从C4至C22,优选地从C8至C18,或从C12至C18。
脂肪疏水性载体的实例包括肉豆蔻酸异丙酯、棕榈酸异丙酯、棕榈酸辛酯、羊毛酸异丙酯、乙酰化羊毛醇、C12-C15醇的苯甲酸酯、辛酸鲸蜡硬脂酸酯、棕榈酸鲸蜡酯、肉豆蔻酸肉豆蔻酯、乳酸肉豆蔻酯、乙酸鲸蜡醇酯、丙二醇二辛酸酯/癸酸酯、油酸癸酯、乙酰化羊毛脂、硬脂醇庚酸酯、苹果酸二异硬脂醇酯、羟基硬脂酸辛酯、羟基硬脂酸辛酯、异硬脂酸异丙酯等。
合适的亲水性载体可以包括例如水、低级醇(C1-6)、经常用于化妆品的二醇和烷氧基化二醇,这些二醇和烷氧基化二醇包括乙二醇、二乙二醇、三乙二醇、丙二醇、二丙二醇等。
局部可接受的媒介物可以处于乳液的形式。合适的乳液的非限制性实例包括油包水乳液,水包油乳液,水包硅酮乳液,硅酮包水乳液,水包蜡乳液,水-油-水三重乳液或具有奶油、凝胶或微乳液的外观的类似物。如在此所用的,术语“油”包括硅酮,除非另有说明。乳液可以包括乳化剂,如非离子、阴离子或两性表面活性剂,或胶凝剂,通常以按重量计从约0.001%至约5%的量。
局部可接受的媒介物可以包括水;植物油;矿物油;酯油如棕榈酸辛酯,肉豆蔻酸异丙酯和棕榈酸异丙酯;醚如二辛醚和二甲基异山梨醇;醇如乙醇和异丙醇;脂肪醇如鲸蜡醇、鲸蜡硬脂醇、硬脂醇和山嵛醇;异链烷烃如异辛烷、异十二烷(IDD)和异十六烷;硅油如环甲聚硅氧烷、二甲聚硅氧烷、二甲聚硅氧烷交联聚合物、聚硅氧烷及其衍生物,优选有机改性衍生物,包括PDMS、二甲聚硅氧烷聚多元醇、二甲聚硅氧烷醇和氨基二甲基聚硅氧烷醇;烃油如矿物油、凡士林、异二十烷和聚烯烃,例如(氢化)聚异丁烯;多元醇如丙二醇,甘油,丁二醇,戊二醇,己二醇,辛乙二醇;蜡如蜂蜡、棕榈蜡、地蜡、微晶蜡、聚乙烯蜡和植物蜡;或上述的任何组合或混合物。水性媒介物可以包括与水混溶的一种或多种溶剂,包括低级醇,如乙醇、异丙醇等。媒介物可以包括按重量计从约50%至约99%的组合物。
在本发明的一个实施例中,组合物可以包括一种或多种另外的皮肤活性物质,包括但不限于类维生素A、植物成分、角质层分离剂、脱屑剂、角质形成细胞增殖增强剂、胶原酶抑制剂、弹性蛋白酶抑制剂、脱色剂、抗炎剂、类固醇、抗痤疮剂、抗氧化剂和高级糖基化终产物(AGE)抑制剂,仅举几例。这些各种成分的量是化妆品领域中通常使用以达到其预期目的的那些,并且范围通常单独地或总体地按组合物的重量计为从约0.001wt%至约20wt%。这些成分的性质及其量必须与本披露的组合物的生产和功能相一致。
示例性的抗衰老组分包括但不限于:植物成分(例如,胶虫树(Butea frondosa)提取物、三药香料藤(Tiliacora triandra)提取物、马齿苋、Melicope elleryana等);植醇;植酸;类维生素A;羟基酸(包括α-羟基酸和β-羟基酸),水杨酸和水杨酸烷基酯;去角质剂(例如,乙醇酸、3,6,9-三噁十一烷二酸等),雌激素合成酶刺激化合物(例如,咖啡因和衍生物);能够抑制5α-还原酶活性的化合物(例如,亚麻酸、亚油酸、非那雄胺、及其混合物);和阻隔功能增强剂(例如,神经酰胺、甘油酯、胆固醇及其酯、α-羟基和ω-羟基脂肪酸及其酯等),仅举几例。
示例性类维生素A包括但不限于:视黄酸(例如,全反式、或9-顺式、或13-顺式),及其衍生物,视黄醛,视黄醇(维生素A)及其酯,如棕榈酸视黄酯、乙酸视黄酯、和丙酸视黄酯及其盐。可具体提及的是视黄醇。当存在时,通常以如下量包括类维生素A:按重量计从约0.0001%至约5%,更通常按重量计从约0.01%至约2.5%,或按重量计从约0.1%至约1.0%。根据该实施例的组合物通常将包括有效稳定类维生素A的量(例如,0.0001%-5%)的抗氧化剂,如抗坏血酸和/或BHT和/或螯合剂如EDTA或其盐(例如,EDTA二钠)。
在另一个实施例中,本发明的局部用组合物还可以包括以下中一种或多种:皮肤渗透增强剂;柔润剂,如肉豆蔻酸异丙酯、凡士林、挥发性或非挥发性硅油(例如,甲基聚硅氧烷、二甲聚硅氧烷)、酯油、矿物油和脂肪酸酯;保湿剂,如甘油、己二醇或辛乙二醇;皮肤丰满剂,如棕榈酰寡肽、胶原蛋白、胶原蛋白和/或糖胺聚糖(GAG)增强剂;防晒剂,如阿伏苯宗或甲氧肉桂酸辛酯;去角质剂;和抗氧化剂。
合适的去角质剂包括例如α-羟基酸,β-羟基酸,氧杂酸,氧杂二酸及其衍生物,如其酯、酸酐及盐。合适的羟基酸包括例如乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、2-羟基链烷酸、扁桃酸、水杨酸及其衍生物。一种示例性的去角质剂是乙醇酸。当存在时,可以包含按组合物的重量计从约0.001%至约20%的去角质剂。
可用于本发明组合物中的抗氧化剂的实例包括具有酚羟基官能团的化合物,如抗坏血酸及其衍生物/酯;β-胡萝卜素;儿茶素;姜黄素;阿魏酸衍生物(例如,阿魏酸乙酯,阿魏酸钠);没食子酸衍生物(例如,没食子酸丙酯);番茄红素;还原酸;迷迭香酸;丹宁酸;四氢姜黄素;生育酚及其衍生物,包括生育酚乙酸酯;尿酸;或其任何混合物。其他合适的抗氧化剂是具有还原或非还原形式的一种或多种硫醇官能团(-SH)的那些,如谷胱甘肽、硫辛酸、巯基乙酸和其他巯基化合物。抗氧化剂可以是无机的,如亚硫酸氢盐、偏亚硫酸氢盐、亚硫酸盐或其他包含硫的无机盐和酸。抗氧化剂可以单独地或总体地占组合物的总重量的从约0.001%至约10%(w/w),或从约0.01%至约5%(w/w)。
其他添加剂包括:维生素,如生育酚和抗坏血酸;维生素衍生物如抗坏血酸单棕榈酸酯、生育酚乙酸酯和维生素E棕榈酸酯;增稠剂,如羟烷基纤维素、羧甲基纤维素、卡波姆(carbomber)和植物树胶,如黄原胶;胶凝剂,如酯-终止的聚酯酰胺;结构化剂;金属螯合剂如EDTA或其盐;色素;着色剂;和pH调节剂(柠檬酸、乙醇胺、氢氧化钠等)。该组合物可以任选地包括本领域技术人员已知的其他组分,这些组分包括但不限于:成膜剂、增湿剂、矿物质、粘度和/或流变调节剂、抗痤疮剂、驱虫剂、皮肤清凉化合物、皮肤保护剂、润滑剂、香料、防腐剂、稳定剂及其混合物。上述物质可以单独地或总体地占组合物的按重量计从约0.0001%至约20%。
此外,本披露内容考虑的组合物可以包括通常使用并且本领域技术人员已知的一种或多种相容的化妆品可接受的辅剂,如着色剂、珍珠、chromalite、云母、颜料、染料、香料、柔润剂、保湿剂、防腐剂、维生素、螯合剂、增稠剂、麻醉剂、抗过敏剂、抗真菌剂、抗微生物剂、其他消炎剂、抗氧化剂、抗菌防腐剂、脱色剂、成膜剂、驱虫剂、药剂、光稳定剂、防晒剂、稳定剂、表面活性剂、增稠剂、粘度调节剂、和植物成分。本披露的局部用组合物还可以包括皮肤渗透增强剂、表面平滑剂、皮肤丰满剂、光扩散剂、去角质促进剂和抗氧化剂。关于这些和其他合适的化妆品成分的细节可以在以下中找到:“国际化妆品成分词典和手册(International Cosmetic Ingredient Dictionary and Handbook)”,第十版(2004),由化妆品、化妆用具和香料协会(CTFA)出版,在第2177-2299页,将其以其全部内容通过引用结合在此。这些不同物质的量是在化妆品或药物领域中常规使用的那些,例如它们可以占组合物总重的从约0.01%至约20%。
可以包括防晒剂以保护皮肤免受紫外线的损害。在本披露的说明性实施例中,防晒剂通过使用单一防晒剂或防晒剂的组合来提供UVA和UVB两者的保护。在本发明组合物中可以使用的防晒剂中有阿伏苯宗、肉桂酸衍生物(如肉桂酸辛基甲氧基酯)、水杨酸辛酯、羟苯甲酮、氰双苯丙烯酸辛酯、二氧化钛、氧化锌、或其任何混合物。防晒剂可以以组合物总重的从约1wt%至约30wt%存在。
在一个实施例中,该局部用组合物具有从1至13的pH范围,其中在从2至12范围内的pH是典型的。在一些实施例中,该组合物具有范围从3.5至7或从7-10.5的pH。在一些实施例中,pH将在3-4、或4-5、或5-6、或6-7、或7-8、或8-9、或9-10、或10-11、或11-12的范围内。可以添加适合的pH调节剂(如氢氧化钠、柠檬酸和三乙醇胺)以使pH在所期望的范围内。
本披露的另一个实施例涉及通过使用靶向递送系统,例如脂质体、微球体(参见昂格尔(Unger)等人的美国专利号5,770,222)等递送所述组合物,这样使得组分和/或活性成分可以更容易地达到并影响施用区域的皮下层,例如面部或颈部、或皮肤的其他区域。
可以将组合物配制成各种产品形式,例如像洗剂、面霜、精华素、喷雾剂、气雾剂、饼状产品、软膏、精华、凝胶、膏状产品、贴片、笔状产品、小湿纸巾、面膜、棒状产品、泡沫、全效精华(elixir),浓缩精华(concentrate)等,特别用于局部给予。优选地,将组合物配制成洗剂、面霜、软膏或凝胶。
本发明还提供了一种用于改善和/或预防人皮肤光衰老和内在衰老迹象的方法,该方法包括局部施用本发明的组合物。本发明的组合物优选每天一次或两次施用于受影响的皮肤区域,持续必要长的时间,以实现所希望的抗衰老结果的时间。
处理方法
提供了用于增强人皮肤中胶原蛋白和/或HA的生产的方法,该方法包括向对其有需要的皮肤区域(例如,下垂的皮肤、变薄的皮肤、具有皱纹和细纹的皮肤等)局部施用局部用组合物,该局部用组合物包括局部可接受的媒介物和有效量的本发明的肽(例如,SEQ IDNO:5-86),持续足以改进其外观的时间。处理可以至少每天一次或两次,并且可以持续至少四周,通常至少八周或更长时间。组合物可以任选地进一步包括有效改进皮肤外观的量的类维生素A和/或α-羟基酸(例如,乙醇酸)和/或β-羟基酸(例如,水杨酸或衍生物)。
在本发明的另一方面,将组合物局部施用以改进人皮肤的美学外观。该方法包括向对其有需要的皮肤区域局部施用包括有效量的本发明的肽(例如,SEQ ID NO:5-86)的组合物,持续足以改进所述人皮肤美学外观的时间。这些组合物以有效量局部施用于皮肤,有效量意指随着每日(一次、两次等)给予,典型地持续至少一周或更长的时间段,足以实现皮肤健康的可测量改进或者一种或多种衰老的皮肤病学迹象减轻的量。
人皮肤美观的改进可以是皮肤任意特质或特征的改进,包括但不限于:
(a)处理、减轻、和/或预防细纹或皱纹;
(b)减小皮肤孔隙大小;
(c)改进皮肤厚度、饱满度、和/或紧致度;
(d)改进皮肤光滑度、柔软度和/或细嫩度;
(e)改进肤色、光泽度和/或透明度;
(f)改进前胶原蛋白、和/或胶原蛋白生产;
(g)改进弹性蛋白的维持和重塑;
(h)促进皮肤纹理的改进和/或再纹理化;
(i)改进皮肤屏障修复和/或功能;
(j)改进皮肤轮廓外观;
(k)恢复皮肤光泽和/或亮度;
(l)补充皮肤中必需营养素和/或成分;
(m)改进由衰老和/或绝经降低的皮肤外观;
(n)改进皮肤保湿;
(o)增加皮肤弹性和/或回弹性;
(p)处理、减少和/或预防皮肤下垂;
(q)改进皮肤紧致度;及
(r)减少色斑和/或斑驳皮肤;以及
(s)改进通过光衍射或反射皮肤的光学性质的。
在相关实施方案中,提供了一种用于处理人皮肤的皮肤上的皱纹和/或细纹的方法(通常是脸部皮肤),该方法包括向对其有需要的皮肤区域(例如,施用于皱纹或细纹)局部施用包括本发明的肽(例如,SEQ ID NO:5-86)的组合物,持续足以改进所述人皮肤的美学外观的时间。处理可以是每天至少一次或两次,并且可以持续至少四周,通常至少八周或更长时间。组合物可以任选地进一步包括有效改进皮肤外观的量的类维生素A(例如,视黄醇或棕榈酸视黄酯)和/或α-羟基酸(例如,乙醇酸)和/或β-羟基酸(例如,水杨酸或衍生物)。
在本发明的又另一方面,提供了用于减轻人皮肤上的皱纹或细纹的严重程度,减少其数量或预防或阻止其发生的方法,该方法包括向对其有需要的皮肤区域(例如,皱纹皮肤)局部施用与以下各项组合的有效量(例如,按重量计0.001%-1%,w/w)的本发明的肽(例如,SEQ ID NO:5-86):有效量(例如,按重量计0.01%-5%,w/w)的视黄醇和/或有效量(例如,按重量计0.001%-5%,w/w)的α-羟酸(例如,乙醇酸)和/或β-羟酸(例如,水杨酸)。
本发明提供了一种通过在受影响的区域上局部施用一种组合物持续足以补救、逆转、减轻、改善、或预防衰老的皮肤病学迹象的时间来处理衰老皮肤的方法,该组合物包括胶原蛋白刺激肽(例如,SEQ ID NO:5-86),通常处于生理学可接受的媒介物中。通常,状况和/或美学外观的改进选自下组,该组由以下各项组成:减少自然衰老(chronologicalaging)、光衰老、激素衰老和/或光化衰老的皮肤病学迹象;预防和/或减少纹和/或皱纹的外观;降低面部纹和皱纹、面颊、前额上的面部皱纹、眼睛之间的垂直皱纹、眼睛上方和嘴周围的水平皱纹、木偶纹,和特别是深度皱纹或褶皱的明显性;改进眶下纹和/或眶周纹的外观;减少眼角鱼尾纹的外观;复原和/或新生皮肤,特别是衰老皮肤;降低皮肤脆性;预防和/或逆转糖胺聚糖和/或胶原蛋白的损失;改善雌激素不平衡的影响;防止皮肤萎缩;预防、减少和/或处理色素沉着过多或色素减退;使皮肤变色最小化;改进肤色、光泽度、透明度和/或紧致度;防止、减少和/或改善皮肤下垂;改进皮肤紧致度、饱满度、柔软度和/或细嫩度;改进前胶原蛋白、和/或胶原蛋白生产;改进皮肤纹理和/或促进再纹理化;改进皮肤屏障修复和/或功能;改进皮肤轮廓外观;恢复皮肤光泽和/或亮度;使疲劳和/或应激的皮肤病学迹象最小化;抵抗环境应激;补充由衰老和/或绝经降低的皮肤中的成分;改进皮肤细胞间通讯;增加细胞增殖和/或繁殖;增加由衰老和/或绝经降低的皮肤细胞代谢;延缓细胞衰老;改进皮肤保湿;增强皮肤厚度;减缓或停止皮肤变薄;增加皮肤弹性和/或回弹性;增强表皮脱落;改进微循环;减少和/或预防脂肪团形成;及其任何组合。在一些实施例中,上述每一项与女性皮肤相关。
在一些实施例中,本发明的肽(例如,SEQ ID NO:5-86)将用于降低细纹或皱纹的严重程度,通常与视黄醇组合。通常每天将组合物施用于皮肤一次、两次或三次,持续必要长的时间,以实现所希望的结果。处理方案可以包括每日施用,持续至少一周、至少两周、至少四周、至少八周或至少十二周或更长。还考虑了慢性处理方案。组合物对细纹和皱纹的形成或外观的影响可以定性地评估,例如通过目视检查,或者定量地,例如通过微观或计算机辅助测量皱纹形态(例如,每单位皮肤皱纹的数量、深度、长度、面积、体积和/或宽度)。在一个实施例中,本发明的组合物将以从约0.001至约100mg/cm2,更典型地从约0.01至约20mg/cm2,或从约0.1至约10mg/cm2的量施用于皮肤。
还考虑了通过将包括活性肽(例如SEQ ID NO:5-86)的组合物局部施用于对其有需要的个体的薄皮肤,本发明的组合物对于处理薄皮肤是有用的。“薄皮肤”旨在包括由于自然衰老、绝经或光损伤而变薄的皮肤以及过早变薄的皮肤。在一些实施例中,处理用于男性中的薄皮肤,而其他实施例处理绝经前或绝经后女性中的薄皮肤,因为据信皮肤在男性和女性(并且特别是在不同生活阶段的女性)中随着年龄不同程度地变薄。
本发明的方法可以预防性地用于阻止衰老,包括在未显现出皮肤衰老迹象的个体中,最常见在25岁以下的个体中。一旦显现出,如在25岁以上的个体中常见的,该方法还可以逆转或处理衰老迹象,或用于减缓这些个体的皮肤病衰老进展。
在一个实施例中,将包括活性肽(例如,SEQ ID NO:5-86)的本发明的组合物施用于人皮肤以减少皮脂产生或改进受脂肪团影响的皮肤的外观和/或减少不希望的脂肪生成或增加脂肪分解。在本实施例中,本发明的肽可以在局部可接受的媒介物中配制(如在此所述),并且可以包括一种或多种另外的试剂,如抗痤疮成分(例如,水杨酸、过氧化苯甲酰和其他过氧化物、硫、类维生素A等),在面部组合物的情况下,或在脂肪团处理的情况下,配置品可以包括适用于处理脂肪团的任何成分,包括但不限于紫苏油以及其他不饱和脂肪油和ω-3脂肪酸,如α-亚麻酸;咖啡因;茶碱;黄嘌呤;类维生素A(例如视黄醇);等。根据本发明的脂肪团处理通常将局部施用于患有脂肪团的皮肤(包括臀部和大腿皮肤)持续足以改进其外观的时间段,包括,例如每日处理,持续至少4周、至少8周、至少12周或更长时间。在一个实施例中,局部施用组合物以处理痤疮。
在某些实施例中,包含活性肽(例如,SEQ ID NO:5-86)的在此所述的组合物可用于处理和/或预防皮肤和/或头发的色素沉着过度,例如使皮肤或毛发增亮。在一些实施例中,将组合物局部施用于皮肤或毛发,例如施用于色素沉着过度的皮肤或毛发的区域。色素沉着过度包括个体的皮肤或毛发的任何着色,其比个体所希望的更暗,并且由黑素细胞引起。这种不想要的色素沉着也可以称为变色。皮肤色素沉着过度区域包括分散或斑驳的色素沉着过度区域。离散的色素沉着过度区域可以是不同的、颜色较深的均匀区域,并且可能在皮肤上显示为褐斑或雀斑,包括通常称为色斑或“老年斑”的痕迹。皮肤斑驳的色素沉着过度区域可以是深色斑点,其在大小上大于分散色素沉着区域并且在形状上比分散色素沉着区域更不规则。色素沉着过度区域还包括晒黑的皮肤区域,例如因暴露于UV而晒黑的皮肤。色素沉着过度毛发包括颜色比期望的深的任意毛发色度。
处理色素沉着过度或色素沉着过度的皮肤/毛发是指根除、减轻、改善或逆转与色素沉着过度相关的不想要的一个或多个特性,如在受影响区域产生可感觉到的皮肤或毛发增亮。在一个实施例中,在如下方面,增亮皮肤的色素沉着过度区域可能是所希望的:减轻老年斑;增亮晒黑;使肤色均匀或优化肤色,例如在斑驳的色素沉着过度区域中;处理黑斑和黄褐斑斑块、雀斑、烧伤后瘢痕和损伤后色素沉着过度。预防色素沉着过度或色素沉着过度的皮肤是指向尚未受色素沉着过度影响的皮肤提供使其避免、延迟、预先阻止或最小化与皮肤色素沉着过度相关的一个或多个不想要的特性的益处,如减少最终形成的色素沉着过度的区域的暗色或大小。
在另一个实施例中,本发明的肽(例如,SEQ ID NO:5-86)旨在用于口服使用,包括用于药物用途。药物配置品将包括药学上可接受的载体(即稀释剂和赋形剂)。药物组合物可以包括在固体剂型中,包括压制的片剂和胶囊剂,或处于液体或粉末形式(包括适于与水重构的肽的冻干粉末)。药物剂型通常将包括从约0.1mg至约200mg,或从约1mg至约100mg本发明的肽。剂型可以是立即释放的,在这种情况下,它们通常将包括水溶性或可分散的载体,如微晶纤维素、甘露醇、羟丙基甲基纤维素、PVP等,或者可以是延迟、维持或改进释放的,在这种情况下,它们可以包括单独的或与水溶性或可分散聚合物组合的水不溶性聚合物如纤维素醚(例如乙基纤维素),以调节剂型在胃中的溶解速率。
在一个实施例中,组合物旨在用作非治疗性处理。在另一个实施例中,根据联邦食品、药品和化妆品法案,§201(i),该组合物是旨在擦、倒、喷洒或喷雾、引入或以其他方式施用于人体的物品,用于清洁、美化、提高吸引力或改变外观。
实例
以下实例说明了本说明书的特定方面。该实例不应被视为起限定作用,因为该实例仅提供对实施例及其不同方面的特定理解和实施。
实例1
本发明的肽由金斯瑞公司(GenScript)(皮斯卡塔韦,新泽西州)合成。
将人真皮成纤维细胞在补充有10%胎牛血清(FBS)和L-谷氨酰胺(0.07x 105个细胞/板)的DMEM培养基(可从康宁公司(Corning),纽约州获得)的96孔板中生长。在达到约75%细胞融合后,将细胞转移到没有FBS的DMEM培养基中,并孵育4-6小时。接下来,在不含FBS的DMEM培养基中,用0.00001%、0.0001%、0.001%终浓度的肽处理细胞,持续48小时。处理后,收集培养基,并且使用MTT测量细胞活力。使用HTRF人前胶原蛋白I试剂盒(可从浠思生物技术有限公司(Cisbio Inc.),贝德福德,马萨诸塞州获得)在培养基中测试分泌的胶原蛋白的量。使用HA Elisa试剂盒(可从科占尼克公司(Corgenix),布鲁姆菲尔德,科罗拉多州获得)在培养基中测试分泌的透明质酸(HA)的量。
结果使用以下检索表总结于下表5中,表示为相对于媒介物对照的前胶原蛋白I和/或HA产生的百分比变化,其中肽浓度提供于括号中:
前胶原蛋白I增加检索表:0:<10%,+:10%-30%,++:30%-50%,+++:50-70%,++++:>70%
HA增加检索表:0:<20%,+:20%-50%,++:50%-90%,+++:90%-150%,++++:>150%
表5
如表5中所示,本发明的肽有效地增加人真皮成纤维细胞中的前胶原蛋白I和/或透明质酸产生。
由于在不脱离本发明的范围和精神的情况下,可以对上述主题进行各种改变,所以旨在将以上述描述中包含的或所附权利要求中限定的所有主题解释为本发明的描述和说明。根据以上传授内容,本发明的很多修改和变化都是可能的。因此,本说明书旨在包含落在所附权利要求的范围内的所有这样的替代方案、修改和变化。
实施方式
1.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于GDF11的序列的、从3至12个氨基酸的肽,或其盐、酯或前药。
2.根据权利要求1所述的方法,其中所述衰老的皮肤病学迹象包括细纹和皱纹的外观。
3.根据权利要求1所述的方法,其中所述肽增加了皮肤中胶原蛋白的产生。
4.根据权利要求1所述的方法,其中所述肽增加了皮肤中透明质酸的产生。
5.根据权利要求1所述的方法,其中将所述组合物每天施用至少一次,持续至少一周。
6.一种化妆品组合物,包括局部可接受的媒介物、包括对应于GDF11的序列的3至12个氨基酸的所述肽,或其盐、酯或前药的。
7.如权利要求6所述的化妆品组合物,其中所述肽按重量计以从约0.000001%至约1%的量存在。
8.如权利要求6所述的化妆品组合物,其中所述局部可接受的媒介物包括油包水、水包油、水包硅酮、或硅酮包水乳液。
9.如权利要求8所述的化妆品组合物,其中所述局部可接受的媒介物进一步包括乳化剂。
10.如权利要求6所述的化妆品组合物,进一步包括选自下组的另外的活性成分,该组由以下各项组成:α-羟基酸、硫代二丙酸或其酯、水杨酸、烟酰胺、己基间苯二酚、植醇和类维生素A。
11.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于TGFβ的序列的、从3至12个氨基酸的肽,或其盐、酯或前药。
12.根据权利要求11所述的方法,其中所述衰老的皮肤病学迹象包括细纹和皱纹的外观。
13.根据权利要求11所述的方法,其中所述肽增加了皮肤中胶原蛋白的产生。
14.根据权利要求11所述的方法,其中所述肽增加了皮肤中透明质酸的产生。
15.根据权利要求11所述的方法,其中将所述组合物每天施用至少一次,持续至少一周。
16.一种化妆品组合物,包括局部可接受的媒介物,包括对应于TGFβ的序列的3至12个氨基酸的所述肽,或其盐、酯或前药的。
17.如权利要求16所述的化妆品组合物,其中所述肽按重量计以从约0.000001%至约1%的量存在。
18.如权利要求16所述的化妆品组合物,其中所述局部可接受的媒介物包括油包水、水包油、水包硅酮、或硅酮包水乳液。
19.如权利要求18所述的化妆品组合物,其中所述局部可接受的媒介物进一步包括乳化剂。
20.如权利要求16所述的化妆品组合物,进一步包括选自下组的另外的活性成分,该组由以下各项组成:α-羟基酸、硫代二丙酸或其酯、水杨酸、烟酰胺、己基间苯二酚、植醇和类维生素A。
21.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于CTGF的序列的、3至15个氨基酸的肽,或其盐、酯或前药。
22.根据权利要求21所述的方法,其中所述衰老的皮肤病学迹象包括细纹和皱纹的外观。
23.根据权利要求21所述的方法,其中所述肽增加了皮肤中胶原蛋白的产生。
24.根据权利要求21所述的方法,其中所述肽增加了皮肤中透明质酸的产生。
25.根据权利要求21所述的方法,其中将所述组合物每天施用至少一次,持续至少一周。
26.一种化妆品组合物,包括局部可接受的媒介物、包括对应于CTGF的序列的3至15个氨基酸的肽,或其盐、酯或前药。
27.如权利要求26所述的化妆品组合物,其中所述肽按重量计以从约0.000001%至约1%的量存在。
28.如权利要求26所述的化妆品组合物,其中所述局部可接受的媒介物包括油包水、水包油、水包硅酮、或硅酮包水乳液。
29.如权利要求28所述的化妆品组合物,其中所述局部可接受的媒介物进一步包括乳化剂。
30.如权利要求26所述的化妆品组合物,进一步包括选自下组的另外的活性成分,该组由以下各项组成:α-羟基酸、硫代二丙酸或其酯、水杨酸、烟酰胺、己基间苯二酚、植醇和类维生素A。
31.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于PDGF的序列的、从3至12个氨基酸的肽,或其盐、酯或前药。
32.根据权利要求31所述的方法,其中所述衰老的皮肤病学迹象包括细纹和皱纹的外观。
33.根据权利要求31所述的方法,其中所述肽增加了皮肤中胶原蛋白的产生。
34.根据权利要求31所述的方法,其中所述肽增加了皮肤中透明质酸的产生。
35.根据权利要求31所述的方法,其中将所述组合物每天施用至少一次,持续至少一周。
36.一种化妆品组合物,包括局部可接受的媒介物、包括对应于PDGF的序列的3至12个氨基酸的所述肽,或其盐、酯或前药。
37.如权利要求36所述的化妆品组合物,其中所述肽按重量计以从约0.000001%至约1%的量存在。
38.如权利要求36所述的化妆品组合物,其中所述局部可接受的媒介物包括油包水、水包油、水包硅酮、或硅酮包水乳液。
39.如权利要求38所述的化妆品组合物,其中所述局部可接受的媒介物进一步包括乳化剂。
40.如权利要求36所述的化妆品组合物,进一步包括选自下组的另外的活性成分,该组由以下各项组成:α-羟基酸、硫代二丙酸或其酯、水杨酸、烟酰胺、己基间苯二酚、植醇和类维生素A。
41.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于与GDF11、TGFβ、CTGF、或PDGF中的两个或更多个的序列同源的序列的、从3至12个氨基酸的肽,或其盐、酯或前药。
42.一种组合物,该组合物在局部可接受的媒介物中包括具有对应于与GDF11、TGFβ、CTGF、或PDGF中的两个或更多个的序列同源的序列的、从3至12个氨基酸的肽,或其盐、酯或前药的组合物。
如权利要求42所述的组合物,进一步包括选自下组的另外的活性成分,该组由以下各项组成:α-羟基酸、硫代二丙酸或其酯、水杨酸、烟酰胺、己基间苯二酚、植醇和类维生素A。
序列表
<110> 依多科韦亚克-博迪,约兰塔(IDKOWIAK-BALDYS, JOLANTA)
桑塔南,乌玛(SANTHANAM, UMA)
<120> 肽及其在皮肤处理中的用途
<130> SC179P-US
<140>
<141>
<160> 92
<170> PatentIn 3.5版
<210> 1
<211> 407
<212> PRT
<213> 智人
<400> 1
Met Val Leu Ala Ala Pro Leu Leu Leu Gly Phe Leu Leu Leu Ala Leu
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Glu Leu Arg Pro Arg Gly Glu Ala Ala Glu Gly Pro Ala Ala Ala Ala
20 25 30
Ala Ala Ala Ala Ala Ala Ala Ala Ala Gly Val Gly Gly Glu Arg Ser
35 40 45
Ser Arg Pro Ala Pro Ser Val Ala Pro Glu Pro Asp Gly Cys Pro Val
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Cys Val Trp Arg Gln His Ser Arg Glu Leu Arg Leu Glu Ser Ile Lys
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Ser Gln Ile Leu Ser Lys Leu Arg Leu Lys Glu Ala Pro Asn Ile Ser
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Arg Glu Val Val Lys Gln Leu Leu Pro Lys Ala Pro Pro Leu Gln Gln
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Ile Leu Asp Leu His Asp Phe Gln Gly Asp Ala Leu Gln Pro Glu Asp
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Phe Leu Glu Glu Asp Glu Tyr His Ala Thr Thr Glu Thr Val Ile Ser
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Met Ala Gln Glu Thr Asp Pro Ala Val Gln Thr Asp Gly Ser Pro Leu
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Cys Cys His Phe His Phe Ser Pro Lys Val Met Phe Thr Lys Val Leu
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Lys Ala Gln Leu Trp Val Tyr Leu Arg Pro Val Pro Arg Pro Ala Thr
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Val Tyr Leu Gln Ile Leu Arg Leu Lys Pro Leu Thr Gly Glu Gly Thr
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Ala Gly Gly Gly Gly Gly Gly Arg Arg His Ile Arg Ile Arg Ser Leu
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Lys Ile Glu Leu His Ser Arg Ser Gly His Trp Gln Ser Ile Asp Phe
225 230 235 240
Lys Gln Val Leu His Ser Trp Phe Arg Gln Pro Gln Ser Asn Trp Gly
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Ile Glu Ile Asn Ala Phe Asp Pro Ser Gly Thr Asp Leu Ala Val Thr
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Ser Leu Gly Pro Gly Ala Glu Gly Leu His Pro Phe Met Glu Leu Arg
275 280 285
Val Leu Glu Asn Thr Lys Arg Ser Arg Arg Asn Leu Gly Leu Asp Cys
290 295 300
Asp Glu His Ser Ser Glu Ser Arg Cys Cys Arg Tyr Pro Leu Thr Val
305 310 315 320
Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile Ile Ala Pro Lys Arg Tyr
325 330 335
Lys Ala Asn Tyr Cys Ser Gly Gln Cys Glu Tyr Met Phe Met Gln Lys
340 345 350
Tyr Pro His Thr His Leu Val Gln Gln Ala Asn Pro Arg Gly Ser Ala
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Gly Pro Cys Cys Thr Pro Thr Lys Met Ser Pro Ile Asn Met Leu Tyr
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Phe Asn Asp Lys Gln Gln Ile Ile Tyr Gly Lys Ile Pro Gly Met Val
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Val Asp Arg Cys Gly Cys Ser
405
<210> 2
<211> 349
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<213> 智人
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Met Thr Ala Ala Ser Met Gly Pro Val Arg Val Ala Phe Val Val Leu
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Leu Ala Leu Cys Ser Arg Pro Ala Val Gly Gln Asn Cys Ser Gly Pro
20 25 30
Cys Arg Cys Pro Asp Glu Pro Ala Pro Arg Cys Pro Ala Gly Val Ser
35 40 45
Leu Val Leu Asp Gly Cys Gly Cys Cys Arg Val Cys Ala Lys Gln Leu
50 55 60
Gly Glu Leu Cys Thr Glu Arg Asp Pro Cys Asp Pro His Lys Gly Leu
65 70 75 80
Phe Cys Asp Phe Gly Ser Pro Ala Asn Arg Lys Ile Gly Val Cys Thr
85 90 95
Ala Lys Asp Gly Ala Pro Cys Ile Phe Gly Gly Thr Val Tyr Arg Ser
100 105 110
Gly Glu Ser Phe Gln Ser Ser Cys Lys Tyr Gln Cys Thr Cys Leu Asp
115 120 125
Gly Ala Val Gly Cys Met Pro Leu Cys Ser Met Asp Val Arg Leu Pro
130 135 140
Ser Pro Asp Cys Pro Phe Pro Arg Arg Val Lys Leu Pro Gly Lys Cys
145 150 155 160
Cys Glu Glu Trp Val Cys Asp Glu Pro Lys Asp Gln Thr Val Val Gly
165 170 175
Pro Ala Leu Ala Ala Tyr Arg Leu Glu Asp Thr Phe Gly Pro Asp Pro
180 185 190
Thr Met Ile Arg Ala Asn Cys Leu Val Gln Thr Thr Glu Trp Ser Ala
195 200 205
Cys Ser Lys Thr Cys Gly Met Gly Ile Ser Thr Arg Val Thr Asn Asp
210 215 220
Asn Ala Ser Cys Arg Leu Glu Lys Gln Ser Arg Leu Cys Met Val Arg
225 230 235 240
Pro Cys Glu Ala Asp Leu Glu Glu Asn Ile Lys Lys Gly Lys Lys Cys
245 250 255
Ile Arg Thr Pro Lys Ile Ser Lys Pro Ile Lys Phe Glu Leu Ser Gly
260 265 270
Cys Thr Ser Met Lys Thr Tyr Arg Ala Lys Phe Cys Gly Val Cys Thr
275 280 285
Asp Gly Arg Cys Cys Thr Pro His Arg Thr Thr Thr Leu Pro Val Glu
290 295 300
Phe Lys Cys Pro Asp Gly Glu Val Met Lys Lys Asn Met Met Phe Ile
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Lys Thr Cys Ala Cys His Tyr Asn Cys Pro Gly Asp Asn Asp Ile Phe
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Glu Ser Leu Tyr Tyr Arg Lys Met Tyr Gly Asp Met Ala
340 345
<210> 3
<211> 431
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<213> 智人
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Met His Val Arg Ser Leu Arg Ala Ala Ala Pro His Ser Phe Val Ala
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Leu Trp Ala Pro Leu Phe Leu Leu Arg Ser Ala Leu Ala Asp Phe Ser
20 25 30
Leu Asp Asn Glu Val His Ser Ser Phe Ile His Arg Arg Leu Arg Ser
35 40 45
Gln Glu Arg Arg Glu Met Gln Arg Glu Ile Leu Ser Ile Leu Gly Leu
50 55 60
Pro His Arg Pro Arg Pro His Leu Gln Gly Lys His Asn Ser Ala Pro
65 70 75 80
Met Phe Met Leu Asp Leu Tyr Asn Ala Met Ala Val Glu Glu Gly Gly
85 90 95
Gly Pro Gly Gly Gln Gly Phe Ser Tyr Pro Tyr Lys Ala Val Phe Ser
100 105 110
Thr Gln Gly Pro Pro Leu Ala Ser Leu Gln Asp Ser His Phe Leu Thr
115 120 125
Asp Ala Asp Met Val Met Ser Phe Val Asn Leu Val Glu His Asp Lys
130 135 140
Glu Phe Phe His Pro Arg Tyr His His Arg Glu Phe Arg Phe Asp Leu
145 150 155 160
Ser Lys Ile Pro Glu Gly Glu Ala Val Thr Ala Ala Glu Phe Arg Ile
165 170 175
Tyr Lys Asp Tyr Ile Arg Glu Arg Phe Asp Asn Glu Thr Phe Arg Ile
180 185 190
Ser Val Tyr Gln Val Leu Gln Glu His Leu Gly Arg Glu Ser Asp Leu
195 200 205
Phe Leu Leu Asp Ser Arg Thr Leu Trp Ala Ser Glu Glu Gly Trp Leu
210 215 220
Val Phe Asp Ile Thr Ala Thr Ser Asn His Trp Val Val Asn Pro Arg
225 230 235 240
His Asn Leu Gly Leu Gln Leu Ser Val Glu Thr Leu Asp Gly Gln Ser
245 250 255
Ile Asn Pro Lys Leu Ala Gly Leu Ile Gly Arg His Gly Pro Gln Asn
260 265 270
Lys Gln Pro Phe Met Val Ala Phe Phe Lys Ala Thr Glu Val His Phe
275 280 285
Arg Ser Ile Arg Ser Thr Gly Ser Lys Gln Arg Ser Gln Asn Arg Ser
290 295 300
Lys Thr Pro Lys Asn Gln Glu Ala Leu Arg Met Ala Asn Val Ala Glu
305 310 315 320
Asn Ser Ser Ser Asp Gln Arg Gln Ala Cys Lys Lys His Glu Leu Tyr
325 330 335
Val Ser Phe Arg Asp Leu Gly Trp Gln Asp Trp Ile Ile Ala Pro Glu
340 345 350
Gly Tyr Ala Ala Tyr Tyr Cys Glu Gly Glu Cys Ala Phe Pro Leu Asn
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Ser Tyr Met Asn Ala Thr Asn His Ala Ile Val Gln Thr Leu Val His
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Phe Ile Asn Pro Glu Thr Val Pro Lys Pro Cys Cys Ala Pro Thr Gln
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Leu Asn Ala Ile Ser Val Leu Tyr Phe Asp Asp Ser Ser Asn Val Ile
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Leu Lys Lys Tyr Arg Asn Met Val Val Arg Ala Cys Gly Cys His
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<210> 4
<211> 241
<212> PRT
<213> 智人
<400> 4
Met Asn Arg Cys Trp Ala Leu Phe Leu Ser Leu Cys Cys Tyr Leu Arg
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Leu Val Ser Ala Glu Gly Asp Pro Ile Pro Glu Glu Leu Tyr Glu Met
20 25 30
Leu Ser Asp His Ser Ile Arg Ser Phe Asp Asp Leu Gln Arg Leu Leu
35 40 45
His Gly Asp Pro Gly Glu Glu Asp Gly Ala Glu Leu Asp Leu Asn Met
50 55 60
Thr Arg Ser His Ser Gly Gly Glu Leu Glu Ser Leu Ala Arg Gly Arg
65 70 75 80
Arg Ser Leu Gly Ser Leu Thr Ile Ala Glu Pro Ala Met Ile Ala Glu
85 90 95
Cys Lys Thr Arg Thr Glu Val Phe Glu Ile Ser Arg Arg Leu Ile Asp
100 105 110
Arg Thr Asn Ala Asn Phe Leu Val Trp Pro Pro Cys Val Glu Val Gln
115 120 125
Arg Cys Ser Gly Cys Cys Asn Asn Arg Asn Val Gln Cys Arg Pro Thr
130 135 140
Gln Val Gln Leu Arg Pro Val Gln Val Arg Lys Ile Glu Ile Val Arg
145 150 155 160
Lys Lys Pro Ile Phe Lys Lys Ala Thr Val Thr Leu Glu Asp His Leu
165 170 175
Ala Cys Lys Cys Glu Thr Val Ala Ala Ala Arg Pro Val Thr Arg Ser
180 185 190
Pro Gly Gly Ser Gln Glu Gln Arg Ala Lys Thr Pro Gln Thr Arg Val
195 200 205
Thr Ile Arg Thr Val Arg Val Arg Arg Pro Pro Lys Gly Lys His Arg
210 215 220
Lys Phe Lys His Thr His Asp Lys Thr Ala Leu Lys Glu Thr Leu Gly
225 230 235 240
Ala
<210> 5
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 5
Gln Ile Leu Ser Lys Leu Arg Leu
1 5
<210> 6
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 6
Leu Arg Leu Lys
1
<210> 7
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 7
Met Val Val
1
<210> 8
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 8
Thr Ala Lys Asp Gly Ala Pro
1 5
<210> 9
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 9
Ile Phe Gly Gly Thr Val Tyr Arg Ser
1 5
<210> 10
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 10
Arg Thr Pro Lys Ile Ser Lys Pro Ile Lys Phe Glu Leu Ser Gly
1 5 10 15
<210> 11
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 11
Ala Glu Cys Lys
1
<210> 12
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 12
Gln Ile Leu
1
<210> 13
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 13
Ile Leu Ser
1
<210> 14
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 14
Leu Ser Lys
1
<210> 15
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 15
Ser Lys Leu
1
<210> 16
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 16
Lys Leu Arg
1
<210> 17
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 17
Leu Arg Leu
1
<210> 18
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 18
Gln Ile Leu Ser
1
<210> 19
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 19
Ile Leu Ser Lys
1
<210> 20
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 20
Leu Ser Lys Leu
1
<210> 21
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 21
Ser Lys Leu Arg
1
<210> 22
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 22
Lys Leu Arg Leu
1
<210> 23
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 23
Leu Arg Leu
1
<210> 24
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 24
Arg Leu Lys
1
<210> 25
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 25
Thr Ala Lys
1
<210> 26
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 26
Ala Lys Asp
1
<210> 27
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 27
Lys Asp Gly
1
<210> 28
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 28
Asp Gly Ala
1
<210> 29
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 29
Gly Ala Pro
1
<210> 30
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 30
Thr Ala Lys Asp
1
<210> 31
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 31
Ala Lys Asp Gly
1
<210> 32
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 32
Lys Asp Gly Ala
1
<210> 33
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 33
Asp Gly Ala Pro
1
<210> 34
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 34
Ile Phe Gly
1
<210> 35
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 35
Phe Gly Gly
1
<210> 36
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 36
Gly Gly Thr
1
<210> 37
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 37
Gly Thr Val
1
<210> 38
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 38
Thr Val Tyr
1
<210> 39
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 39
Val Tyr Arg
1
<210> 40
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 40
Tyr Arg Ser
1
<210> 41
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 41
Ile Phe Gly Gly
1
<210> 42
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 42
Phe Gly Gly Thr
1
<210> 43
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 43
Gly Gly Thr Val
1
<210> 44
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 44
Gly Thr Val Tyr
1
<210> 45
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 45
Thr Val Tyr Arg
1
<210> 46
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 46
Val Tyr Arg Ser
1
<210> 47
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 47
Arg Thr Pro
1
<210> 48
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 48
Thr Pro Lys
1
<210> 49
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 49
Pro Lys Ile
1
<210> 50
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 50
Lys Ile Ser
1
<210> 51
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 51
Ile Ser Lys
1
<210> 52
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 52
Ser Lys Pro
1
<210> 53
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 53
Lys Pro Ile
1
<210> 54
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 54
Pro Ile Lys
1
<210> 55
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 55
Ile Lys Phe
1
<210> 56
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 56
Lys Phe Glu
1
<210> 57
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 57
Phe Glu Leu
1
<210> 58
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 58
Glu Leu Ser
1
<210> 59
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 59
Leu Ser Gly
1
<210> 60
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 60
Arg Thr Pro Lys
1
<210> 61
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 61
Thr Pro Lys Ile
1
<210> 62
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 62
Pro Lys Ile Ser
1
<210> 63
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 63
Lys Ile Ser Lys
1
<210> 64
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 64
Ile Ser Lys Pro
1
<210> 65
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 65
Ser Lys Pro Ile
1
<210> 66
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 66
Lys Pro Ile Lys
1
<210> 67
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 67
Pro Ile Lys Phe
1
<210> 68
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 68
Ile Lys Phe Glu
1
<210> 69
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 69
Lys Phe Glu Leu
1
<210> 70
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 70
Phe Glu Leu Ser
1
<210> 71
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 71
Glu Leu Ser Gly
1
<210> 72
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 72
Ile Phe Gly
1
<210> 73
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 73
Phe Gly Gly
1
<210> 74
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 74
Gly Gly Thr
1
<210> 75
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 75
Gly Thr Val
1
<210> 76
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 76
Thr Val Tyr
1
<210> 77
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 77
Val Tyr Arg
1
<210> 78
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 78
Tyr Arg Ser
1
<210> 79
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 79
Ile Phe Gly Gly
1
<210> 80
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 80
Phe Gly Gly Thr
1
<210> 81
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 81
Gly Gly Thr Val
1
<210> 82
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 82
Gly Thr Val Tyr
1
<210> 83
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 83
Thr Val Tyr Arg
1
<210> 84
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 84
Val Tyr Arg Ser
1
<210> 85
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 85
Ala Glu Cys
1
<210> 86
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 86
Glu Cys Lys
1
<210> 87
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 87
Gly Asp Ala Leu Gln Pro Glu
1 5
<210> 88
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 88
Gln Pro Glu Asp
1
<210> 89
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 89
Glu Ala Ser Ala Glu Pro Glu
1 5
<210> 90
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 90
Arg Lys Ile Glu
1
<210> 91
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 91
Asn Arg Asn Val
1
<210> 92
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 92
Leu Glu Asn Thr Lys Arg Ser
1 5
Claims (21)
1.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于GDF11的序列的、从3至12个氨基酸的肽,或其盐、酯或前药。
2.根据权利要求1所述的方法,其中所述衰老的皮肤病学迹象包括细纹和皱纹的外观。
3.根据权利要求1所述的方法,其中所述肽增加了皮肤中胶原蛋白的产生。
4.根据权利要求1所述的方法,其中所述肽增加了皮肤中透明质酸的产生。
5.根据权利要求1所述的方法,其中将所述组合物每天施用至少一次,持续至少一周。
6.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于TGFβ的序列的、从3至12个氨基酸的肽,或其盐、酯或前药。
7.根据权利要求6所述的方法,其中所述衰老的皮肤病学迹象包括细纹和皱纹的外观。
8.根据权利要求6所述的方法,其中所述肽增加了皮肤中胶原蛋白的产生。
9.根据权利要求6所述的方法,其中所述肽增加了皮肤中透明质酸的产生。
10.根据权利要求6所述的方法,其中将所述组合物每天施用至少一次,持续至少一周。
11.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于CTGF的序列的、从3至15个氨基酸的肽,或其盐、酯或前药。
12.根据权利要求11所述的方法,其中所述衰老的皮肤病学迹象包括细纹和皱纹的外观。
13.根据权利要求11所述的方法,其中所述肽增加了皮肤中胶原蛋白的产生。
14.根据权利要求11所述的方法,其中所述肽增加了皮肤中透明质酸的产生。
15.根据权利要求11所述的方法,其中将所述组合物每天施用至少一次,持续至少一周。
16.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于PDGF的序列的、从3至12个氨基酸的肽,或其盐、酯或前药。
17.根据权利要求16所述的方法,其中所述衰老的皮肤病学迹象包括细纹和皱纹的外观。
18.根据权利要求16所述的方法,其中所述肽增加了皮肤中胶原蛋白的产生。
19.根据权利要求16所述的方法,其中所述肽增加了皮肤中透明质酸的产生。
20.根据权利要求16所述的方法,其中将所述组合物每天施用至少一次,持续至少一周。
21.一种用于减轻衰老的皮肤病学迹象外观的方法,该方法包括向皮肤局部施用一种组合物,该组合物在局部可接受的媒介物中包括具有对应于与GDF11、TGFβ、CTGF、或PDGF中的两个或更多个的序列同源的序列的、从3至12个氨基酸的肽,或其盐、酯或前药。
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PCT/US2015/048240 WO2016105607A1 (en) | 2014-12-23 | 2015-09-03 | Peptides and their use in the treatment of skin |
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EP (1) | EP3236992A4 (zh) |
CN (1) | CN107106652A (zh) |
BR (1) | BR112017013696B1 (zh) |
CA (1) | CA2972015A1 (zh) |
MX (1) | MX2017008454A (zh) |
PH (1) | PH12017501070A1 (zh) |
RU (1) | RU2709778C2 (zh) |
WO (1) | WO2016105607A1 (zh) |
ZA (1) | ZA201704726B (zh) |
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CN109069588A (zh) * | 2016-02-04 | 2018-12-21 | 康干细胞生物技术有限公司 | 包含gdf11的组合物和其用途 |
CN111093687A (zh) * | 2017-09-15 | 2020-05-01 | 凯恩塞恩斯株式会社 | 作为自身免疫疾病及骨病治疗剂的肽的用途 |
CN114007589A (zh) * | 2019-04-24 | 2022-02-01 | 富力卡姆股份公司 | 局部制剂 |
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RU2709778C2 (ru) | 2019-12-20 |
EP3236992A4 (en) | 2018-09-05 |
CA2972015A1 (en) | 2016-06-30 |
BR112017013696A2 (pt) | 2018-02-06 |
MX2017008454A (es) | 2017-10-31 |
WO2016105607A1 (en) | 2016-06-30 |
US10034826B2 (en) | 2018-07-31 |
US20160175225A1 (en) | 2016-06-23 |
ZA201704726B (en) | 2019-01-30 |
EP3236992A1 (en) | 2017-11-01 |
RU2017123388A (ru) | 2019-01-24 |
BR112017013696B1 (pt) | 2024-01-02 |
PH12017501070A1 (en) | 2017-12-11 |
RU2017123388A3 (zh) | 2019-01-25 |
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