CN101990544A - 用于处理皮肤的合成肽及其在美容或皮肤用药物组合物中的用途 - Google Patents
用于处理皮肤的合成肽及其在美容或皮肤用药物组合物中的用途 Download PDFInfo
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- CN101990544A CN101990544A CN2007800191740A CN200780019174A CN101990544A CN 101990544 A CN101990544 A CN 101990544A CN 2007800191740 A CN2007800191740 A CN 2007800191740A CN 200780019174 A CN200780019174 A CN 200780019174A CN 101990544 A CN101990544 A CN 101990544A
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Abstract
本发明涉及能够调节原纤维形成的通式(I)的肽、其立体异构体及其混合物,其可以是或者可以不是外消旋的,以及其美容学或皮肤用药物学可接受的盐,其中Z是丙氨酰基、别-异亮氨酰基、甘氨酰基、异亮氨酰基、异丝氨酰基、异缬氨酰基、亮氨酰基、正亮氨酰基、正缬氨酰基、脯氨酰基、丝氨酰基、苏氨酰基、别-苏氨酰基或缬氨酰基;n和m可为1-5;AA选自以其L-或D-型编码的天然的氨基酸和非编码的氨基酸;x和y可为0-2;R1是H或烷基、芳基、芳烷基或酰基;和R2为氨基、羟基或硫醇,它们都可以是被脂肪族或环状基团取代的或是为未被取代的。还公开了得到包含它们的美容或皮肤用药物组合物的方法及其用于处理皮肤的用途,优选用于处理需要调节原纤维形成的那些皮肤状态,例如老化,和/或用于处理需要软化疤痕外观的那些皮肤状态。
Description
发明领域
本发明涉及调节原纤维形成的合成肽和涉及可用于处理皮肤的包含所述肽的皮肤用药物组合物,优选用于处理需要调节原纤维形成的那些皮肤状态,例如处理老化的皮肤(由于时间的推移和遗传因素而致的内因老化或由于长时间暴露于太阳和/或由于环境污染物(例如来自日光的紫外(UV)辐射、化学污染物、香烟的烟雾和污染)所致的外因老化),或者作为用于软化疤痕外观的愈合过程的辅助剂。
发明背景
皮肤包括两层:表皮和真皮。最外层是表皮,其主要由角化细胞、黑素细胞和Langerhans细胞形成,其基本功能是保持身体的水,作为抵抗有害化学试剂以及抵抗致病生物的屏障机制起作用和执行细胞更新过程。最内层的真皮由成纤维细胞、脂肪细胞和巨噬细胞形成,其通过基底膜坚固地结合于表皮并且包含许多提供触感和温度感觉的神经末梢。其还容纳毛囊、汗腺、皮脂腺、顶泌腺和血管,并且其主要功能之一是保持皮肤的弹性和外观。
真皮还包括细胞外基质,所述细胞外基质由一组细胞外蛋白质(纤维状蛋白、糖蛋白、和蛋白多糖)形成,其主要功能是保持皮肤结构和正确的功能以及组织的发育,这取决于它们的形成和调节是正确的[Wiberg C.、KlattA.R.、WagenerR.、PaulssonM.、BatemanJ.F.、Heinegard D.和Morgelin M.(2003)“Complexes of matrilin-1 andbiglycan or decorin connect collagen VI microfibrils to bothcollagen II and aggrecan”J.Biol.Chem.278,37698-37704]。细胞外基质的两种最主要的纤维状蛋白是胶原和弹性蛋白,其负责组织的机械性质,例如抵抗应力、压力、可延伸性和扭转的能力。蛋白多糖具有结构和代谢功能,而糖蛋白与蛋白多糖一起起到基质组分与细胞之间的连接桥的作用[Aumailley M.和Gayraud B.(1998)“Structure and biological activity of the extracellularmatrix”J.Mol.Med.76,253-265;CulavE.M.、Clark C.H.和Merrilees M.J.(1999)“Connective tissues:matrix compositionand its relevance to physical therapy”Phys.Ther.79,308-319;Scott J.E.(2003)“Elasticity in extracellular matrix′shapemodules′ of tendon,cartilage,etc.A slidingproteoglycan-filament model”J.Physiol.553,335-343]。
胶原
胶原是细胞外基质的纤维状蛋白家族,其形成哺乳动物中总蛋白质质量的25%。它们已经被分为超过20个家族,它们都具有在不同组织中执行特殊功能的单独的特征。
胶原的主要特征在于其由三个富含甘氨酸和脯氨酸的多肽链的结合而形成的螺旋结构。其氨基酸组成的改变引起其功能异常和机械性质损失[Culav E.M.,Clark C.H.和Merrilees M.J.(1999)“Connective tissues:matrix composition and its relevance tophysical therapy”Phys.Ther.79,308-319]。这些多肽链可以彼此结合,形成在成熟组织中为直径10-300nm和长度达到数百个微米的小纤维。这些小纤维经常聚集为更大的结构,例如索缆束,其可以通过电子显微技术作为直径几微米的胶原纤维看见。这一过程是已知的[Aumailley M.和Gayraud B.(1998)“Structure and biologicalactivity of the extracellular matrix”J.Mol.Med.76,253-265]。不是所有的胶原都具有形成小纤维的能力,只有I、II、III、V和XI型胶原可以,其被称为原纤胶原。
成年人的真皮基本上由I型(80-90%)、III型、和V型原纤胶原形成。I型胶原纤维通常具有更大的直径,这是与它们支持更大的机械载荷的能力有关的特征。II型胶原在组织的可延伸性方面起作用,并且经过若干年被I型胶原分子替代,这一过程是引起成年的皮肤比幼年期皮肤的可延伸性差的部分原因。V型胶原通过调节小纤维的直径结合于I型和III型胶原[“The Biology of the Skin”,FreinkelR.K.和Woodley D.T.,eds.The Parthenon Publishing Group,2001;Culav E.M.,ClarkC.H.;和MerrileesM.J.(1999)“Connectivetissues:matrix composition and its relevance to physicaltherapy”Phys.Ther.79,308-319]。
胶原分子或涉及胶原原纤维形成的分子的突变可以引起胶原变性,例如在例如埃-当综合征中发现的那种[Ameye L.和YoungM.G.(2002)“Mice deficient in small leucine-rich proteoglycans:novel in vivo models for osteoporosis,osteoarthritis,Ehlers-Danlos syndrome,muscular dystrophy and cornealdiseases”Glycobiology 12,107R-116R]。同样地,长时间暴露于UV射线可以损坏胶原结构并且引起其更换为结构较差的胶原,随后皮肤变薄并且和形成皱纹,最后,对胶原结构的破坏可以引起修复过程中破坏组织的胶原沉淀,如在肝硬化、肺纤维化或皮肤疤痕形成过程中所发生的。因此,胶原组织的调节不仅可用于美容学或皮肤用药物处理,而且可能用于治疗各种临床状况。
蛋白多糖
蛋白多糖是细胞外基质的主要组分,其特征在于具有与称为氨基多糖(GAG)的碳水化合物共价结合的蛋白质核心。它们涉及许多通过细胞表面的分子间相互作用发生的细胞过程,例如细胞-细胞外基质、细胞-细胞和受体-配体相互作用,这是因为它们贪婪地结合于蛋白质,并且在这些区域中含量非常高[Perrimon N.和Bernfield M.(2001)“Cellular functions o fproteoglycans-an overview”Semin.CellDev.Biol.12,65-67]。蛋白多糖起到组织的组织者作用,它们促进细胞生长和专门化组织的成熟,它们作为生物学过滤器起到重要作用,并且调节生长因子的活性[Iozzo R.V.(1998)“Matrix proteoglycans:from molecular design to cellular function”Annu.Rev.Biochem.67,609-652;Ruoslahti E.(1989)“Proteoglycans in cellregulation”J.Biol.Chem.264,13369-13372]。
GAG是由二糖重复单位形成的聚合物,所述二糖重复单位通常是与糖醛酸(葡糖醛酸酯或艾杜糖醛酸酯)交替的乙酰化的氨基糖(N-乙酰基葡糖胺或N-乙酰基半乳糖胺),并且除了透明质酸之外,都具有高的硫酸根基团指数。由于它们的高的酸基团含量,它们带负电荷并且倾向于吸引阳离子例如Na+,并且由于它们是渗透活性的,它们吸引水并且保持组织水合。最常见的GAG是透明质酸、硫酸软骨素、硫酸皮肤素、硫酸乙酰肝素和硫酸角质素[Sugahara K.和KitagawaH.(2000)“Recent advances in the study of the biosynthesis andfunctions of sulfated glycosaminoglycans”Curr.Opin.Struct.Biol.10,518-527;Zamfir A.、Seidler D.G.、KresseH.和Peter-Katalinic J.(2003)“Structural investigation ofchondroitin/dermatan sulfated oligosaccharides from human skinfibroblast decorin”Glycobiology 13,733-742]。
蛋白多糖的一个类型是所谓的“富含亮氨酸的蛋白多糖”,其不与透明质酸相互作用并且涉及构建细胞外基质、调制生长因子的活性以及调节细胞生长性质[Iozzo R.V.(1997)“The family of the smallleucine-rich proteoglycans:key regulators of matrix assemblyand cellular growth”Crit.Rev.Biochem.Mol.Biol.32,141-174]。尽管不同的富含亮氨酸的蛋白多糖具有共同的结构特性,但是它们在其遗传调节、表达模式以及功能性相互作用方面有显著不同[Ramamurthy P.、Hocking A.M.和McQuillan D.J.(1996)“Recombinant decorin glycoforms.Purification and structure”J.Biol.Chem.271,19578-19584]。
皮肤的蛋白多糖包括多能聚糖、核心蛋白聚糖、双糖链蛋白聚糖、和透明质酸。这些分子位于皮肤的特定区域中。因此,核心蛋白聚糖与皮肤纤维有关[Bianco P.、Fisher L.W.、Young M.F.、Termine J.D.和Robey P.G.(1990)“Expression and localization of the two smallproteoglycans biglycan and decorin in developing human skeletaland non-skeletal tissues”J.Histochem.Cytochem.38,1549-1563],双糖链蛋白聚糖在表皮和血管内皮中的分化角化细胞中[Bianco P.、Fisher L.W.、YoungM.F.、Termine J.D.和RobeyP.G.(1990)“Expression and localization of the two smallproteoglycans biglycan and decorin in developing human skeletaland non-skeletal tissues”J.Histochem.Cytochem.38,1549-1563]而多能聚糖在表皮的基底层中检测到,并且与真皮的弹性网络的纤维结合,以及在汗腺和毛囊表层中检测到[ZimmermannD.R.、Dours-Zimmermann M.T.、Schubert M.和Bruckner-Tuderman L.(1994)“Versican is expressed in the proliferating zone in theepidermis and in association with the elastic network of thedermis”J.Cell Biol.124,817-825]。其它研究显示,多能聚糖不存在于成年皮肤的上皮中,但是存在于与这些区域邻近的结缔组织中,包括真皮和毛囊表层[Carrino D.A.、Sorrell J.M.和CaplanA.I.(2000)“Age-related changes in the proteoglycans of humanskin”Arch.Biochem.Biophys.373,91-101]。
核心蛋白聚糖
核心蛋白聚糖被认为是调节细胞外基质的许多单元的结构和功能的一种关键的蛋白多糖。核心蛋白聚糖结合于生长因子,包括转化生长因子-β(TGF-β),结合于细胞外基质的其它蛋白质例如纤连蛋白和凝血酶敏感蛋白,结合于细胞膜受体(核心蛋白聚糖胞吞受体),并且还可以通过诱导p21直接干涉细胞周期,p21是一种有效的周期素依赖性蛋白激酶(CDK)抑制剂[Stander M.、Naumann U.、Wick W.和Weller M.(1999)“Transforming growth factor-beta and p-21:multiple molecular targets of decorin-mediated suppression ofneoplastic growth”Cell Tissue Res.296,221-227]。
关于核心蛋白聚糖的相互作用的许多研究都是关于对I型胶原的结合,尽管众所周知它们还与其它胶原例如IIIII型、和VI型胶原相互作用。尽管认为影响体内胶原纤维形成的主要因素是胶原的实际结构,但是有不同的分子例如核心蛋白聚糖可以调节和控制这一过程。核心蛋白聚糖延迟小纤维的形成并且使其变得困难,其引起随后发生的小纤维平均直径降低并且迫使胶原纤维采取规则的空间分布[Danielson k.g.、fazzio A.、Cohen I.、Cannizzaro L.A.、Eichstetter L.和Iozzo R.V.(1993)“The human decorin gene:intron-exon organization,discovery of two alternativelyspliced exons in the 5′untranslated region,and mapping of thegene to chromosome 12q23”Genomics 15,146-160]。这个过程是由蛋白多糖的蛋白质核心介导的,并且要求其保持其三级结构[Svensson L.、Heinegard D.和Oldberg A.(1995)“Decorin-bindingsites for collagen type I are mainly located in leucine-richrepeats 4-5”J.Biol.Chem.270,20712-20716;Keene D.R.、Ridgway C.C.和Iozzo R.V.(1998)“Type VI microfilaments interactwith a specific region of banded collagen fibrils in skin”J.Histochem.Cytochem.46,215-220]。有证据说明I型胶原的三股螺旋具有特定的核心蛋白聚糖-结合部位[Keene D.R.、Ridgway C.C.和Iozzo R.V.(1998)“Type VI microfilaments interact with aspecific region of banded collagen fibrils in skin”J.Histochem.Cytochem.46,215-220]并且与硫酸皮肤素分子具有另外的相互作用[Kresse H.、Liszio C.、Schonherr E.和FisherL.W.(1997)“Critical role of glutamate in a central leucine-richrepeat of decorin for interaction with type I collagen”J.Biol.Chem.272,18404-18410]。核心蛋白聚糖结合于小纤维的两个邻近的平行胶原分子,帮助稳定小纤维并且使原纤维形成定向进行。在其结合于胶原原纤维表面之后,胶原的三股螺旋之间的侧向相互作用变得更加困难,因为其起到间隔物的作用并且小纤维的直径减小,从而控制小纤维的尺寸,具体地,使其直径均匀和它们之间的距离规则,从而允许其保持组织形状[Tenni R.、Viola M.、Welser F.、Sini P.、Giudici C.、Rossi A.和TiraM.E.(2002)“Interaction of decorinwith CNBr peptides from collagens I and II.Evidence formultiple binding sites and essential lysyl residues incollagen”Eur.J.Biochem.269,1428-1437;Scott J.E.(1996)“Proteodermatan and proteokeratan sulfate(decorin,lumican/fibromodulin)proteins are horseshoe shaped.Implications for their interactions with collagen”Biochemistry 35,8795-8799]。
核心蛋白聚糖与胶原的这些相互作用的重要性也已经借助转基因小鼠在活体内得到证明,所述转基因小鼠没有核心蛋白聚糖基因,因此在它们的生物体中不产生核心蛋白聚糖。这些动物可以存活,但是皮肤非常脆弱,真皮非常薄,弹性强度降低和抗张强度降低,并且它们的组织病理学分析表明,由于不受控制的侧向聚集,它们的胶原纤维沿着小纤维具有不规则的直径[Kresse H.、Liszio C.、SchonherrE.和Fisher L.W.(1997)“Critical role of glutamate in a centralleucine-rich repeat of decorin for interaction with type Icollagen”J.Biol.Chem.272,18404-18410;Danielson K.G.、Baribault H.、Holmes D.F.、Graham H.、Kadler K.E.和Iozzo R.V(1997)“Targeted disruption of decorin leads to abnormal collagenfibril morphology and skin fragility”J.Cell.Biol.136,729-743;Keene D.R.、Ridgway C.C.和Iozzo R.V.(1998)“Type VImicrofilaments interac twith a specific region of bandedcollagen fibrils in skin”J.Histochem.Cytochem.46,215-220]。这种观察结果与广泛接受的事实是一致的,即,皮肤的强度与原纤胶原网状结构的一般组织、含量和物理性能直接相关[Dombi G.W.、HautR.C.和Sullivan W.G.(1993)“Correlation of high-speed tensilestrength with collagen content in control andl athyritic ratskin”J.Surg.Res.54,21-28]。此外,所述转基因动物还具有增加的胶原降解,其也是它们皮肤质量差的原因之一[Schaefer L.、Macakova K.、Raslik I.、Micegova M.、Grne H-J.、Schnherr E.、Robenek H.、Echtermeyer F.G.、 S.、Bruckner P.、SchaeferR.M.、Iozzo R.V.和Kresse H.(2002)“Absence of decorin adverselyinfluences tubulointerstitial fibrosis of the obstructedkidney by enhanced apoptosis and increased inflammatoryreaction”Am.J.Pathol.160,1181-1191]。还可以观察到引起皮肤脆弱的表现型的在不同的人病理学中的胶原纤维的不规则组织,表明原纤维形成过程的改变足以引起皮肤脆弱和基质结构破坏,因此,原纤维形成过程失控的个体具有伤害以及异常痊愈过程的较高发生率[Keene D.R.、Ridgway C.C.和Iozzo R.V.(1998)“Type VImicrofilaments interact with a specific region of bandedcollagen fibrils in skin”J.Histochem.Cytochem.46,215-220;IozzoR.V.(1999)“The biology of the small leucine-richproteoglycans”J.Biol.Chem.274,18843-18846]。
核心蛋白聚糖不仅与胶原纤维相互作用,而且与其它结构蛋白相互作用。这大概是由于其马蹄形的三维结构,其中富含亮氨酸区域的重复单位并联排列,只有少数重复单位是其结合于配体所必须的[Schonherr E.、Brosza tM.、Brandan E.、Bruckner P.和KresseH.(1998)“Decorin core protein fragment Leu155-Va1260 interactswith TGF-beta but does not compete for decorin binding to typeI collagen”Arch.Biochem.Biophys.355,241-248]。从进行的分子动力学研究结果推断,核心蛋白聚糖马蹄形的凹面具有一个开口,所述开口的角度足以容纳三股螺旋,直径为约2nm,其比胶原的直径(1.5nm)略大,而马蹄形的臂具有类似于胶原分子的厚度[Kresse H.、Liszio C.、Schonherr E.和Fisher L.W.(1997)“Critical role ofglutamate in a central leucine-rich repeat of decorin forinteraction with type I collagen”J.Biol.Chem.272,18404-18410;Scott J.E.(1996)“Proteodermatan and proteokeratansulfate(decorin,lumican/fibromodulin)proteins are horseshoeshaped.Implications for their interactions with collagen”Biochemistry 35,8795-8799]。
进行的理论结构研究考虑了Lys130-Arg133和Arg272-His275核心蛋白聚糖区域,特别地是Asp857-Arg-Gly-Glu860区域负责结合于胶原的假设[Kresse H.、Liszio C.、Schonherr E.和Fisher L.W.(1997)“Critical role of glutamate in a central leucine-rich repeatof decorin for interaction with type I collagen”J.Biol.Chem.272,18404-18410]。这两个核心蛋白聚糖区域在马蹄形的每个臂中,与分子末端大约等距,并且为反平行方向。然而,核心蛋白聚糖采取马蹄形的事实使得马蹄形的一个臂的线性序列相对于另一个臂的线性序列旋转180°,两个片段实际上是平行排列的。因此实现了相互作用所涉及的侧链残基电荷的互补性(胶原[-,+,0,-]和核心蛋白聚糖片段[+,-,0,+]),这对于稳定两个分子之间的相互作用来说似乎是决定性的[Scott J.E.(1996)“Proteodermatan and proteokeratansulfate(decorin,lumican/fibromodulin)proteins are horseshoeshaped.Implications for their interactions with collagen”Biochemistry 35,8795-8799]。
老化
皮肤随着年龄发生显著的变化,包括其形态学、生理学及其机械性质的改变。婴儿的皮肤光滑并且柔软,有一层厚的脂肪和非常薄的角蛋白保护层,而老年人的皮肤非常薄并且具有许多皱纹,具有非常薄的脂肪层。细胞外基质也随年龄经历变化,并且这些改变是与老化相关的皮肤物理性能改变的原因之一[Wiberg C.、Klatt A.R.、Wagener R.、Paulsson M.、Bateman J.F.、Heinegard D.和MorgelinM.(2003)“Complexes of matrilin-1 and biglycan or decorinconnect collagen VI microfibrils to both collagen II andaggrecan”J.Biol.Chem.278,37698-37704]。长时间暴露于太阳和环境污染物加速皮肤老化过程,因为暴露于UV射线抑制成纤维细胞中胶原和纤连蛋白的合成,并且通过刺激使胶原降解的酶(基质金属蛋白酶)的合成而催化胶原降解。已经描述了作为真皮细胞外基质的主要组分的I型胶原分子的改变[Hunzelmann N.、Ueberham U.、EckesB.、Hermann K.和Krieg T.(1997)“Transforming growth factor-betareverses deficient expression of type(I)collagen in culturedfibroblasts of a patient with metageria”Biochim.Biophys.Acta.1360,64-70]。
美容工业中已经进行了重要的努力来对抗细胞外基质的组分的这种随年龄而发生的功能损失。皮肤的重要生物分子(例如,胶原)的产生和降解之间的平衡随着年龄而偏向于降解过程,这引起真皮进行性地变薄和组织破坏,并且引起真皮松弛,随后形成皱纹。在微观水平,老化的皮肤(包括年龄上老化的皮肤-成年皮肤-和由于长时间暴露于太阳或暴露于环境污染物所致的皮肤老化)的胶原的特征在于以与索缆束相似的方式组织的密集的小纤维,其不如年轻皮肤中那样对准[Oikarinen A.(1990)“The aging of the skin:chronoaging versusphotoaging”Photodermatol.Photoimmunol.Photomed.7,3-4]。因此,允许胶原纤维更好地组织的方法可能对成熟皮肤或对老化皮肤产生有利的影响,允许其部分地恢复随着老化或暴露于太阳和/或暴露于环境污染物损失的机械性质(弹性、柔韧性和紧实),和具有更好的外观,皱纹的存在更少和皮肤更光滑。
除胶原之外,皮肤的细胞外基质还包含涉及组织性能并且随老化改变的蛋白多糖。这其中,核心蛋白聚糖被分解代谢为称为decorunt的片段,其相当于没有羧基末端片段的核心蛋白聚糖形式。然而,胎儿来源的皮肤不具有可检测的decorunt水平,而在30岁之后测定到最大的decorunt水平,这是老化迹象开始明显的年龄。decorunt结合于胶原分子的能力比单独的核心蛋白聚糖小100倍,这是与decorunt不含对于与胶原结合来说必不可少的核心蛋白聚糖区域的事实有关的一个因素[Wiberg C.、Klatt A.R.、Wagener R.、PaulssonM.、Bateman J.F.、Heinegard D.和Morgelin M.(2003)“Complexesof matrilin-1 and biglycan or decorin connect collagen VImicrofibrils to both collagen II and aggrecan”J.Biol.Chem.278,37698-37704]。已知核心蛋白聚糖影响胶原原纤维形成过程并且调节小纤维的直径,decorunt的外观可以对年轻皮肤的胶原纤维和老化皮肤的胶原纤维之间的弹性和形态差异具有重要影响[CarrinoD.A.、Sorrell J.M.和Caplan A.I.(2000)“Age-related changes inthe proteoglycans of human skin”Arch.Biochem.Biophys.373,91-101]。还已经证明了在长时间暴露于太阳或暴露于环境污染物而老化的皮肤中,核心蛋白聚糖的合成减少[Bernstein E.F.、Fisher L.W.、LiK.、LeBaronR.G.、Tan E.M.和Uitto J.(1995)“Differentialexpression of the versican and decorin genes in photoaged andsun-protected skin.Comparison by immunohistochemical andnorthern analyses”Lab.Invest.72,662-669],因此,这类皮肤的胶原发生了组织破坏。因此,由于老化或由于长时间暴露于太阳和暴露于环境污染物所致的老化皮肤的功能性核心蛋白聚糖含量降低与变性的原纤胶原网状结构的形成有直接关系,引起皮肤脆弱、弹性减小、和抗张强度减小。
愈合
成人的伤口愈合是复杂的修复过程。愈合过程从募集各种特化细胞开始,使它们转移到伤口位置,并且涉及细胞外基质和基底膜沉积、血管生成、选择性的蛋白酶活性和上皮再形成。成年哺乳动物的愈合过程的重要成分是用于产生细胞外基质的成纤维细胞刺激。这种细胞外基质是形成为用于修复伤口区域的结缔组织的主要组分。
在愈合过程过程中形成的结缔组织通常具有纤维的性质。疤痕是由于先前的伤害或伤口(诸如例如,切口、切除术或创伤)产生的异常的形态结构,并且是由主要是I型和II型胶原基质和纤连蛋白的结缔组织形成的。在皮肤中,疤痕由异常组织中的胶原纤维以及过量的胶原沉积构成。在哺乳动物中,在疤痕高出皮肤表面而具有凸起的外观时,这是由于它们包含以不规则的方式排列的过量胶原的事实,并且倍分类为肥厚性疤痕。瘢痕瘤是病理学疤痕的另一种形式,其不仅高出皮肤表面,而且延伸到超过原来伤害的界限,并且其还具有以异常的方式组织的过量的结缔组织,所述异常的方式主要是形成结缔组织的旋涡状的带。对肥厚性瘢痕中核心蛋白聚糖含量的分析表明,其浓度只有健康组织中的25%[Scott P.G.、Dodd C.M.、Ghahary A.、ShenJ.和Tredget E.E.(1998)“Fibroblasts from post-burnhypertrophic scar tissue synthesize less decorin than normaldermal fibroblasts”Clin.Sci.(Lond).94,541-547],这一事实解释了在肥厚性瘢痕中存在的胶原的不规则组织。
同样地,已经在肥厚性瘢痕中检测到核心蛋白聚糖的截短形式[Honda T.、Matsunaga E.、Katagiri K.、和Shinkai H.(1986)“Theproteoglycans in hypertrophic scar”J.Dermatol.13,326-333;Garg H.G.、Lippay E.W.、Burd D.A.R and Neame P.J.(1990)“Purification and characterization of iduronic acid-rich andglucuronic acid-rich proteoglycans implicated in humanpost-burn keloid scar”Carbohydr.Res.207,295-305],并且已经证明了这些截短形式在原纤维形成试验中不能调节胶原纤维的形成[Carrino D.A.、nnerf jord P.、Sandy J.D.、CS-Szabo G.、ScottP.G.、Sorrell J.M.、Heinegard D.和CaplanA.I.(2003)“Age relatedchanges in the proteoglycans of human skin”J.Biol.Chem.278,17566-17572]。
皮肤中疤痕的存在是大多数人在美学上不能接受的一个因素。医疗部门已经进行了重要的努力来开发最小侵入性的外科方法,例如关节镜检查或腹腔镜检查,其不仅降低了手术后并发症的危险,而且具有只留下非常小的疤痕或几乎看不见的疤痕的优点。尽管有这些努力,但是大多数外科手术仍是通过开放性手术进行,使得控制正确的愈合过程仍是极端重要的课题。防止肥厚性瘢痕和/或瘢痕瘤(其都具有不规则组织的胶原)的形成是美容部门和皮肤用药物学部门的目标之一。因此,允许胶原纤维的更好组织的方法可能对疤痕具有有利的影响,允许它们软化其外观。
因此,包含通过与胶原纤维或纤维相互作用、调节原纤维形成过程来模仿核心蛋白聚糖活性的分子的美容学或皮肤用药物学组合物可能是候选物,可用作用于增加皮肤弹性、牢固性、结构和柔韧性的抗老化产品,或者用作在外科治疗后用于软化疤痕外观的辅助剂。
有关于美容学或皮肤用药物应用的不同专利提及了核心蛋白聚糖用于处理或预防老化,以及用于软化疤痕外观。专利申请US2003/0124152描述了核心蛋白聚糖在美容学或皮肤学组合物中的用途,用于处理内因(由于时间的推移和由于遗传因素)或外因(由于长时间暴露于太阳或环境因素例如紫外(UV)辐射、化学污染物、香烟烟雾和污染)的老化。专利US5,510,328描述了核心蛋白聚糖在药物组合物中的用途,用于减少或抑制伤口收缩,并且专利US6,509,314描述了核心蛋白聚糖用于防止或减少伤口疤痕的用途。还有其它专利描述了刺激内源性核心蛋白聚糖合成的植物提取物或化合物,诸如例如,在专利JP2004051508、FR2834462、EP1367988、US6,551,602、US6,455,057、US6,440,434、US6,423,325、US6,287,553和US6,042,841中描述的那些。已经在文献中刊登了集中在考察核心蛋白聚糖结合于胶原的结构域的研究工作,其描述了一些能够与胶原结合的合成肽,并且其可能具有与核心蛋白聚糖相同的活性,但是所有的序列与天然的核心蛋白聚糖片段相对应[Vides V.M.、LaschingerC.A.、Arora P.D.、Lee W.、Hakkinen L.、Larjava H.、Sodek J.和McCulloch C.A.(2005)“Collagen phagocytosis by fibroblastsis regulated by decorin”J.Biol.Chem.280,23103-23113;Schonherr E.、Broszat M.、Brandan E.、Bruckner P.和Kresse H.(1998)“Decorin core protein fragment Leu155-Va1260 interacts withTGF-beta but does not compete for decorin binding to type lcollagen”Arch.Biochem.Biophys.355,241-248]。然而,目前尚未提及不包含在天然的核心蛋白聚糖序列中的肽的应用,其在结合于胶原方面模仿核心蛋白聚糖的作用,调节原纤维形成并且帮助保持构成的胶原网状结构。
本发明的申请人已经测定了本发明的合成肽有效地调节原纤维形成,从而模拟核心蛋白聚糖的功能。本发明的肽的序列没有包含在天然的核心蛋白聚糖序列中,因此它们可以被认为是核心蛋白聚糖活性的肽模拟物。在文献中已经有如下的假定:对于它们结合于胶原并且因此调节原纤维形成,肽序列必须具有电荷分布为[+,-,0,+]的四个氨基酸[Scott J.E.(1996)“Proteodermatan and proteokeratansulfate(decorin,lumican/fibromodulin)proteins are horseshoeshaped.Implications for their interactions with collagen”Biochemistry 35,8795-8799],使得具有允许相互作用稳定的与Asp857-Arg-Gly-Glu860胶原片段的电荷互补性。本发明的申请人已经测定了不是所有由Scott假定的符合所述电荷互补性的序列都能够调节原纤维形成。尽管相当于核心蛋白聚糖序列272-275的合成肽RELH符合该电荷分布并且能够调节原纤维形成,可肽His-Asp-Ala-Arg、Orn-Asp-Nva-His、His-Asp-Ile-His也符合该电荷分布但是对原纤维形成没有影响。因此,符合Scott假定的[+,-,0,+]电荷分布不是肽调节原纤维形成的充分条件。本发明申请人进行的研究意外地确立了原纤维形成的调节是由具有瓜氨酸氨基酸残基以及[+,-,0]电荷分布的肽序列决定的,诸如例如,序列Lys-Asp-Ile-Cit或Lys-Asp-Val-Cit。专利RU2,181,728描述了一种10氨基酸的合成肽,其通过二硫键结合于序列包括序列Lys-Glu-Leu-Cit的12个氨基酸的肽,其是基于白细胞介素-8分子并且刺激嗜中性白细胞的迁移。尽管所述肽符合[+,-,0]电荷分布并且具有邻近的瓜氨酸残基,但是其不被包括在本发明的肽的家族内,因为其总共具有22个氨基酸。此外,所述专利没有给出任何指示或建议提及所述的肽能够抑制原纤维形成。
因此,在现有技术中没有关于瓜氨酸是调节原纤维形成必需的残基的指示,因此本领域技术人员不能推断出调节原纤维形成的肽的性质。
因此,本发明的肽可用于处理需要调节原纤维形成的皮肤状态,例如处理老化皮肤(由于老化或由于暴露于太阳和/或暴露于环境污染物),或者作为辅助剂用于愈合过程来软化疤痕外观。
发明详述
本发明提供用于处理需要调节原纤维形成的皮肤状态例如老化或疤痕的简单的、有效的和无风险的解决方案,其包括对皮肤施用包含至少一种通式(I)的肽的美容学或皮肤用药物学组合物。在本发明的范围中,术语“处理”涉及减少、延迟和/或预防老化迹象或者涉及软化疤痕外观。术语“老化”涉及随着年龄(年龄上的)或由于暴露于太阳(光老化)或暴露于环境因素例如香烟烟雾、冷或风的极端气候条件、化学污染物或污染而发生的皮肤改变,并且包括所有的外部可见的改变以及可以通过接触察觉到的那些,诸如例如和在非限制性的意义上,在皮肤中发展不连续性,例如尤其是皱纹、细线、裂纹、不规则或粗糙、孔径增加、弹性消失、牢固性损失、光滑性损失、变形恢复能力损失、皮肤下垂(例如面颊下垂)、出现眼袋或出现双下巴;皮肤颜色的改变,例如斑点、发红、深色的圈或出现过度着色的区域例如尤其是小麻点或雀斑、异常的差异、角化过度、弹性组织变性、角化病、毛发损失、胶原结构损失,以及尤其是角质层、真皮、表皮、血管系统(例如,出现蛛网静脉或毛细管扩张)或接近皮肤的组织的其它组织学改变。
因此,本发明的主要方面涉及通式(I)的能够调节原纤维形成的肽:
其立体异构体及其混合物(所述混合物可以是或可以不是外消旋的),及其美容学或皮肤用药物学可接受的盐,其中:
Z选自丙氨酰基、别-异亮氨酰基(allo-isoleucyl)、甘氨酰基、异亮氨酰基、异丝氨酰基、异缬氨酰基、亮氨酰基、正亮氨酰基、正缬氨酰基、脯氨酰基、丝氨酰基、苏氨酰基、别-苏氨酰基或者缬氨酰基;
n和m可以独立地为1到5;
AA选自以L-或D-型天然编码的氨基酸或非编码的氨基酸;
x和y可以独立地为0到2;
R1选自H或烷基、芳基、芳烷基或酰基;和
R2选自被脂肪族或环状基团取代或未被取代的氨基、羟基或硫醇。
通式(I)中所示的肽的优选结构为如下的那些,其中:
Z可以是异亮氨酰基、苏氨酰基或缬氨酰基;
R1可以是:H或直链、支链或环状的饱和或不饱和的C2到C24酰基;和
R2可以是:被直链、支链或环状的饱和或不饱和的C1到C24脂族基团取代或未被取代的氨基或羟基。
本发明的肽可以作为立体异构体或立体异构体混合物存在;例如,形成本发明的肽的氨基酸可以具有L-、D-构型,或者可以彼此独立地为外消旋的。因此,有可能得到同分异构的混合物以及外消旋物或非对映异构体混合物、或纯的非对映异构体或对映体,这取决于不对称碳的数目和存在的异构体或同分异构混合物。
通式(I)的肽的优选结构为纯的异构体,即,对映异构体或非对映异构体。
在本发明的范围中,术语“非编码的氨基酸”是指不是由遗传密码编码的氨基酸,其为天然的或非天然的,诸如例如和以非限制性的意义上尤其是瓜氨酸、鸟氨酸、肌氨酸、锁链赖氨素、正缬氨酸、4-氨基丁酸、2-氨基丁酸、2-氨基异丁酸、6-氨基己酸、1-萘基丙氨酸、2-萘基丙氨酸、2-氨基苯甲酸、4-氨基苯甲酸、4-氯苯丙氨酸、2,3-二氨基丙酸、2,4-二氨基丁酸、环丝氨酸、肉毒碱、胱氨酸、青霉胺、焦谷氨酸、噻吩丙氨酸、羟脯氨酸、别-异亮氨酸、别-苏氨酸、异哌啶酸、异丝氨酸、苯基甘氨酸、他汀类、β-alanin、正亮氨酸、N-甲基氨基酸、β-氨基酸或γ-氨基酸,以及它们的衍生物。非天然氨基酸的列表可以在D.C.Roberts和F.Vellaccio在ThePeptides,Vol.5(1983),Chapter VI,Gross E.和Meienhofer J.、Eds.、Academic Press,New York,USA中的文章“Unusual aminoacids in peptide synthesis”中找到,或者在诸如例如尤其是NeoMPS、Bachem、Novabiochem、Sigma-Aldrich、PeptidesInternational、Advanced ChemTech、Chem-Impex、MaybridgeChemical、Chirotech Technology、Peninsula Laboratories或RSPAmino Acid Analogues的专业公司的商业目录中找到。
在本发明的范围中,在x和y不是0时,应该清楚地理解,AA的性质没有使得本发明的肽的活性变差,而使其有助于调节原纤维形成或对其没有影响。
在本发明的范围中,术语“脂族基团”是指饱和或不饱和的、直链或环状的烃基。
用于本发明的术语“烃基”是指例如烷基、烯基或炔基。
术语“烷基基团”是指饱和的、直链或支链的烃基,包括例如甲基、乙基、异丙基、异丁基、叔丁基、庚基、十二烷基、十六烷基、十八烷基、戊基、2-乙基己基、2-甲基丁基、5-甲基己基等。
术语“烯基”是指具有一个或多个碳-碳双键的不饱和的直链或支链径的烃基,例如乙烯基。
术语“炔基”是指具有一个或多个碳-碳三键的不饱和的直链或支链径的烃基。
术语“环状基团”是指闭合的烃环,其可以分类为脂环族、芳香族或杂环基团。
术语“脂环族基团”是指具有类似于脂族基团的性质的环状烃基。
术语“芳香族基团”或“芳基”是指单环或多环芳烃基团。
术语“杂环基团”是指闭合的烃环,其中环的一个或多个原子是不同于碳的元素(例如,氮、氧、硫等)。
如这个技术领域中理解的,高的取代程度的存在不仅是可接受的而且是推荐的。因此,在本发明的肽中可能有取代。为了使本发明的说明书简化,使用术语“基团”和“嵌段”来区别允许取代或可以被取代的化学物类(“基团”)以及不允许取代或不能被取代的那些(“嵌段”)。这样,在使用术语“基团”描述化学取代基时,描述的化学物质包括未被取代的基团和包含O、N、或S原子的那些。
另外,在使用术语“嵌段”描述化合物或取代基时,只可以包括未被取代的化学物质。例如,表达“烷基基团”不仅包括开链的饱和烷基化合物例如甲基、乙基、丙基、异丁基等,而且包括包含本领域中已知的其它取代基的烷基取代基,其它取代基例如羟基、烷氧基、氨基、羧基、羧酰胺基、卤素原子、氰基、硝基、烷基磺酰基和其它。因此,“烷基基团”包括醚、卤代烷基、醇、硫醇、羧基、胺、羟烷基、磺基烷基、胍基团以及其它基团。另外,表达“烷基嵌段”只限于包含开链的饱和烷基取代基,例如甲基、乙基、丙基、异丁基等。
本发明提供的式(I)的肽的美容学和皮肤用药物学可接受的盐在本发明的范围内。术语“美容学和皮肤用药物学可接受的盐”包括通常用于形成金属盐或酸加成盐的盐,包括有机盐(诸如例如和在非限制性意义上包括乙酸盐、柠檬酸盐、油酸盐、乙二酸盐或葡糖酸盐)或无机盐(诸如例如和在非限制性意义上包括氯化物、硫酸盐、硼酸盐或碳酸盐)。盐的性质不是决定性的,条件是其是美容学或药学上可接受的。式(I)的肽的美容学或药学可接受的盐可以通过本领域公知的常规方法得到。
通式(I)的肽的合成可以根据本领域中公知的常规方法进行,诸如例如,固相多肽合成方法的改进[Stewart J.M.和Young J.D.(1984)“Solid Phase Peptide Synthesis,2nd edition”,Pierce ChemicalCompany,Rockford,Illinois.Bodanzsky M.和Bodanzsky A.(1984)“The practice of Peptide Synthesis”,Springer Verlag,NewYork;Lloyd-Williams,P.、Albericio,F.和Giralt,E.(1997)“Chemical Approaches to the Synthesis of Peptides andProteins”CRC,BocaRaton(FL,USA)]、溶液合成、固相合成和溶液合成法或酶促合成方法的组合[Kullmann W.(1980)“Proteases ascatalysts for enzymic syntheses of opioid peptides”J.Biol.Chem.255,8234-8238]。肽也可以通过经过基因工程修饰以便产生期望序列的或未经修饰的菌株发酵得到。
例如,得到通式(I)的肽的一种方法是其中使具有游离羧基的通式(I)的肽的片段或其活性衍生物与具有至少一个游离氢原子的氨基的互补性片段反应,随后形成酰胺型键,并且其中将不参与形成酰胺型键的所述片段的官能团(如果存在)方便地用暂时性或永久性保护基保护起来。
得到通式(I)的肽的方法的另一个实例是其中使具有离去基团(诸如例如尤其是甲苯磺酰基、甲磺酰基、和卤素基团)的通式(I)的肽的片段通过亲核取代反应与具有至少一个游离氢原子的氨基的互补性片段反应,并且其中将不参与形成N-C键的所述片段的官能团(如果存在)方便地用暂时性或永久性保护基保护起来。保护基的实例、它们的插入和消除在文献中有所描述[Greene T.W.(1981)“Protectivegroups in organic synthesis”John Wiley & Sons,New Cork;Atherton B.和Sheppard R.C.(1989)“SolidPhase Peptide Synthesis:Apractical approach”IRL Oxford University Press]。术语“保护基”还包括用于固相合成中的聚合物支持物。
在合成完全或部分地以固相进行时,作为用于本发明方法中的固体支持物,可以提及以下:由聚苯乙烯、聚乙二醇接枝的聚苯乙烯等制成的支持物,诸如例如由对甲基二苯甲胺树脂(MBHA)[Matsueda G.R.和Stewart J.M.(1981)“A p-methylbenzhydrylamine resin forimproved solid-phase synthesis of peptide amides”Peptides 2,45-50],2-chlorotrityl resins[BarlosK.、GatosD.、KallitsisJ.、Papaphotiu G.、Sotiriu P.、Wenqing Y.和 W.(1989)“Darstellung gesch ü tzter peptid-fragmente unter einsatzsubstituierter triphenylmethyl-harze”Tetrahedron Lett.30,3943-3946;Barlos K.、Gatos D.、Kapolos S.、Papaphotiu G.、 W.和Wenqing Y.(1989)“Veresterung von partiell geschü tzten peptid-fragmenten mit harzen.Einsatz von2-chlorotritylchlorid zur synthese von Leu15-gastrin I”Tetrahedron Lett.30,3947-3951]、树脂等制成的支持物,其可以包括或不包括不稳定的间隔物例如5-(4-氨基甲基-3,5-二甲氧基苯氧基)戊酸(PAL)[Albericio F.、Kneib-Cordonier N.、Biancalana S.、Gera L.、Masada R.I.、Hudson D.和Barany G.(1990)“Preparation and application of the5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy-phenoxy)-valeric acid(PAL)handle for the solid-phasesynthesis of C-terminal peptide amides under mild conditions”J.Org.Chem.55,3730-3743]、2-[4-氨基甲基-(2,4-二甲氧基苯基)苯氧基乙酸(AM)[Rink H.(1987)“Solid-phase synthesis ofprotected peptide fragments using atrialkoxy-diphenyl-methylester resin”Tetrahedron Lett.28,3787-3790]、Wang[Wang S.S.(1973)“p-Alkoxybenzyl Alcohol Resinand p-Alkoxybenzyloxycarbonylhydrazide Resin for Solid PhaseSynthesis of Protected Peptide Fragments”J.Am.Chem.Soc.95,1328-1333]等,以便允许脱保护和同时发生化合物从聚合物支持物上裂解。
由于在哺乳动物(优选人类)的身体外部的应用,本发明的肽可以形成各种类型的组合物的一部分。在这种意义上讲,本发明提供了包括至少一种通式(I)的肽的美容或皮肤用药物组合物。所述组合物可以通过本领域技术人员已知的常规方法制备。
根据R1、R2、AA和Z的基团以及n、m、x和y的数值,本发明的肽目标产物具有可变的水溶性。非水溶性的那些可以溶解在常规的美容学或皮肤用药物学可接受的溶剂中,诸如例如乙醇、丙醇或异丙醇、丙二醇、甘油、丁二醇或聚乙二醇或其任何组合。还可以将肽预先并入美容或药物递送系统和/或持续释放系统,诸如例如和在非限制性意义上为脂质体、毫米级粒子(milliparticle)、微粒和纳米粒子以及海绵、囊泡、胶束、毫米级球体(millispheres)、微球体、和纳米球体、脂球体(liposhere)、毫米级胶囊(millicapsule)、微胶囊和纳米囊剂中,以便实现活性成分的更大的渗透。同样地,本发明的肽还可以被吸附在固体有机聚合物或矿物支持物上,例如尤其是滑石粉、皂土、二氧化硅、淀粉或麦芽糖糊精。
这些制备物可以用于不同类型的制剂,诸如例如霜剂、水包油和硅氧烷的乳剂、水包油乳剂、水包硅氧烷的乳剂、油和硅氧烷包水的乳剂、油包水乳剂、硅氧烷包水的乳剂、油剂、乳剂、香膏、泡沫、洗剂、凝胶剂、搽剂、血清剂、肥皂、油膏、奶油冻(mousses)、软膏、条棒、画笔或喷雾剂,包括保留和洗掉的制剂,并且还可以通过本领域技术人员已知的技术结合到不同类型的固体附属品中,例如湿巾、水凝胶、粘合性(或非粘合性)贴片或面膜,或者可以结合到不同的化妆系列产品中,例如遮瑕膏(concealer)、化妆粉底、卸妆乳或洗液、眼影膏和口红。
还可以将肽结合到用于制成直接接触身体皮肤的服装的织物中,使得本发明的肽通过固定于织物的系统的生物降解而释放,或者借助服装与身体的摩擦、借助身体的水分、借助皮肤的pH或借助体温而释放。服装、织物和用于将肽固定在织物中的方法(包括微囊包封)的实例在文献中有所描述并且是本领域中已知的[SchaabC.K.(1986)″Impregnating Fabrics With Microcapsules″,HAPPI May1986;Nelson G.(2002)“Application of microencapsulation intextiles”Int.J.Pharm.242,55-62]。优选的服装是绷带、腰带、裤袜、短袜、短裤、胸罩和用于胳膊和前臂的带子。
本发明的美容或药物组合物目标产物可应用在要求通过皮下注射、皮内注射、蒸汽覆盖(steam wrap)或通过离子参渗疗法处理的身体区域,以便实现更大的活性成分渗透。应用的优选区域是面部、颈部、前臂、胸部、臀部、腹部和大腿。
本发明提及的组合物可以包含通常用于护理和处理皮肤的组合物中的另外的成分,诸如例如和在非限制性的意义上尤其是,乳剂、润肤剂、有机溶剂、皮肤调理剂诸如例如湿润剂、α-醇酸、增湿剂、维生素、颜料或染料、凝胶聚合物、增稠剂、软化剂、抗皱纹剂、能够减少或治疗眼袋的试剂、增白剂或脱色剂、剥离剂、防老剂、抗自由基剂和/或抗大气污染剂、NO合酶抑制剂、抗氧剂、抗糖化剂、刺激皮肤或表皮高分子合成和/或能够抑制它们降解的试剂,诸如例如刺激胶原合成的试剂、刺激弹性蛋白合成的试剂、刺激层纤连蛋白合成的试剂、刺激核心蛋白聚糖合成的试剂、抑制胶原降解的试剂、抑制弹性蛋白降解的试剂、刺激成纤维细胞增殖的试剂、刺激角化细胞增殖的试剂、刺激角化细胞分化的试剂、刺激脂质和角质层组分(神经酰胺、脂肪酸等)合成的试剂、皮肤弛缓剂、刺激氨基多糖合成的试剂、紧实剂、抗妊娠纹剂、镇静剂(calming agent)、抗炎剂、作用于毛细血管循环和/或微循环的试剂、作用于细胞代谢的试剂、刺激和/或抑制黑色素合成的试剂、改善皮肤-表皮接合的试剂、抗微生物剂、防腐剂、芳香剂、螯合剂、植物提取物、精油、海洋提取物、由生物发酵产生的试剂、无机盐、细胞抽提物和防晒剂(具有针对紫外线A和B射线的活性的有机或无机的光保护剂),条件是它们与组合物的其余组分在物理和化学上相容,特别是与本发明的通式(I)的肽相容。所述另外的成分的性质可以是合成的或天然的,诸如例如,植物提取物。
同样地,本发明的组合物可以包含止痛化合物和/或抗炎化合物或可以与止痛化合物和/或抗炎化合物共同给予,以便减少与敏感性皮肤和愈合过程有关的肿胀和刺激,或者用于治疗过度生长的疤痕或瘢痕瘤疤痕。在所述化合物中,可以着重强调的是类固醇型化合物例如氢化可的松、非类固醇型化合物例如对乙酰氨基酚或乙酰水杨酸、或具有固有的止痛和抗炎活性的天然提取物或精油。
本发明的另一个方面涉及美容或皮肤用药物组合物,其包括美容学或皮肤用药物学有效量的至少一种通式(I)的肽,并且另外包括美容学或皮肤用药物学有效量的至少一种具有抗皱纹和/或抗老化活性的提取物,诸如例如和在非限制性意义上尤其是欧洲葡萄、犬蔷薇、姜黄、香根鸢尾、可可、银杏、或杜氏盐藻提取物,和/或美容学或皮肤用药物学有效量的至少一种具有抗皱纹和/或抗老化活性的合成化合物、提取物或生物发酵产物,诸如例如和在非限制性意义上尤其是由Sederma销售的由Pentapharm销售的或由Cognis销售的MyoxinolTM;由Exsymol销售的Algisum或Hydroxyprolisilane 由Lipotec销售的 或由Institut Europeen deBiologie Cellulaire销售的由Vincience销售的或Ca2+通道拮抗剂例如阿尔维林、锰或镁盐、某些仲胺或叔胺、维生素A及其衍生物、艾地苯醌及其衍生物、辅酶Q10及其衍生物、乳香酸及其衍生物、γ-氨基丁酸或氯离子通道激动剂。
本发明的另一个方面涉及美容或皮肤用药物组合物,包括美容学或皮肤用药物学有效量的至少一种通式(I)的肽,和另外的美容学或皮肤用药物学有效量的至少一种具有紧实、再增浓和/或重构活性的提取物或提取物的组合,诸如例如和在非限制性意义上尤其是Malpighia punicitolia、洋蓟、草本棉、巴巴多芦荟、黍、黑桑、芝麻、野大豆、小麦提取物;由Provital销售的RefirmingHSC或Refirming;由Atrium销售的由Pentapharm销售的-Nutrix;或包含异黄酮的植物提取物,例如尤其是由Vichy销售的Phyto-或美容学或皮肤用药物学有效量的至少一种具有紧实、再增浓和/或重构活性的合成化合物、提取物或生物发酵产物,诸如例如和在非限制性意义上尤其是由Sederma销售的Biopeptide ELTM、Biopeptide CLTM、 或Bio-BustylTM;由Laboratoires Serobiologiques销售的HC、 LS或LS9120;由Silab销售的 或Ridulisse 由Lipotec销售的由Coletica/Engelhard销售的或由Pentapharm销售的-Coll;由Atrium销售的或由Institut Europeen de Biologie Cellulaire销售的
本发明的另一个方面涉及美容或皮肤用药物组合物,包括美容学或皮肤用药物学有效量的至少一种通式(I)的肽,和另外的美容学或皮肤用药物学有效量的至少一种具有愈合或再生上皮活性或在愈合或再生上皮过程中具有辅助剂效力的提取物或提取物的组合,诸如例如和在非限制性意义上尤其是积雪草、麝香蔷薇、紫锥花属窄叶烟草、西门肺草属药用植物、问荆、贯叶连翘(Hypericumperforatum)、细花含羞草(Mimosa tenuiflora)、芦荟(Aloe vera)提取物;由Provital销售的Epithelizing;由Pentapharm销售的LS 9028;或由Coletica/Engelhard销售的或美容学或皮肤用药物学有效量的至少一种具有愈合或再生上皮活性或在愈合或再生上皮过程中具有辅助剂效力的合成化合物、提取物或生物发酵产物,诸如例如和在非限制性意义上尤其是由Lipotec销售的
通式(I)的肽以美容学或药学有效的浓度用于本发明的美容或皮肤用药物组合物中,以实现期望的效果;优选为0.000001%(按重量计算)到20%(按重量计算);更优选为0.00001%(按重量计算)到10%(按重量计算),甚至更优选为0.0001%(按重量计算)到5%(按重量计算)。
因此,本发明的另一个方面涉及至少一种通式(I)的肽在制备美容或皮肤用药物组合物中的用途,所述组合物用于施用在皮肤上,优选用于处理需要调节原纤维形成的那些皮肤状态,例如处理老化皮肤(由于年龄或由于暴露于太阳和/或暴露于环境污染物所致)或作为辅助剂用于愈合过程以软化疤痕外观。优选的应用是用于大腿、腹部、臀部、胸部、前臂、颈部和面部、或用于具有疤痕的那些身体区域。
本发明另外提供用于处理需要调节原纤维形成的那些皮肤状态(优选人的皮肤)的美容学或皮肤药学方法,包括施用有效量的通式(I)的肽,优选为包含所述有效量肽的美容学或皮肤用药物学组合物的形式。皮肤上的施用频率可以广泛地改变,取决于每个受试者的需要,建议为一月一次直到一天10次的施用频率范围,优选一周一次直到一天4次,优选一周三次直到一天两次,更优选一天一次。
优选的美容学或皮肤用药学方法是其中调节原纤维形成的目的是减少、延迟和/或防止老化迹象或软化疤痕外观的那些。
具体实施方式
实施例
本文提供的以下具体实施例可用于举例说明本发明的性质。包括这些实施例只用于说明性目的,不能将其解释为对本文要求保护的本发明的限制。
一般方法
化学合成
所有的合成方法都是在装备有多孔性聚乙烯盘的聚丙烯注射器中进行。所有的试剂和溶剂是用于合成的质量,并且不经任何附加处理直接使用。通过抽吸除去溶剂和试剂。Fmoc基团的消除使用哌啶-DMF(2:8,v/v)(1 x 1 min,1 x 5 min;5mL/g树脂)进行[Lloyd-Williams P.、Albericio F.和Giralt,E.(1997)“ChemicalApproaches to the Synthesis of Peptides and Proteins”CRC,Boca Raton(FL,USA)]。脱保护、偶联和再次脱保护的步骤之间进行的洗涤是使用DMF(3x1min)进行的,每次使用10mL溶剂/g树脂。偶联反应用3mL溶剂/g树脂进行。对偶联的控制是通过茚三酮试验进行的[Kaiser E.、Colescott R.L.、Bossinger C.D.和CookP.I.(1970)“Color test for detection of free terminal aminogroups in the solid-phase synthesis of peptides”Anal.Biochem.34,595-598]。所有的合成转换和洗涤都在25℃进行。
HPLC色谱分析在Shimadzu装置(Kyoto,Japan)进行,使用恒温在30℃的反相柱(250 x 4.0mm,Kromasil C8,5μm,Akzo Nobel,Sweden)。借助流速为1mL/min的含乙腈(+0.07%TFA)梯度的水(+0.1%TFA)进行洗脱,并且在220nm进行检测。
缩写:
用于氨基酸的缩写遵循在Eur.J.Biochem.(1984)138,9-37and in J.Biol.Chem.(1989)264,633-673中指定的IUPAC-IUBCommission on Biochemical Nomenclature的规则。
Ac,乙酰基;AM,2-[4-氨基甲基-(2,4-二甲氧基苯基)-苯氧基乙酸;Boc,叔丁基氧羰基;Cit,瓜氨酸;Dap,2,3-二氨基丙酸;DCM,二氯甲烷;DIEA,N,N-二异丙基乙基胺;DIPCDI,N,N’-二异丙基碳二亚胺;DMF,N,N-二甲基甲酰胺;equiv,当量;DPPC,二棕榈酰基磷脂酰胆碱;ES-MS,电喷射质谱;Fmoc,芴基甲氧基羰基;GAGs,氨基多糖;HOBt,1-羟基苯并三唑;HPLC,高效液相色谱;MBHA,对甲基二苯甲基胺树脂;MeCN,乙腈;MeOH,甲醇;MLV,多层囊泡;Nva,正缬氨酸;Orn,鸟氨酸;Palm,棕榈酰基;tBu,叔丁基;TFA,三氟乙酸;TGF-β,转化生长因于-β;THF,四氢呋喃;TIS,三异丙基硅烷;ULV,单层囊泡。
实施例1:
得到Palm-Dap-Glu-Ile-Cit-OH
向溶解于55mL DCM中的3.5g的Fmoc-L-Cit-OH(8.8mmol,1equiv)加入1.3mL DIEA(7.6mmol,0.86equiv),将其结合到2-氯三苯甲基树脂(chlorotrityl resin)(5.5g,8.8mmol)中。将其搅拌5分钟,之后加入2.5mL的DIEA(14.6mmol,1.66equiv)。使其反应40分钟。残余的氯基团通过用4.4mL MeOH处理进行封闭。
将氨基末端Fmoc基团如一般方法所述脱保护并且在DIPCDI(3.39mL,22mmol,2.5equiv)和HOBt(3.37g,22mmol,2.5equiv)的存在下将7.77g的Fmoc-L-Ile-OH(22mmol,2.5equiv)结合到肽酰-树脂中,使用DMF作为溶剂,进行1小时。随后将树脂如一般方法中所述进行洗涤并且重复Fmoc基团的脱保护处理,以结合下一个氨基酸。遵循所述的规程,顺序地偶联9.36g的Fmoc-L-Glu(OtBu)-OH(22mmol,2.5equiv)和9.38g的Fmoc-L-Dap(Boc)-OH(22mmol,2.5equiv),每个偶联中都在3.37g的HOBt(22mmol,2.5equiv)和3.39mL的DIPCDI(22mmol,2.5equiv)的存在下进行。
将N末端的Fmoc基团如一般方法所述脱保护,并且在13.55g的HOBt(88mmol,10equiv)和13.55mL的DIPCDI(88mmol,10equiv)的存在下结合预溶解在DMF(10mL)中的22.5g的棕榈酸(88mmol,10equiv)。使其反应15小时,之后将树脂用THF(5x1min)、DCM(5x1min)、DMF(5x1min)、MeOH(5x1min)、DMF(5x1min)、THF(5x1min)、DMF(5x1min)、DCM(4x1min)、乙醚(3x1min)洗涤,并且真空干燥。
将12.36g的干燥肽酰基-树脂在室温下用87mL的TFA-TIS-H2O(90:5:5)处理2小时。将滤液收集在冷的乙醚(700mL)中,过滤通过多孔板并将沉淀用乙醚(500mL)洗涤5次。将最终的沉淀真空干燥。
实施例2:
H-Lys-Asp-Val-Cit-NH2的合成
使0.685mg的具有0.73mmol/g(0.5mmol)官能度的Fmoc-AM-MBHA树脂与哌啶-DMF根据一般规程所述脱除Fmoc基团。在DIPCDI(385μL,2.5mmol,5equiv)和HOBt(385mg,2.5mmol,5equiv)的存在下为脱保护的树脂结合0.99g的Fmoc-L-Cit-OH(2.5mmol,5equiv),使用DMF作为溶剂,进行1小时。
随后将树脂如一般方法中所述进行洗涤并且重复Fmoc基团的脱保护处理,以结合下一个氨基酸。遵循所述的规程,顺序地偶联0.85g的Fmoc-L-Val-OH(2.5mmol,5equiv)、1.03g的Fmoc-L-Asp(OtBu)-OH(2.5mmol,5equiv)和1.17g的Fmoc-L-Lys(Boc)-OH(2.5mmol,5equiv),每个偶联中都在385mg的HOBt(2.5mmol,5equiv)和385L的DIPCDI(2.5mmol,5equiv)的存在下进行。
如一般方法所述将N末端Fmoc基团脱保护,用DMF(5x1min)、DCM(4x1min)、乙醚(4x1min)洗涤并且真空干燥。
将1.17g的干燥的肽酰基-树脂在室温下用15mL的TFA-TIS-H2O(90:5:5)处理2小时。将滤液收集在冷的乙醚(100mL)中,以4000rpm离心5分钟,并且将乙醚溶液倾析掉。重复用乙醚洗液5次。将最终的沉淀真空干燥。
通过用含5-95%MeCN(+0.07%TFA)梯度的H2O(+0.1%TFA)进行的HPLC分析显示大于70%的纯度。通过ES-MS测定其分子量[(M+H)+ 理论517.59,(M+H)+ 实验517.7]。
实施例3:
得到Ac-Orn-Asp-Thr-Cit-NH-(CH2)9-CH3
使溶解于已经向其中加入500μL DIEA(2.9mmol,0.90equiv)的20mL DCM中的1.28g的Fmoc-L-Cit-OH(3.23mmol,1equiv)结合于干燥的2-氯三苯甲基树脂(chlorotrityl resin)(2.0g,3.3mmol)。将其搅拌5分钟,之后加入1mL的DIEA(5.9mmol,1.81equiv)。使其反应40分钟。残余的氯基团通过用1.6mL MeOH处理进行封闭。
在1mmol的氨酰基-树脂上,如一般方法所述将氨基末端的Fmoc基团脱保护,并且在DIPCDI(770μL,5mmol,5equiv)和HOBt(770mg,5mmol,5equiv)的存在下结合1.99g的Fmoc-L-Thr(tBu)-OH(5mmol,5equiv),使用DMF作为溶剂,进行1小时。随后将树脂如一般方法中所述进行洗涤并且重复Fmoc基团的脱保护处理,以结合下一个氨基酸。遵循所述的规程,顺序地偶联2.06g的Fmoc-L-Asp(OtBu)-OH(5mmol,5equiv)和2.27g的Fmoc-L-Orn(Boc)-OH(5mmol,5equiv),每个偶联中都在770mgHOBt(5mmol,5equiv)和770μL DIPCDI(5mmol,5equiv)的存在下进行。
如一般方法所述将N末端Fmoc基团脱保护,将肽酰基-树脂在4.28mL的DIEA(25mmol,25equiv)的存在下用2.36mL的乙酸酐(25mmol,25equiv)处理30分钟,使用DMF作为溶剂,用DMF(5x1min)、DCM(4x1min)、乙醚(4x1min)洗涤并且真空干燥。
通过在KOH的存在下用含3%TFA的DCM溶液处理在真空下预先干燥的肽酰基-树脂5分钟,得到完全保护的肽[Ac-L-Orn(Boc)-L-Asp(OtBu)-L-Thr(tBu)-L-Cit-OH]。将滤液收集在冷的乙醚上,并且重复处理三次。将乙醚溶液在室温下旋转蒸干,将沉淀再悬浮在含50%MeCN的H2O中并且冻干。在气球中称量279mg的所得粗产物(367μmol),加入350mg的癸胺(3equiv)和30mL的无水DMF。加入120μL的DIPCDI(2equiv)并且使其在47℃磁力搅拌下反应。借助HPLC,通过起始物质的消失控制反应,反应在24小时之后完成。将溶剂蒸干并且与DCM共同蒸发两次。将得到的残余物[Ac-L-Orn(Boc)-L-Asp(OtBu)-L-Thr(tBu)-L-Cit-NH-(CH2)9-CH3]再悬浮在TFA-DCM-苯甲醚(49:49:2)的50mL混合物中并且使其在室温下反应30分钟。加入250mL的冷的乙醚,将溶剂旋转蒸发并且用乙醚进行两次另外的共同蒸发。将残余物溶解于含50%MeCN的H2O的混合物中并且冻干。
通过用含5-95%MeCN(+0.07%TFA)梯度的H2O(+0.1%TFA)进行的HPLC分析指示大于70%的纯度。通过ES-MS测定其分子量[(M+H)+ 理论686.8,(M+H)+ 实验686.9]。
实施例4:
从EFT-200三维人皮肤模型(MatTek Corporation)开始,将组织用包含在培养基中的0.1mg/mL浓度的H-Lys-Asp-Ile-Cit-NH2和H-Lys-Asp-Val-Cit-NH2处理。培养基每天更换,进行14天,在每次更换时加入相同浓度的肽。在第14天,在4℃,将组织用含2%低聚甲醛和2.5%戊二醛的0.1M磷酸盐缓冲液溶液,pH7.4固定至少2小时。然后在4℃用包含0.8%铁氰化钾的1%四氧化锇进行后固定(post-fixing),进行1小时。然后将组织在乙醇中脱水并且缓慢地包括在环氧树脂(Spurr)中。切取样品并且在封闭液(block)中正确定向,使它们在60℃聚合48小时。随后使用Ultracut E超薄切片机(Reichert-Jung)将它们切片并且得到切片,在对比染色之后(oncecontrasted),用Jeol JEM 1010透射电子显微镜观察,用AxioVision.AC程序(Carl Zeiss Vision)测定纤维的直径。
观察到的胶原纤维直径的平均值是未经处理的组织为6.825nm,H-Lys-Asp-Val-Cit-NH2处理的组织为5.774nm和H-Lys-Asp-Ile-Cit-NH2处理的组织为5.791nm,这说明通过将组织用H-Lys-Asp-Val-Cit-NH2处理使胶原纤维直径减小15.5%,用H-Lys-Asp-Ile-Cit-NH2处理使胶原纤维直径减小15.1%。
实施例5:
制备包含Palm-Lys-Asp-Ile-Cit-NH2的美容组合物
如本发明所述制备以下制剂:
将A相的组分称重到足够大的反应器中并将混合物在80℃加热,以使蜡熔化。将B相的组分称重在适合于全部内容物的容器中并且在70℃加热。缓慢地并且在剧烈搅拌下将A相加入到B相中,随后在搅拌下将C相加入到先前的混合物中。在加入完成之后,在温和的搅拌下使其冷却并且在混合物为室温时加入Palm-Lys-Asp-Ile-Cit-NH2和卵磷脂的水溶液,将其均化并且在必要的情况下用三乙醇胺校正pH。
得到的霜剂的pH为6-7,粘度为10,000-15,000cps(6/50)。
实施例6:
包含H-Lys-Asp-Val-Cit-NH2的脂质体的制备
称量二棕榈酰基磷脂酰胆碱(DPPC)并且将其溶解于氯仿。将溶剂真空蒸发,直到得到磷脂的薄层,通过在55℃用包含所需浓度的肽的水溶液(包含)处理使这个层水合,得到MLV脂质体。通过将MLV脂质体浸没在55℃的超声波浴中8个周期得到ULV脂质体,每个周期2分钟,间隔5分钟。
根据第一方面,本发明涉及通式(I)的肽:
其立体异构体、其美容学和皮肤用药物学可接受的盐、及其混合物,其中:
Z选自丙氨酰基、别-异亮氨酰基(allo-isoleucyl)、甘氨酰基、异亮氨酰基、异丝氨酰基、异缬氨酰基、亮氨酰基、正亮氨酰基、正缬氨酰基、脯氨酰基、丝氨酰基、苏氨酰基、别-苏氨酰基或者缬氨酰基;
n和m可以独立地为1到5;
AA选自以L-和D-型天然编码的氨基酸和非编码的氨基酸;
x和y可以独立地为0到2;
R1选自H或烷基、芳基、芳烷基或酰基;和
R2选自被脂肪族或环状基团取代或未被取代的氨基、羟基或硫醇。
根据重要的第二方面,在通式(I)的肽中,R1优选为H或直链、支链或环状的饱和或不饱和的C2-C24酰基。
根据本发明的一个重要方面,在通式(I)的肽中,R2优选为被直链、支链或环状的饱和或不饱和的C1-C24脂族基取代或未被取代的氨基或羟基。
根据本发明的重要方面,在通式(I)的肽中,Z优选为L-异亮氨酰基、L-苏氨酰基或L-缬氨酰基。
根据本发明的重要方面,在通式(I)的肽中,Z优选为L-异亮氨酰基,n为4,m为1,R1为H或乙酰基或棕榈酰基,R2为被甲基或乙基或己基或十二烷基或十六烷基取代或未被取代的氨基或羟基。
根据本发明的重要方面,在通式(I)的肽中,Z优选为L-苏氨酰基,n为4,m为1,R1为H或乙酰基或棕榈酰基,R2为被甲基或乙基或己基或十二烷基或十六烷基取代或未被取代的氨基或羟基。
根据本发明的重要方面,在通式(I)的肽中,Z优选为L-缬氨酰基,n为4,m为1,R1为H或乙酰基或棕榈酰基,R2为被甲基或乙基或己基或十二烷基或十六烷基取代或未被取代的氨基或羟基。
根据本发明的重要方面,在通式(I)的肽中,Z优选为L-异亮氨酰基,n为4,m为1,x和y都是0,R1为H或乙酰基或棕榈酰基,R2为被甲基或乙基或己基或十二烷基或十六烷基取代或未被取代的氨基或羟基。
根据本发明的重要方面,在通式(I)的肽中,Z优选为L-苏氨酰基,n为4,m为1,x和y都是0,R1为H或乙酰基或棕榈酰基,R2为被甲基或乙基或己基或十二烷基或十六烷基取代或未被取代的氨基或羟基。
根据本发明的重要方面,在通式(I)的肽中,Z优选为L-缬氨酰基,n为4,m为1,x和y都是0,R1为H或乙酰基或棕榈酰基,R2为被甲基或乙基或己基或十二烷基或十六烷基取代或未被取代的氨基或羟基。
根据另一个重要的方面,本发明涉及基于固相多肽合成得到通式(I)的肽的方法。
根据另一个重要的方面,本发明涉及得到通式(I)的肽的方法,其使用了选自Fmoc/叔丁基、Fmoc/三苯甲基和Fmoc/烯丙基的保护基。
根据另一个重要的方面,本发明涉及美容或皮肤用药物组合物,包括美容学或皮肤用药物学有效量的至少一种式(I)的肽和至少一种美容学或皮肤用药物学可接受的赋形剂或助剂。
根据另一个重要的方面,本发明涉及美容或皮肤用药物组合物,包括并入到美容学或皮肤用药物学可接受的持续释放系统和/或输送系统中的至少一种通式(I)的肽,所述美容学或皮肤用药物学可接受的持续释放系统和/或输送系统选自脂质体、毫米级胶囊、微胶囊、纳米囊剂、海绵、囊泡、胶束、毫米级球体、微球体、纳米球体、脂球体、毫米级离子、微粒和纳米粒子。
根据另一个重要的方面,本发明涉及美容或皮肤用药物组合物,包括被吸附在固体有机聚合物或无机支持物上的至少一种通式(I)的肽,所述固体有机聚合物或无机支持物选自滑石粉、膨润土、二氧化硅、淀粉和麦芽糖糊精。
根据另一个重要的方面,本发明涉及美容或皮肤用药物组合物,其中通式(I)的肽存在于选自以下的制剂中:霜剂、水包油和硅氧烷的乳剂、水包油乳剂、水包硅氧烷的乳剂、油和硅氧烷包水的乳剂、油包水乳剂、硅氧烷包水的乳剂、油剂、乳剂、香膏、泡沫、洗剂、凝胶剂、搽剂、血清剂、肥皂、油膏、奶油冻(mousses)、软膏、条棒、画笔或喷雾剂。
根据另一个重要的方面,本发明涉及美容或皮肤用药物组合物,其中通式(I)的肽被并入到选自以下的固体支持物中:湿巾、水凝胶、粘性贴片、非粘性贴片和面膜。
根据另一个重要的方面,本发明涉及美容或皮肤用药物组合物,其中通式(I)的肽被并入到选自以下的织物中:绷带、腰带、裤袜、短袜、短裤、胸罩和用于胳膊和前臂的带子。
根据另一个重要的方面,本发明涉及美容或皮肤用药物组合物,其包含并入到化妆系列产品中的通式(I)的肽,所述化妆系列产品包括遮瑕膏、化妆粉底、卸妆乳剂或洗液、眼影膏和口红。
根据另一个重要的方面,本发明涉及美容或皮肤用药物组合物,包括浓度为0.000001%(按重量计算)到20%(按重量计算)的通式(I)的肽。
根据另一个重要的方面,本发明涉及式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于处理皮肤。
根据另一个重要的方面,本发明涉及式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于减少、延迟和/或防止老化迹象。
根据另一个重要的方面,本发明涉及式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于处理大腿、腹部、臀部、胸部、前臂、颈部和面部的皮肤。
根据另一个重要的方面,本发明涉及式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于处理皮肤软化疤痕外观。
根据另一个重要的方面,本发明涉及式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于处理具有疤痕的那些身体区域的皮肤。
Claims (31)
2.权利要求1的肽,其中R1是H或直链、支链或环状的饱和或不饱和的C2-C24酰基。
3.权利要求1的肽,其中R2是被直链、支链或环状的饱和或不饱和的C1-C24脂族基取代的或未被取代的氨基或羟基。
4.权利要求1的肽,其中Z是L-异亮氨酰基、L-苏氨酰基或L-缬氨酰基。
5.权利要求1到4中任一项的肽,其中Z为L-Ile,R1为H、乙酰基或棕榈酰基,m为1,n为4,和R2为被甲基或乙基或己基或十二烷基或十六烷基取代或未被取代的氨基或羟基。
6.权利要求5的肽,其中x和y是0。
7.权利要求1到4中任一项的肽,其中Z为L-Thr,R1为H、乙酰基或棕榈酰基,m为1,n为4,和R2为被甲基或乙基或己基或十二烷基或十六烷基取代或未被取代的氨基或羟基。
8.权利要求7的肽,其中x和y是0。
9.权利要求1到4中任一项的肽,其中Z为L-Val,R1为H、乙酰基或棕榈酰基,m为1,n为4,和R2为被甲基或乙基或己基或十二烷基或十六烷基取代或未被取代的氨基或羟基。
10.权利要求9的肽,其中x和y是0。
11.得到权利要求1到10中任一项的通式(I)的肽的方法,其特征在于所述方法在固相上进行。
12.权利要求11的得到通式(I)的肽的方法,其特征在于使用了选自Fmoc/叔丁基、Fmoc/三苯甲基和Fmoc/烯丙基的保护基。
13.美容或皮肤用药物组合物,其包括美容学或皮肤用药物学有效量的至少一种权利要求1到10中任一项的式(I)的肽,其特征在于包括至少一种美容学或皮肤用药物学可接受的赋形剂或助剂。
14.权利要求13的美容或皮肤用药物组合物,其特征在于通式(I)的肽被并入到美容学或皮肤用药物学可接受的递送系统和/或持续释放系统中,所述递送系统和/或持续释放系统选自脂质体、毫米级胶囊、微胶囊、纳米囊剂、海绵、囊泡、胶束、毫米级球体、微球体、纳米球体、脂球体、毫米级粒子、微粒和纳米粒子。
15.权利要求13的美容或皮肤用药物组合物,其特征在于将通式(I)的肽吸附在美容学或皮肤用药物学可接受的有机聚合物或无机固体支持物上,所述有机聚合物或无机固体支持物选自滑石粉、膨润土、二氧化硅、淀粉或麦芽糖糊精。
16.权利要求13到15中任一项的美容或皮肤用药物组合物,其特征在于其为选自以下的制剂:霜剂、水包油和硅氧烷的乳剂、水包油乳剂、水包硅氧烷的乳剂、油和硅氧烷包水的乳剂、油包水乳剂、硅氧烷包水的乳剂、油剂、乳剂、香膏、泡沫、洗剂、凝胶剂、搽剂、血清剂、肥皂、油膏、奶油冻、软膏、条棒、画笔或喷雾剂。
17.权利要求13到15中任一项的美容或皮肤用药物组合物,其特征在于通式(I)的肽被并入到选自以下的固体支持物中:湿巾、水凝胶、粘性贴片、非粘性贴片和面膜。
18.权利要求13到15中任一项的美容或皮肤用药物组合物,其特征在于通式(I)的肽被并入到选自以下的化妆系列产品中:遮瑕膏、化妆粉底、卸妆洗液、卸妆乳剂、眼影膏和口红。
19.权利要求13到15中任一项的美容或皮肤用药物组合物,其特征在于将通式(I)的肽并入到织物中。
20.权利要求19的美容或皮肤用药物组合物,其特征在于将通式(I)的肽并入到绷带、裤袜、短袜、短裤、胸罩、腰带和用于胳膊和前臂的带子中。
21.美容或皮肤用药物组合物,包括美容学或皮肤用药物学有效量的至少一种权利要求1到10中任一项的式(I)的肽,其特征在于通式(I)的肽的浓度为0.000001重量%到20重量%。
22.权利要求21的美容或皮肤用药物组合物,其特征在于通式(I)的肽的浓度为0.0001重量%到5重量%。
23.美容或皮肤用药物组合物,包括美容学或皮肤用药物学有效量的至少一种权利要求1到10中任一项的式(I)的肽,其特征在于其包括另外的美容学或皮肤用药物学有效量的选自以下的活性剂:剥离剂、润湿剂、脱色剂或增白剂、促脱色剂、抗妊娠纹、抗皱纹剂、抗氧剂、抗糖化剂、NO合成酶抑制剂、防老剂、能够减少或除去眼袋的试剂、刺激皮肤或表皮高分子合成和/或能够抑制它们降解的试剂、刺激角化细胞增殖的试剂、刺激成纤维细胞增殖的试剂、刺激成纤维细胞和角化细胞增殖的试剂、刺激角化细胞分化的试剂、改善皮肤-表皮接合的试剂、皮肤弛缓剂、紧实剂、抗大气污染和/或抗自由基的试剂、作用于毛细血管循环和/或微循环的试剂、镇静剂、抗炎剂、抗微生物剂、作用于细胞代谢的试剂、维生素、具有针对紫外线A和B射线的活性的有机或无机光保护剂、或其混合物。
24.权利要求23的美容或皮肤用药物组合物,其特征在于活性剂是合成或植物提取物或者是通过生物发酵生产的。
25.权利要求1到10中任一项的式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于处理哺乳动物的皮肤。
26.权利要求25的式(I)的肽用于制备美容或人生物用药物组合物的用途,所述组合物用于处理人的皮肤。
27.权利要求1到10中任一项的式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于处理需要调节原纤维形成的哺乳动物的那些皮肤状态。
28.权利要求1到10中任一项的式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于减少或延迟老化迹象。
29.权利要求28的式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于处理颈部和面部的皮肤。
30.权利要求1到10中任一项的式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于软化疤痕外观。
31.权利要求30的式(I)的肽用于制备美容或皮肤用药物组合物的用途,所述组合物用于处理哺乳动物的具有疤痕的那些皮肤区域。
Applications Claiming Priority (3)
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ES200600846A ES2283212B1 (es) | 2006-03-31 | 2006-03-31 | Peptidos sinteticos utiles en el tratamiento de la piel y su uso en composiciones cosmeticas o dermofarmaceuticas. |
ESP200600846 | 2006-03-31 | ||
PCT/ES2007/000180 WO2007113356A2 (es) | 2006-03-31 | 2007-03-30 | Peptidos sintéticos útiles en el tratamiento de la piel y su uso en composiciones cosméticas o dermofarmacéuticas |
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CN101990544A true CN101990544A (zh) | 2011-03-23 |
CN101990544B CN101990544B (zh) | 2014-09-24 |
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CN200780019174.0A Active CN101990544B (zh) | 2006-03-31 | 2007-03-30 | 用于处理皮肤的合成肽及其在美容或皮肤用药物组合物中的用途 |
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US (1) | US9393186B2 (zh) |
EP (1) | EP2025681B1 (zh) |
JP (1) | JP5247676B2 (zh) |
KR (1) | KR20090014150A (zh) |
CN (1) | CN101990544B (zh) |
AR (1) | AR060251A1 (zh) |
AU (1) | AU2008243084B2 (zh) |
BR (1) | BRPI0708841B1 (zh) |
CA (1) | CA2647775C (zh) |
ES (2) | ES2283212B1 (zh) |
HK (1) | HK1153206A1 (zh) |
MX (1) | MX2008012444A (zh) |
WO (1) | WO2007113356A2 (zh) |
Cited By (2)
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CN103083715A (zh) * | 2011-11-03 | 2013-05-08 | 杭州炬九生物科技有限公司 | 一种软化、淡化疤痕的水凝胶疤痕贴 |
CN108536995A (zh) * | 2017-03-03 | 2018-09-14 | 塔塔顾问服务有限公司 | 用于在人体皮肤上对活性物质进行计算机模拟测试的方法和系统 |
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ES2349972B1 (es) * | 2009-02-16 | 2011-11-24 | Lipotec, S.A. | Péptidos útiles en el tratamiento y/o cuidado de la piel, mucosas y/o cuero cabelludo y su uso en composiciones cosméticas o farmacéuticas. |
BRPI1012728A8 (pt) * | 2009-03-16 | 2016-11-22 | Dsm Ip Assets Bv | Uso de tripeptídeos |
DE102009027024A1 (de) * | 2009-06-18 | 2010-12-23 | Henkel Ag & Co. Kgaa | Antifalten-Kosmetikum mit Antioxidantien |
MX365465B (es) | 2013-03-21 | 2019-06-04 | Sanofi Aventis Deutschland | Sintesis de productos peptidicos que contienen imida ciclica. |
SG11201506804VA (en) | 2013-03-21 | 2015-09-29 | Sanofi Aventis Deutschland | Synthesis of hydantoin containing peptide products |
FR3007289B1 (fr) * | 2013-06-24 | 2015-06-19 | Caster | Compositions cosmetiques comprenant des extraits de plantes pour lutter contre le vieillissement cutane |
US10905646B2 (en) | 2014-10-31 | 2021-02-02 | Lubrizol Advanced Materials, Inc. | Thermoplastic polyurethane film for delivery of active agents to skin surfaces |
US20180311358A1 (en) | 2015-11-05 | 2018-11-01 | Lubrizol Advanced Materials, Inc. | Thermoformable dual network hydrogel compositions |
KR101895906B1 (ko) * | 2016-07-07 | 2018-10-04 | 주식회사 한국화장품제조 | 펩타이드 리포좀을 포함하는 스틱형 화장료 조성물 |
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- 2007-03-30 US US12/295,554 patent/US9393186B2/en active Active
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- 2007-03-30 JP JP2009502124A patent/JP5247676B2/ja active Active
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Publication number | Publication date |
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KR20090014150A (ko) | 2009-02-06 |
CN101990544B (zh) | 2014-09-24 |
JP5247676B2 (ja) | 2013-07-24 |
EP2025681B1 (en) | 2016-02-17 |
CA2647775C (en) | 2017-04-18 |
AU2008243084A1 (en) | 2008-11-27 |
ES2283212A1 (es) | 2007-10-16 |
BRPI0708841B1 (pt) | 2015-10-27 |
US9393186B2 (en) | 2016-07-19 |
WO2007113356A3 (es) | 2012-12-20 |
WO2007113356A2 (es) | 2007-10-11 |
AU2008243084B2 (en) | 2012-03-08 |
JP2009535297A (ja) | 2009-10-01 |
EP2025681A2 (en) | 2009-02-18 |
ES2283212B1 (es) | 2008-08-16 |
MX2008012444A (es) | 2009-03-06 |
AR060251A1 (es) | 2008-06-04 |
EP2025681A4 (en) | 2015-01-07 |
CA2647775A1 (en) | 2007-10-11 |
BRPI0708841A2 (pt) | 2011-06-14 |
HK1153206A1 (zh) | 2012-03-23 |
US20130309281A1 (en) | 2013-11-21 |
ES2566493T3 (es) | 2016-04-13 |
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