CN102802656B - 包含昼夜节奏基因激活物和Sirt1基因激活物的协同组合的皮肤修复组合物 - Google Patents
包含昼夜节奏基因激活物和Sirt1基因激活物的协同组合的皮肤修复组合物 Download PDFInfo
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Abstract
用于增强皮肤细胞中受损DNA修复的组合物和方法。局部组合物包含上调皮肤细胞中的昼夜节奏基因表达的至少一种试剂和延迟皮肤细胞中的有丝***的至少一种非昼夜节奏试剂。优选地,此类组合物包含一种或多种角化细胞clock和per1基因激活物,连同SIRT1或一种或多种sirt1激活物。更优选地,sirt1激活物是特异性肽sirt1激活物和白藜芦醇的协同组合。优选地,此类组合物是易于使用,有效,美容上可接受的,化学、热力学和光稳定的,对于局部使用安全的,具有很少的副作用或无副作用,并且在个人护理市场中商业上可行的。
Description
本申请是于2007年8月13日提交的悬而未决的申请US 11/837,658的部分继续申请,和于2009年2月9日提交的悬而未决的申请US12/367,705的部分继续申请,所述2个申请整体引入本文作为参考。
技术领域
本发明在皮肤处理领域中。更具体而言,本发明涉及用于增强皮肤细胞中的损伤DNA修复的组合物和方法。
发明背景
目前充分理解皮肤处于来自各种环境和生活方式因素的每日袭击下。这些因素的短列举包括UVA辐射、UVB辐射、污染、吸烟、饮食不良、休息不足和心理学应激。这种袭击表现为对皮肤细胞DNA和蛋白质的损伤。皮肤中的皱纹和褶皱在皮肤细胞损伤的较不严重后果中,而黑素瘤是更严重情况之一。
DNA
损伤
某些环境和生活方式因素与皮肤细胞DNA和/或蛋白质直接相互作用,以引起损伤,某些因素间接引起损伤,并且某些因素可以引起这两种损伤。直接DNA损伤的一个例子将是当皮肤细胞DNA吸收来自光谱的UVB部分的光子时。光子的吸收可以引起DNA序列中的突变。例如,所有黑素瘤发生中的约8%是由于直接DNA突变。
对皮肤细胞DNA和蛋白质的间接损伤的一个例子在紫外线光子进入皮肤且由生色团吸收时可见。在激发状态,生色团进入导致活性氧种类形成的反应内。例如,在人皮肤中,UVB暴露与过氧化氢的产生相关,而UVA与单线态氧的产生相关。如果皮肤不能通过中和活性种类维持稳态,那么活性种类将通过氧化损伤皮肤细胞DNA和蛋白质。对DNA和蛋白质的这种损伤称为氧化性应激且是皮肤衰老的主要原因。此外,所有黑素瘤发生中的约92%是由于间接、氧化性DNA损伤。
DNA
损伤:预防和遏制与修复比较
含DNA的皮肤细胞包括角化细胞干细胞和黑色素细胞。估计单次日光灼伤导致无数DNA诱变碱基修饰,例如受累细胞中的T-T(硫胺素-硫胺素)二聚物;8-氧代-7,8-二氢-2’-脱氧鸟苷(8-氧代-DG);06MeG(06-甲基鸟嘌呤);环丁烷嘧啶二聚体(CPD);和6-4光产物(6-4PP)。这些突变触发在皮肤细胞内的各种应答,这可以导致细胞的进一步DNA损伤或凋亡的预防。例如,黑色素细胞中的黑色素产生已知通过UV辐射上调,作为防护措施。为了处理来自UV的威胁,黑色素通过下表皮中的黑色素细胞产生,并且在向外迁移的角化细胞的帮助下,它分布遍及上和下表面。在第一种情况下,黑色素看起来通过充当UV滤器阻止进一步的UV诱导DNA损伤,所述UV滤器限制穿透至下表皮的UV的量,黑色素细胞和角化细胞干细胞定位于所述下表皮。然而,作为第二线防御,通过诱导角化细胞的凋亡,黑色素含有由于UV辐射的DNA损伤。通过促进凋亡,受损DNA得以包含,所述受损DNA具有传递给子细胞的较少机会(参见例如,Yamaguchi等人,Melanin mediated apoptosis of epidermal cells damaged by
ultraviolet radiation: factors influencing the incidence of skin cancer;Arch Dermatol Res. 2008 Apr;300 Suppl 1: S43-S50)。
除预防和含有DNA损伤外,健康角化细胞和黑色素细胞具有用于修复DNA损害的天然内部机制。这些机制不同于预防和遏制的那些机制,其涉及不同的(尽管有时重叠的)反应级联。本发明的组合物和方法最主要涉及DNA损伤的修复。
存在细胞修复机制,以修复来自各种原因的DNA损害,不仅是我们已讨论的UV诱导的损伤。然而,DNA损害的修复花费时间。例如,如果不通过外来影响加速,通过UVB暴露形成的TT二聚物和6-4PP损伤的修复可以分别花费高达48和8小时。由于UVA或UVB暴露、臭氧或吸烟和污染的8-氧代-dG和06MeG损害的修复可以花费高达2小时。理想地,DNA损害在细胞***发生前修复。如果不如此,那么优选后果是凋亡。但如果DNA损伤碰巧不利地影响凋亡的上调,或如果突变变得未被检测,那么受损DNA可以传递给下一代。本发明的组合物和方法最主要涉及在细胞***发生前使DNA损伤的修复达到最大。
细胞的预防和修复机制受昼夜节奏钟(
Circadian Clock
)控制
在正常条件下,包括DNA表达和修复的细胞功能不在随机时间以等概率发生。相反,每种细胞具有约24小时(即昼夜节律)的内源周期(或钟),并且细胞的活性受这种内源周期调节。不存在某些外部刺激,每个细胞将根据其内源性钟自由运行。然而,遍及全身的细胞的内源性钟是同步的。为了同步细胞与彼此和环境的活性,身体能够接受来自环境的暗示。最显著的环境暗示是日光的存在或不存在。因此,昼夜节奏周期由与太阳日的时期大致同时的亮和暗时期组成。
目前理解昼夜节律允许细胞预期环境中可能影响细胞的改变,且以及时的方式适应那些改变。只要细胞昼夜节律的遗传机制适当起作用,细胞就在对于细胞活力和/或稳态最佳的时候以同步方式执行其多种功能中的每一种。例如,当日光接近时(但甚至是在皮肤处于来自UV的袭击下之前),某些基因激活以产生保护细胞不受预期UV辐射损伤的蛋白质。随后,当日光减弱时,这些基因关闭。另一方面,昼夜节奏基因自身可以遭受通过环境因素的攻击。对于调节细胞的昼夜节律的一种或多种基因的损伤可以使细胞脱离与环境和其他细胞的同步。
核心昼夜节奏机制
转录因子是与特异性DNA序列结合,以控制遗传信息从DNA到RNA的转移的蛋白质。核心昼夜节奏机制或“细胞钟”包含参与异相、负和正反馈环的转录因子,这导致摆动基因转录。
在哺乳动物的主要负反馈环中,CLOCK和BMAL1转录因子的异二聚体激活period(per)和cryptochrome(cry)基因的转录。在人中,period基因实际上是3种基因per1、per2和per3的家族,并且cry基因家族包括cry1和cry2。在其转录后,PER和CRY蛋白质迁移到细胞质内且形成PER/CRY复合物。翻译后调节产生故意延迟,这之后PER/CRY复合物再定位到细胞核内。在核中PER和CRY的浓度在昼夜节奏日间结束时达到峰值,在这时CRY蛋白质随后作用于抑制CLOCK/BMAL1异二聚体的转录活性。因此,CRY看起来关闭其自身转录。
另一方面,在一个正反馈环中,在易位至核后,PER2看起来上调BMAL1的转录,最终导致period和cry基因的转录。此外,CLOCK/BMAL1二聚体看起来上调rev-erbα和rora基因。Rora激活BMAL1转录,而rev-erbα抑制CLOCK和BMAL1。所谓的“规范时钟基因”(clock 、 bmal1、 per1、per2、per3、cry1和cry2)的峰活性是异相的,从而使得自我维持环产生,其具有约24小时的时期。
细胞周期
细胞周期指在细胞中发生的系列事件,其导致细胞的***和复制。周期通常描述为需要约24小时完成的4个或5个序贯时期。在细胞周期的每个时期内,存在确保给定时期的所有必要过程在下一个时期起始前完成的检查点。在人细胞中,“第一个”时期是其中拷贝且合成细胞的DNA的合成(S)期。S期一般可以持续6-8小时。在持续3-4小时的G2期中,合成蛋白质且细胞大小加倍。在有丝***(M)过程中,核被膜分解,从而使得遗传物质的每个拷贝可以分离至细胞的相反极。在围绕每组染色体的新核被膜形成后,细胞缩成2个(胞质***)。M期约1小时长。第四个和最长的时期(6 – 12小时)是G1,其特征在于RNA和蛋白质合成。从G1期开始,细胞可再次进入S期或它可进入G0期。在G0中,细胞是静止的。G0可以持续数天或数年。干细胞可以从G0期返回,在G1进入。分化细胞一般不从G0返回。此外,具有受损DNA的细胞可以进入G0,而不是凋亡。
细胞周期检查点抑制受损
DNA
传递
在细胞***过程中,检查点用于调节细胞通过细胞周期的进展。检查点阻止细胞进展至下一个时期,直至所有必需过程完成,包括受损DNA的任何修复。以这种方式,检查点确保受损或不完全DNA不传递给子细胞。存在几个检查点。G1/S检查点(限制检查点)中断细胞周期,从而使得可以做出进入静止期或不进入的“决定”。在G2/M检查点,如果检测到受损DNA,那么细胞周期停止,这并不罕见。复制后检查点涉及已在合成期中复制的受损DNA。受损DNA的复制触发细胞应答,这阻止细胞周期进展直至复制后修复过程完成。在人细胞中,复制后检查点通过延迟有丝***期的开始产生用于修复的时间。chk1基因施加对复制后检查点的控制,而p53基因在触发G1/S和G2/M检查点处的控制机制中起重要作用。
昼夜节奏钟还调节细胞增殖
近年来,昼夜节奏钟在调节细胞增殖中的重要性已得到理解。例如:
“昼夜节奏定时的破坏 …已对细胞***的正常调节引起深远后果。”(Reddy等人,2005 Circadian clocks: neural and peripheral pacemakers that
impact upon the cell division cycle. Mutation Research 574 76–91)
“对钟成分与细胞周期调节机构相互作用的机制的详细洞察来自近期的小鼠研究,例如,…在肝组织的去除(部分肝切除术)与随后的第一波有丝***之间的延迟取决于实施手术的日子的时间。”(Vallone等人,2007 Start the clock! Circadian rhythms and development. Developmental
Dynamics 236 142–155)
“从蓝细菌到高级脊椎动物,存在昼夜节奏钟的许多例子,所述昼夜节奏钟“门控”细胞周期的S-期和有丝***在夜间期间发生。”(Vallone等人)。[大概,DNA合成和有丝***在夜间发生以保护DNA免于有害的UV或来自日光的其他电离辐射]。
因此,昼夜节奏钟对DNA和蛋白质合成、有丝***和胞质***、RNA合成和修复的细胞周期发挥拱形影响。因此,当环境因素干扰细胞的昼夜节奏机制时,细胞功能受损。我们假定当处理可以产生或再次同步细胞的昼夜节奏钟时,或当处理可以恢复昼夜节奏基因表达的“正常”水平时,那么细胞功能可以得到改善,细胞损伤可以以加速方式得到修复,或凋亡可以以更及时的方式发生。
环境可以使昼夜节律脱离同步
干扰调节细胞的昼夜节律的一种或多种基因的试剂可以使细胞脱离与环境和其他细胞的同步。例如,在UV暴露后的数小时,可能多达20小时,人角化细胞中clock、bmal1和per1基因表达的水平是显著降低的(参见图1)。“显著降低的”意指低于这些基因在其正常昼夜节奏周期中经历的最低表达,如上所述。此外,在UV暴露后,可描述为大致正弦式的基因表达的通常模式丧失。
在图1中,水平线标记clock基因表达的通常平均水平,且在UV暴露后约44小时时开始,显示关于那条线的一般昼夜节奏变动。相比之下,在UVB暴露后即刻,基因表达的水平下降到充分低于正常,并且不回到正常水平达约20小时。在该20小时过程中,基因表达的正常模式对于所有3种基因是丧失的。并且即使当基因表达的水平不回到接近正常水平时,需要约20小时至约44小时的时期用于表达的正常正弦式模式恢复。因此UV暴露实际上具有2种效应。一种效应是在昼夜节奏基因的表达水平中的显著减退,并且另一种是模式,也就是说,其表达的时机。在UV暴露后0至约44小时,DNA和蛋白质合成、有丝***和胞质***、RNA合成和修复以及程序性细胞死亡(凋亡)的时机都受损。
当然,UV暴露在日间期间发生,特别是在关键的10
a.m.至2 p.m.窗口期间。如已指出的,在核中PER和CRY蛋白质的浓度在昼夜节奏日间结束时达到峰值,在这时CRY蛋白质作用于抑制CLOCK/BMAL1异二聚体的转录。达到关闭clock和bmal1表达的临界浓度中的任何延迟将延长昼夜节奏周期。因此,UV暴露趋于延长昼夜节奏周期。这使细胞周期脱离与环境的同步。DNA复制和有丝***可能在对于细胞复制是最佳的晚上不发生。此外,昼夜节奏基因对细胞周期施加的门控影响可能是受损的,从而使得DNA损伤可未检测到或可不进行修复,并且可允许传递给子细胞。
据报道
Sirtuins
延迟有丝***的发生
Sirtuin 1(也称为SIRT1或沉默信息调节物二直向同源物1)是响应应激调节代谢和细胞存活的酶。它与细胞寿命相关。编码SIRT1酶的sirt1基因不是昼夜节奏基因。Chua等人已建议SIRT1通过停滞细胞周期促进复制性衰老(Chua等人(2005) Mammalian SIRT1
limits replicative life span in response to chronic genotoxic stress.
Cell Metabolism 2,67-76)。
US
2009-0082278(整体引入本文作为参考)进一步描述这种基因和可能上调其的局部皮肤组合物。段落8-13写到:
“申请人近期已发现新蛋白质在皮肤细胞机制中的牵涉,其在衰老过程和细胞保护中有重要作用。”
“申请人已证明,SIRT蛋白质、并且更准确地SIRT1蛋白质在皮肤细胞中表达,并且其表达与皮肤细胞遇到的不同应激有关。他们已具体证明,应用不同试剂对该蛋白质表达的诱导允许细胞保护并且更好地帮助它们对抗应激和内在衰老。”
“SIRT蛋白质是Sirtuin家族的一部分,并且是在组蛋白脱乙酰化中起重要作用的NAD+依赖性核蛋白质。编码SIR蛋白质的SIR基因(沉默信息调节物)在1979年在酿酒酵母(S. cerevisiae)中首次描述(Rine
J和A l.,Genetics
1979)。其后,证明SIR2P蛋白质在秀丽隐杆线虫(C.
elegans)中的过量表达允许该生物体的寿命增加(Tissenbaum和A l.,Nature 2001)。该研究允许假设这些蛋白质与寿命有关。”
“SIRT1蛋白质是最佳表征的人sirtuin并且与众多转录调节物相互作用。人SIRT1蛋白质已描述为牵涉p53调节(Cheng H L和A l. Proc Natl
Acad Sci USA. 2003),并且在更近期描述为细胞衰老的调节剂(Langley
E和A l.,EMBO
J. 2002)。其它人SIRT蛋白质已得到发现(SIRT2、SIRT3、SIRT4-7)。人SIRT2蛋白质被研究得非常少;但一些研究已证明其在有丝***活性的控制中的作用(Dryden
S C和A l. Mol Cell Bio. 2003)以及其在p53蛋白质的调节中的牵涉(Vaziri H和A l.,Cell. 2001)。迄今,脱乙酰酶sirtuins被认为是在细胞死亡及其生命周期中起重要作用的酶家族(Porcu
M.和Chiarugi A,Trends
Pharmacol Sci.,2005)。”
“本发明[即US
2009-0082278]涉及美容或药物组合物,其包含在美容或药学上可接受的介质中的可能激活皮肤细胞中SIRT蛋白质合成的至少一种化合物。优选地,根据本发明,该化合物会激活特定类型的SIRT蛋白质,SIRT1蛋白质。”
“迄今,尚未描述充当皮肤细胞中SIRT家族蛋白质的合成的诱导物的化合物的应用”。
本说明书做出下述论点:迄今为止,包含与昼夜节奏基因激活物协同的sirt1激活物的组合物的使用从未得到描述,即使在US2009-0082278中。就申请人所知,包含一种或多种非昼夜节奏、有丝***延迟试剂的,致力于人表皮角化细胞中CLOCK和PER1蛋白质的降低水平的局部组合物是未知的。
用于
DNA
修复的局部(
topical
)组合物
用于应用于皮肤以促进细胞修复过程的局部产品是已知的。例如,此类产品可以包括用于改善天然细胞DNA修复的有效性的DNA修复酶、用于维持角化细胞水合的保湿成分、用于改善皮肤屏障功能的补水成分等等。虽然这些成分可以改善角化细胞修复自身的能力,但始终存在改善的空间。与现有技术对比,本发明提供了恢复皮肤细胞中未受损昼夜节奏蛋白质的水平的方法,和恢复昼夜节奏基因表达的正常模式的方法,所述方法与抑制受损DNA传递给子细胞的方法组合。
发明目的
本发明的一个目的是提供局部组合物,当应用时,所述局部组合物以加速方式恢复皮肤细胞中昼夜节奏蛋白质的正常水平,且恢复昼夜节奏基因表达的正常模式。
本发明的一个目的是提供通过上调clock和per1基因表达并且通过延迟皮肤细胞的有丝***修复光损伤和/或氧化损伤的皮肤的局部组合物。
本发明的一个目的是提供减少增殖性受损皮肤细胞DNA的机会的局部组合物。
本发明的一个目的是提供减少已通过环境攻击物特别是UV暴露而损伤的增殖性皮肤细胞DNA的机会的局部组合物。
本发明的又一目的是提供用于处理皮肤的组合物,其包含至少一种角化细胞clock或per1基因激活物、至少一种非昼夜节奏有丝***延迟试剂和任选地至少一种DNA修复酶。
发明概述
所有前述通过局部组合物实现,所述局部组合物包含上调皮肤细胞中的昼夜节奏基因表达的至少一种试剂和延迟皮肤细胞中的有丝***的至少一种非昼夜节奏试剂。已发现,包含上调(或激活)clock基因和per1基因、同时还增加SIRT1的水平的试剂的组合物协同促进细胞活力、细胞寿命,抑制由于环境攻击物的细胞损伤,改善DNA损伤的修复且协同减少增殖性受损皮肤细胞DNA的机会。任选地,该组合物包含一种或多种DNA修复酶。
本发明的优选实施方案是表现上述效应的局部皮肤组合物。优选地,此类组合物包含一种或多种角化细胞clock和per1基因激活物,连同SIRT1或一种或多种sirt1激活物。优选地,此类组合物是易于使用,有效,美容上可接受的,化学、热力学和光稳定的,对于局部使用安全的,具有很少的副作用或无副作用,并且在个人护理市场中商业上可行的。
附图描述
图1显示在UV暴露后72小时,人角化细胞中clock、bmal1和per1基因表达的水平。
图2显示sirt1激活物Orsirtine™和白藜芦醇对人角化细胞存活的作用。
图3显示与sirt1激活物Orsirtine™和白藜芦醇组合的昼夜节奏基因激活物的作用。
发明详述
就申请人已知,包含与恢复正常昼夜节奏周期的昼夜节奏基因激活物的局部应用协同,促进细胞周期停滞的sirt1激活物的局部组合物的使用从未得到描述。
定义
本文提及的所有百分率是重量百分率,除非另有说明。与基因有关,术语“激活”和“上调”或语源上相关的术语意指引起由该基因编码的一种或多种蛋白质的表达的成分。
术语“钟基因(clock gene)”有时在文献中用于指所谓的“规范”昼夜节奏基因中的任何,包括clock、bmal1、period和cryptochrome基因。在本说明书中,“clock”(以斜体)总是指编码CLOCK蛋白质的基因。总的来说,基因clock、bmal1、period和cryptochrome在本文中称为“昼夜节奏基因”。
术语“DNA修复酶”意指能够修复DNA碱基诱变损伤的酶。此类酶通常通过其修复的DNA损伤类型分类。例如,BER(碱基切除修复)酶、核苷酸切除修复(NER)酶;错配修复(MMR)酶;DNA解旋酶;DNA聚合酶等等。例如,突变例如8-氧代-7,8-二氢-2’-脱氧鸟苷可以通过OGG1(8-氧代鸟嘌呤糖基化酶修复。T-T二聚体可以通过核苷酸切除修复酶光解酶修复。6-4光产物可以通过NER修复。06-甲基鸟嘌呤可以通过06-烷基鸟嘌呤转移酶(AGT)修复。
就皮肤或皮肤细胞而言,“修复”意指角化细胞活力、强度和寿命是一般上改善的。修复的例子包括修复受损角化细胞DNA,且逆转由于UV光、吸烟或其他环境攻击物的细胞水合的丧失。
“对于局部使用安全的”意指顺应管理美容产品的安全性的所有地区和当地规章。“美容上可接受的”意指组合物的外观、感觉和气味在消费者可接受性的限制内,如由本领域普通技术人员理解的。“化学稳定的”、“热力学稳定的”和“光稳定的”意指从制造到至少6个月(更优选3年)的时期,组合物保持美容上可接受的。“在个人护理市场中商业上可行的”意指组合物的制造和发送成本应不超过个人护理工业中已经历的。
CLOCK
和
PERIOD1
上调
本发明的组合物含有上调clock和/或per1角化细胞基因的至少一种试剂。总的来说,相对于最终组合物的总重量,这些试剂的建议浓度范围为约0.000001 - 约40%、优选约0.000005 - 35%、更优选约0.00001 - 25%。一般而言,这些范围可以理解为是有效量。“有效量”意指在环境袭击下在应用于人皮肤的局部组合物中,这些试剂的浓度足以使角化细胞存活比率改善至少5%。合适的clock或per1激活物可以以植物提取物、多肽、肽、氨基酸等的形式存在。
特别优选的clock和/或per1基因激活物包含式(I)的肽:
R1-(AA)n- X1 –S – T – P – X2 –(AA)p – R2
其中(AA)n- X1
–S – T – P – X2 –(AA)p是(SEQ ID No. 1)和:
X1代表苏氨酸或丝氨酸,或等于不存在,
X2代表异亮氨酸或亮氨酸或脯氨酸或缬氨酸或丙氨酸或甘氨酸,或等于不存在,
AA代表任何氨基酸或其衍生物,并且n和p是在0 – 4之间(包括0和4在内)的整数,
R1代表游离或由保护基团取代的N末端氨基酸的伯胺官能,所述保护基团可以选自乙酰基、苯甲酰基、甲苯磺酰基或苄氧羰基,
R2代表由保护基团取代的C末端氨基酸的羧基官能的羟基,所述保护基团可以选自C1 - C20烷基链或NH2、NHY或NYY基团,其中Y代表C1 – C4烷基链,
并且其中通式(I)的序列包含约3 – 13个氨基酸残基。
通式(I)的序列可以含有氨基酸X1和X2由其他化学等价氨基酸的取代,其中氨基酸是:丙氨酸(A)、精氨酸(R)、天冬酰胺(N)、天冬氨酸(D)、半胱氨酸(C)、谷氨酸(E)、谷氨酰胺(Q)、甘氨酸(G)、组氨酸(H)、异亮氨酸(I)、亮氨酸(L)、赖氨酸(K)、甲硫氨酸(M)、苯丙氨酸(F)、脯氨酸(P)、丝氨酸(S)、苏氨酸(T)、色氨酸(W)、酪氨酸(Y)和缬氨酸(V)。
式I的更优选形式是如下的肽:
(SEQ ID No. 2) Y – V - S –T –P – Y– N– NH2
Tyr-Val-Ser-Thr-Pro-Tyr-Asn-NH2
(SEQ ID NO. 3) NH2 –V -S –T –P –E – NH2
NH2-Val-Ser-Thr-Pro-Glu-NH2
S –T –P – NH2
Ser-Thr-Pro-NH2
(SEQ ID No. 4) NH2 –L -H –S –T– P – P – NH2
NH2-Leu-His-Ser-Thr-Pro-Pro-NH2
(SEQ ID No. 5) CH3NH –R -H –S –T –P –E – NH2
CH3-NH-Arg-His-Ser-Thr-Pro-Glu-NH2
(SEQ ID No. 6) CH3NH - H –S –T –P –E - CH3NH
CH3-NH-His-Ser-Thr-Pro-Glu-CH3-NH。
更优选的是S-T-P-NH2肽、SEQ
ID No. 4或其混合物。最优选的是在商品名Chronolux®下具有INCI名称三肽-32的由ISP-Vinscience制造的肽。
相关申请US12/367,705的图1、2和3以及描述这些图的正文证实Chronolux®改善针对UV诱导的应激的角化细胞存活的能力,尤其是当与至少一种DNA修复酶组合时。
同时应用clock和per1基因激活物将产生有益结果不是立即显而易见的。毕竟,在正常昼夜节律中,CLOCK和Period1蛋白质的细胞浓度是异相的(out of phase)。然而,有益结果得以实现。可以暗示在环境袭击下皮肤细胞在CLOCK和Period1蛋白质水平方面被如此耗尽,使得通过尽可能快速上调2种蛋白质来实现益处。
SIRTUIN1
上调
我们已意外地发现,当与角化细胞sirt1激活物组合时,通过应用clock和per1角化细胞基因激活物实现的有益结果得以修饰,有时得以显著改善。SIRT1趋于诱导细胞周期停滞。考虑到昼夜节奏机制及其与细胞周期的调节相互作用的复杂性,根据现有技术可能未预期诱导细胞周期停滞同时恢复昼夜节奏蛋白质的正常水平将是有利的。
尽管不希望受任何一种理论束缚,应当理解除通过昼夜节奏失察外,PER1在细胞周期中具有直接作用。例如,除其作为昼夜节奏周期的核心组分的作用外,据报道PER1能够激活ATM激酶途径,导致细胞周期停滞。ATM(突变的运动失调性毛细血管扩张症)激酶是响应DNA双链断裂召募的核蛋白激酶。ATM激酶使CHK1和CHK2细胞周期检查点调节物磷酸化,其涉及细胞周期停滞且延迟进入有丝***内。由于某些环境应激,当PER1表达不足时,细胞周期停滞可能不发生或可能是延迟的。因此,在有丝***或胞质***前,可能存在不足够的时间以实现对受损DNA的修复。同时,PER1的表达减少已与凋亡减少相关联。因此,应死亡的受损细胞可能存活且***。因此,考虑到环境应激导致PER1水平中的异常减少(这导致不能停滞细胞周期)和减少的凋亡(这导致受损DNA的传播),可以预期per1激活将校正该问题。然而,我们已观察到当sirt1基因激活物与clock和per1基因激活物组合使用时,角化细胞活力得到显著改善。虽然不希望受任何一种理论束缚,但这个观察可以暗示per1自身的激活未能足够快速恢复PER1的水平,以在受损DNA可以传播至子细胞前实现修复。
“SIRT1激活物”意指可能支持SIRT1蛋白质的内源产生的任何化合物,特别是涉及前体例如DNA或RNA的正面控制的分子。在皮肤细胞中可能激活SIRT1蛋白质的合成的这些化合物中,不同分子例如多酚已得到描述。更具体而言,可以提及反式-茋的衍生物(例如白藜芦醇、白皮杉醇(piceatannol))、查耳酮的衍生物(例如异甘草素、紫铆因)、和黄酮的衍生物(例如漆黄素(fistein)、木犀草素、槲皮素)。与至少一种DNA修复酶组合的白藜芦醇或白藜芦醇衍生物的功效已显示于相关申请US
11/837,658中。然而,由于其与皮肤中的肽的固有结构相似性,某些肽是优选sirt1激活物。更优选的是一种或多种肽激活物和白藜芦醇的协同作用(关于这点更多在下文描述)。
肽
sirt
1
激活物
由于其与皮肤中的肽的固有结构相似性,肽是优选sirt1激活物。在肽性质的化合物中,可以提及蛋白质片段、肽和多肽片段、肽以及通过肽键连接在一起的2个或更多个氨基酸的所有序列。在本发明的一个优选实施方案中,肽片段大小范围为3 – 50个氨基酸,更具体而言3 – 10个氨基酸。所有这些肽片段具有生物学活性。优选肽是:
(SEQ ID No. 7)(AA)n- G -
L - Y - D - N - L- E -(AA)n
(AA)n- Gly
- Leu - Tyr - Asp - Asn - Leu- Glu -(AA)n
其中(AA) 是任何特定氨基酸或其衍生物,并且n是在0 – 3之间(包括0和3在内)的整数。特别优选的肽是:
(SEQ ID No. 8) G - L - Y - D - N - L- E
Gly-Leu-Tyr-Asp-Asn-Leu-Glu。
这种肽可作为可从ISP Vincience获得的Orsirtine™ GL(INCI名称: 水(和) 甘油(和) 水稻(Oryza Sativa)(稻) 提取物)获得。在本发明的组合物中,相对于最终组合物的总重量,肽SIRT1激活物以约0.000001%- 20%的量、且优选以约0.0001 - 5%的量存在。
白藜芦醇及其衍生物
白藜芦醇也称为3,5,4’-三羟基茋,是存在于红葡萄、覆盆子、蓝莓和某些其他植物浆果或提取物中的多羟基取代的茋化合物,其具有通式:
白藜芦醇已显示是有效的抗氧化剂,并且还显示出强抗增殖和抗炎性质。近期已报道白藜芦醇可以模拟各种生物中的热量限制(CR),所述生物例如酵母、蛔虫、果蝇、短寿命鱼和小鼠,减慢在此类生物中的衰老过程,并且显著延长其生活期限。尽管不希望受任何具体理论束缚,但本发明的发明人认为白藜芦醇可以减少细胞增殖且减缓凋亡过程,从而允许用于细胞中的DNA损伤修复的更多时间。假定当与DNA修复酶组合时,白藜芦醇可以导致对加强或另外增强细胞的天然DNA修复能力的协同作用。
然而,白藜芦醇在某些美容制剂中可以是潜在不稳定的。特别地,白藜芦醇在水基制剂中对水解是敏感的,并且可能促使此类制剂变得脱色。解决白藜芦醇在水基制剂中的不稳定性的一个途径是通过用其他官能团取代在3、5和4’位置上的羟基来修饰白藜芦醇,以形成在美容配方中更稳定的白藜芦醇衍生物。此类衍生物优选超过白藜芦醇。已发现白藜芦醇的无机酸、有机羧酸,单、二或多糖,或其他官能团的衍生物在水基制剂中是更稳定的。取代基团作用于保护且稳定白藜芦醇的酚基团,且使得白藜芦醇衍生物更适合于在水基美容制剂中使用。取代基团还可以是在应用于皮肤后由化合物容易水解的,所述水解优选通过皮肤表面上的酶和其他成分,以将活性形式的白藜芦醇释放到皮肤内。本发明的白藜芦醇衍生物具有通式:
其中X、Y和Z是氢或保护基团,条件是X、Y和Z中的至少一个是保护基团。适合于在本发明的美容或局部组合物中使用的示例性白藜芦醇衍生物在下文中更详细地描述。
A.
白藜芦醇的无机或有机酸酯
白藜芦醇的无机酸酯可以在本发明中使用,其中X、Y和Z中的一个或多个是无机酸官能团例如磷酸根、硝酸根、磺酸根和碳酸根。下述是特别适合于实践本发明的示例性无机酸酯的列举:
3-磷酸根-5,4’-二羟基茋 5-磷酸根-3,4’-二羟基茋
4’-磷酸根-3,5-二羟基茋 3,5-二磷酸根-4’-羟基茋
3,4’-二磷酸根-5-羟基茋 4’,5-二磷酸根-3-羟基茋
3,5,4’-三磷酸根茋
3-硝酸根-5,4’-二羟基茋
5-硝酸根-3,4’-二羟基茋 4’-硝酸根-3,5-二羟基茋
3,5-二硝酸根-4’-羟基茋 3,4’-二硝酸根-5-羟基茋
4’,5-二硝酸根-3-羟基茋 3,5,4’-三硝酸根茋
3-磺酸根-5,4’-二羟基茋 5-磺酸根-3,4’-二羟基茋
4’-磺酸根-3,5-二羟基茋 3,5-二磺酸根-4’-羟基茋
3,4’-二磺酸根-5-羟基茋 4’,5-二磺酸根-3-羟基茋
3,5,4’-三磺酸根茋
3-碳酸根-5,4’-二羟基茋
5-碳酸根-3,4’-二羟基茋 4’-碳酸根-3,5-二羟基茋
3,5-二碳酸根-4’-羟基茋 3,4’-二碳酸根-5-羟基茋
4’,5-二碳酸根-3-羟基茋 3,5,4’-三碳酸根茋。
上文列出的白藜芦醇酯的药学可接受的盐也可以用于本发明的美容组合物中。此类盐可以包括选自Na、K、Mg、Ca、Fe和NH4的一种或多种单价或二价阳离子。盐可以通过将相应碱加入含有白藜芦醇酯的溶液中形成,所述碱例如氢氧化钠、氢氧化钾等。
白藜芦醇的无机酸酯可以通过众所周知的化学过程容易地形成,所述化学过程用磷酸根、磺酸根和碳酸根官能团取代苯酚或多酚的羟基。例如,美国专利号4003966描述了用于选择性磷酸化苯酚以形成其磷酸酯的一步过程,所述专利的内容为了所有目的在此整体引入本文作为参考。
用于实践本发明的特别优选的白藜芦醇衍生物是3,4’,5 – 三磷酸根茋,也称为具有下式的白藜芦醇三磷酸酯:
白藜芦醇的磷酸酯包括白藜芦醇三磷酸酯公开于国际专利申请公开号2006/029484A1中,其在此整体引入作为参考。白藜芦醇三磷酸酯可通过如WO 2006/029484A1的实施例2中所示的方法合成。更具体而言,将白藜芦醇(3,4,5-三羟基茋)(25 mmols,5.7克)和二甲氨基吡啶(7.5 mmols,0.93克)的100 ml乙腈溶液在氮下冷却直到-10℃。在10分钟后,使四氯化碳(375 mmol,36.2 ml)和DIEA(159 mmol;27.7 ml)和混合物在搅拌下维持30分钟。加入二苄基磷酸酯(113 mmols,25.0 ml),并且使混合物在室温搅拌另外12小时。通过TLC(二氧化硅F254,洗脱剂乙酸乙酯/正己烷80/20 v/v)监控反应的过程。加入1升0.5 M KH2PO4,并且随后用乙酸乙酯萃取混合物。通过在硅胶上过滤纯化所得到的产物三(二苄基磷酸酯)白藜芦醇,首先用乙酸乙酯/正己烷(80/20 v/v)的混合物洗涤,以去除任何剩余未反应的白藜芦醇,并且随后用甲醇洗涤,以获得黄色油。
在0℃向三(二苄基磷酸酯)白藜芦醇(12.5
mmol)的200 mL无水DCM溶液中加入溴甲基硅烷(79 mmols,10.4
mL)。在2小时后,加入300
mL H2O,并且使反应混合物搅拌1小时。将水相再次用乙酸乙酯洗涤,随后冻干以获得橙色油。
向在400 mL乙醇中溶解的上文获得的产物中加入CH3ONa(37 mmol;2.03 g),并且使反应在室温搅拌12小时。在旋转蒸发仪(rotavapor)中蒸发乙醇,并且将残渣溶解于H2O中。将水相用乙酸乙酯洗涤且冻干。所得到的白色固体的质谱显示白藜芦醇三磷酸酯(PM =
468.1)的存在,就白藜芦醇而言具有> 90%的总收率。
需要时,白藜芦醇三磷酸酯可以用有机或无机碱例如氢氧化钠、氢氧化钾等中和。特别优选的是其中白藜芦醇三磷酸酯用氢氧化钠中和,以形成白藜芦醇三磷酸酯三钠。白藜芦醇三磷酸酯还可以以中和形式购自Ajinomoto,其具有CTFA白藜芦醇三磷酸酯三钠。
B.
白藜芦醇的羧酸酯
可以在本发明中使用的另一组白藜芦醇衍生物是白藜芦醇和脂肪族或芳香族羧酸的酯,其中X、Y和Z中的一个或多个是–C(O)-R1基团,其中R1选自线性、支链、饱和或不饱和的、或环状C1-C40烷基、取代的C1-C40烷基、C1-C40烯基、取代的C1-C40烯基、C1-C40炔基、取代的C1-C40炔基、芳基、C1-C40芳基、和C1-C40取代的芳基。在一个优选实施方案中,R基团是直链或支链脂肪、或C6-30饱和或不饱和的烷基。取代基可以选自C1-C40直链或支链、饱和或不饱和的烷基,卤素(例如氟),氢,烷氧基,羟基等。
可以用于形成白藜芦醇的酯的示例性羧酸包括但不限于:饱和单羧酸例如乙酸、丙酸、丁酸(C4)、戊酸、己酸、辛酸(C8)、月桂酸、硬脂酸(C18)、异硬脂酸(支链C18)、亚油酸、亚麻酸、肉豆蔻酸(C14)、花生酸(C20)、花生四烯酸、芥子酸、山俞酸、月桂酸(C12)、癸酸(C10)、己酸(C6)和棕榈酸(C16);不饱和的单羧酸例如丙烯酸、甲基丙烯酸、山梨酸、油酸、亚油酸、亚麻酸、二十二碳六烯酸和二十碳五烯酸;氨基酸例如精氨酸、谷氨酰胺和酪氨酸;酮酸例如丙酮酸和乙酰乙酸;芳香族羧酸例如抗坏血酸、苯甲酸、水杨酸和阿魏酸;二和三羧酸例如草酸、丙二酸、苹果酸、琥珀酸和戊二酸。随后为数目的指名“C”指示烷基链中的碳原子数目。
下述是特别适合于本发明实践的白藜芦醇的示例性羧酸酯的列举:
3-乙酸根-5,4’-二羟基茋 5-乙酸根-3,4’-二羟基茋
4’-乙酸根-3,5-二羟基茋 3,5-二乙酸根-4’-羟基茋
3,4’-二乙酸根-5-羟基茋 4’,5-二乙酸根-3-羟基茋
3,5,4’-三乙酸根茋
3-丙酸根-5,4’-二羟基茋
5-丙酸根-3,4’-二羟基茋 4’-丙酸根-3,5-二羟基茋
3,5-二丙酸根-4’-羟基茋 3,4’-二丙酸根-5-羟基茋
4’,5-二丙酸根-3-羟基茋 3,5,4’-三丙酸根茋
3-丁酸根-5,4’-二羟基茋 5-丁酸根-3,4’-二羟基茋
4’-丁酸根-3,5-二羟基茋 3,5-二丁酸根-4’-羟基茋
3,4’-二丁酸根-5-羟基茋 4’,5-二丁酸根-3-羟基茋
3,5,4’-三丁酸根茋
3-戊酸根-5,4’-二羟基茋
5-戊酸根-3,4’-二羟基茋 4’-戊酸根-3,5-二羟基茋
3,5-二戊酸根-4’-羟基茋 3,4’-二戊酸根-5-羟基茋
4’,5-二戊酸根-3-羟基茋 3,5,4’-三戊酸根茋
3-己酸根-5,4’-二羟基茋 5-己酸根 -3,4’-二羟基茋
4’-己酸根-3,5-二羟基茋 3,5-二己酸根-4’-羟基茋
3,4’-二己酸根-5-羟基茋 4’,5-二己酸根-3-羟基茋
3,5,4’-三己酸根茋
3-辛酸根-5,4’-二羟基茋
5-辛酸根-3,4’-二羟基茋 4’-辛酸根-3,5-二羟基茋
3,5-二辛酸根-4’-羟基茋 3,4’-二辛酸根-5-羟基茋
4’,5-二辛酸根-3-羟基茋 3,5,4’-三辛酸根茋
3-月桂酸根-5,4’-二羟基茋 5-月桂酸根-3,4’-二羟基茋
4’-月桂酸根-3,5-二羟基茋 3,5-二月桂酸根-4’-羟基茋
3,4’-二月桂酸根-5-羟基茋 4’,5-二月桂酸根-3-羟基茋
3,5,4’-三月桂酸根茋
3-硬脂酸根-5,4’-二羟基茋
5-硬脂酸根-3,4’-二羟基茋 4’-硬脂酸根-3,5-二羟基茋
3,5-二硬脂酸根-4’-羟基茋 3,4’-二硬脂酸根-5-羟基茋
4’,5-二硬脂酸根-3-羟基茋 3,5,4’-三硬脂酸根茋
3-棕榈酸根-5,4’-二羟基茋 5-棕榈酸根-3,4’-二羟基茋
4’-棕榈酸根-3,5-二羟基茋 3,5-二棕榈酸根-4’-羟基茋
3,4’-二棕榈酸根-5-羟基茋 4’,5-二棕榈酸根-3-羟基茋
3,5,4’-三棕榈酸根茋
3-丙烯酸根-5,4’-二羟基茋
5-丙烯酸根-3,4’-二羟基茋 4’-丙烯酸根-3,5-二羟基茋
3,5-二丙烯酸根-4’-羟基茋 3,4’-二丙烯酸根-5-羟基茋
4’,5-二丙烯酸根-3-羟基茋 3,5,4’-三丙烯酸根茋
3-甲基丙烯酸根-5,4’-二羟基茋 5-甲基丙烯酸根-3,4’-二羟基茋
4’-甲基丙烯酸根-3,5-二羟基茋 3,5-二甲基丙烯酸根-4’-羟基茋
3,4’-二甲基丙烯酸根-5-羟基茋 4’,5-二甲基丙烯酸根-3-羟基茋
3,5,4’-三甲基丙烯酸根茋
3-山梨酸根-5,4’-二羟基茋
5-山梨酸根-3,4’-二羟基茋 4’-山梨酸根-3,5-二羟基茋
3,5-二山梨酸根-4’-羟基茋 3,4’-二山梨酸根-5-羟基茋
4’,5-二山梨酸根-3-羟基茋 3,5,4’-三山梨酸根茋
3-油酸根-5,4’-二羟基茋 5-油酸根-3,4’-二羟基茋
4’-油酸根-3,5-二羟基茋 3,5-二油酸根-4’-羟基茋
3,4’-二油酸根-5-羟基茋 4’,5-二油酸根-3-羟基茋
3,5,4’-三油酸根茋
3-亚油酸根-5,4’-二羟基茋
5-亚油酸根-3,4’-二羟基茋 4’-亚油酸根-3,5-二羟基茋
3,5-二亚油酸根-4’-羟基茋 3,4’-二亚油酸根-5-羟基茋
4’,5-二亚油酸根-3-羟基茋 3,5,4’-三亚油酸根茋
3-亚麻酸根-5,4’-二羟基茋 5-亚麻酸根-3,4’-二羟基茋
4’-亚麻酸根-3,5-二羟基茋 3,5-二亚麻酸根-4’-羟基茋
3,4’-二亚麻酸根-5-羟基茋 4’,5-二亚麻酸根-3-羟基茋
3,5,4’-三亚麻酸根茋
3-二十二碳六烯酸根-5,4’-二羟基茋
5-二十二碳六烯酸根-3,4’-二羟基茋 4’-二十二碳六烯酸根-3,5-二羟基茋
3,5-二二十二碳六烯酸根-4’-羟基茋 3,4’-二二十二碳六烯酸根-5-羟基茋
4’,5-二二十二碳六烯酸根-3-羟基茋 3,5,4’-三二十二碳六烯酸根茋
3-二十碳五烯酸-5,4’-二羟基茋 5-二十碳五烯酸-3,4’-二羟基茋
4’-二十碳五烯酸-3,5-二羟基茋 3,5-二二十碳五烯酸-4’-羟基茋
3,4’-二二十碳五烯酸-5-羟基茋 4’,5-二二十碳五烯酸-3-羟基茋
3,5,4’-三二十碳五烯酸茋
3-精氨酸根-5,4’-二羟基茋
5-精氨酸根-3,4’-二羟基茋 4’-精氨酸根-3,5-二羟基茋
3,5-二精氨酸根-4’-羟基茋 3,4’-二精氨酸根-5-羟基茋
4’,5-二精氨酸根-3-羟基茋 3,5,4’-三精氨酸根茋
3-谷氨酸根-5,4’-二羟基茋 5-谷氨酸根-3,4’-二羟基茋
4’-谷氨酸根-3,5-二羟基茋 3,5-二谷氨酸根-4’-羟基茋
3,4’-二谷氨酸根-5-羟基茋 4’,5-二谷氨酸根-3-羟基茋
3,5,4’-三谷氨酸根茋
3-酪氨酸根-5,4’-二羟基茋
5-酪氨酸根-3,4’-二羟基茋
4’-酪氨酸根-3,5-二羟基茋
3,5-二酪氨酸根-4’-羟基茋
3,4’-二酪氨酸根-5-羟基茋
4’,5-二酪氨酸根-3-羟基茋
3,5,4’-三酪氨酸根茋
3-丙酮酸根-5,4’-二羟基茋 5-丙酮酸根-3,4’-二羟基茋
4’-丙酮酸根-3,5-二羟基茋 3,5-二丙酮酸根-4’-羟基茋
3,4’-二丙酮酸根-5-羟基茋 4’,5-二丙酮酸根-3-羟基茋
3,5,4’-三丙酮酸根茋
3-乙酰乙酸根-5,4’-二羟基茋
5-乙酰乙酸根-3,4’-二羟基茋 4’-乙酰乙酸根-3,5-二羟基茋
3,5-二乙酰乙酸根-4’-羟基茋 3,4’-二乙酰乙酸根-5-羟基茋
4’,5-二乙酰乙酸根-3-羟基茋 3,5,4’-三乙酰乙酸根茋
3-抗坏血酸根-5,4’-二羟基茋
5-抗坏血酸根-3,4’-二羟基茋
4’-抗坏血酸根-3,5-二羟基茋
3,5-二抗坏血酸根-4’-羟基茋
3,4’-二抗坏血酸根-5-羟基茋
4’,5-二抗坏血酸根-3-羟基茋
3,5,4’-三抗坏血酸根茋
3-苯甲酸根-5,4’-二羟基茋
5-苯甲酸根-3,4’-二羟基茋 4’-苯甲酸根-3,5-二羟基茋
3,5-二苯甲酸根-4’-羟基茋 3,4’-二苯甲酸根-5-羟基茋
4’,5-二苯甲酸根-3-羟基茋 3,5,4’-三苯甲酸根茋
3-水杨酸根-5,4’-二羟基茋 5-水杨酸根-3,4’-二羟基茋
4’-水杨酸根-3,5-二羟基茋 3,5-二水杨酸根-4’-羟基茋
3,4’-二水杨酸根-5-羟基茋 4’,5-二水杨酸根-3-羟基茋
3,5,4’-三水杨酸根茋
3-阿魏酸根-5,4’-二羟基茋
5-阿魏酸根-3,4’-二羟基茋 4’-阿魏酸根-3,5-二羟基茋
3,5-二阿魏酸根-4’-羟基茋 3,4’-二阿魏酸根-5-羟基茋
4’,5-二阿魏酸根-3-羟基茋 3,5,4’-三阿魏酸根茋
3-草酸根-5,4’-二羟基茋 5-草酸根-3,4’-二羟基茋
4’-草酸根-3,5-二羟基茋 3,5-二草酸根-4’-羟基茋
3,4’-二草酸根-5-羟基茋 4’,5-二草酸根-3-羟基茋
3,5,4’-三草酸根茋
3-丙二酸根-5,4’-二羟基茋
5-丙二酸根-3,4’-二羟基茋 4’-丙二酸根-3,5-二羟基茋
3,5-二丙二酸根-4’-羟基茋 3,4’-二丙二酸根-5-羟基茋
4’,5-二丙二酸根-3-羟基茋 3,5,4’-三丙二酸根茋
3-苹果酸根-5,4’-二羟基茋 5-苹果酸根-3,4’-二羟基茋
4’-苹果酸根-3,5-二羟基茋 3,5-二苹果酸根-4’-羟基茋
3,4’-二苹果酸根-5-羟基茋 4’,5-二苹果酸根-3-羟基茋
3,5,4’-三苹果酸根茋
3-琥珀酸根-5,4’-二羟基茋
5-琥珀酸根-3,4’-二羟基茋 4’-琥珀酸根-3,5-二羟基茋
3,5-二琥珀酸根-4’-羟基茋 3,4’-二琥珀酸根-5-羟基茋
4’,5-二琥珀酸根-3-羟基茋 3,5,4’-三琥珀酸根茋
3-戊二酸根-5,4’-二羟基茋 5-戊二酸根-3,4’-二羟基茋
4’-戊二酸根-3,5-二羟基茋 3,5-二戊二酸根-4’-羟基茋
3,4’-二戊二酸根-5-羟基茋 4’,5-二戊二酸根-3-羟基茋
3,5,4’-三戊二酸根茋
3-戊二酸根-5,4’-二羟基茋
5-戊二酸根-3,4’-二羟基茋 4’-戊二酸根-3,5-二羟基茋
3,5-二戊二酸根-4’-羟基茋 3,4’-二戊二酸根-5-羟基茋
4’,5-二戊二酸根-3-羟基茋 3,5,4’-三戊二酸根茋。
白藜芦醇的羧酸酯的一个特别优选的组是白藜芦醇的饱和或不饱和的脂肪酸酯,例如白藜芦醇丁酸酯、白藜芦醇戊酸酯、白藜芦醇己酸酯、白藜芦醇山梨酸酯、白藜芦醇月桂酸酯、白藜芦醇硬脂酸酯、白藜芦醇棕榈酸酯、白藜芦醇油酸酯、白藜芦醇亚油酸酯、白藜芦醇亚麻酸酯、白藜芦醇二十碳五烯酸酯和白藜芦醇二十二碳六烯酸酯。白藜芦醇的此类脂肪酸酯可以通过白藜芦醇与酸衍生物的酯化反应容易地形成,其根据在碱性水介质中的肖-包二氏(Schotten-Baumann)反应,如由美国专利号6,572,882描述的,所述专利的内容为了所有目的整体引入本文作为参考。
白藜芦醇的羧酸酯的另一个特别优选的组是白藜芦醇的芳香族羧酸酯,例如白藜芦醇阿魏酸酯,其可以通过使白藜芦醇与阿魏酸在水介质中反应形成。
C.
白藜芦醇醚衍生物
可以在本发明中使用的另外一组白藜芦醇衍生物是白藜芦醇醚,其中X、Y和Z中的一个或多个是-R2,其中R2选自线性、支链或环状C1-C40烷基、取代的C1-C40烷基、C1-C40烯基、取代的C1-C40烯基、C1-C40炔基、取代的C1-C40炔基、C1-C40芳基、取代的C1-C40芳基、以及单、二、寡和多糖。下述是特别适合于本发明实践的示例性白藜芦醇醚的列举:
3-甲氧基-5,4’-二羟基茋 5-甲氧基-3,4’-二羟基茋
4’-甲氧基-3,5-二羟基茋 3,5-二甲氧基-4’-羟基茋
3,4’-二甲氧基-5-羟基茋 4’,5-二甲氧基-3-羟基茋
3,5,4’-三甲氧基茋
3-乙氧基-5,4’-二羟基茋
5-乙氧基-3,4’-二羟基茋 4’-乙氧基-3,5-二羟基茋
3,5-二乙氧基-4’-羟基茋 3,4’-二乙氧基-5-羟基茋
4’,5-二乙氧基-3-羟基茋 3,5,4’-三乙氧基茋
3-丙氧基-5,4’-二羟基茋 5-丙氧基-3,4’-二羟基茋
4’-丙氧基-3,5-二羟基茋 3,5-二丙氧基-4’-羟基茋
3,4’-二丙氧基-5-羟基茋 4’,5-二丙氧基-3-羟基茋
3,5,4’-三丙氧基茋
3-苯氧基-5,4’-二羟基茋
5-苯氧基-3,4’-二羟基茋 4’-苯氧基-3,5-二羟基茋
3,5-二苯氧基-4’-羟基茋 3,4’-二苯氧基-5-羟基茋
4’,5-二苯氧基-3-羟基茋 3,5,4’-三苯氧基茋
3-葡糖苷-5,4’-二羟基茋 5-葡糖苷-3,4’-二羟基茋
4’-葡糖苷-3,5-二羟基茋 3,5-二葡糖苷-4’-羟基茋
3,4’-二葡糖苷-5-羟基茋 4’,5-二葡糖苷-3-羟基茋
3,5,4’-三葡糖苷茋。
在本发明的一个特定实施方案中,使用甲氧基-取代的白藜芦醇衍生物。例如,本发明的组合物可以包含3,5-二甲氧基-4’-羟基茋,其可以从印度吉纳树(Indian Kino Tree)(花榈木(Pterocarpus
marsupium))中提取,并且在商品名PTEROSTILBENE下从在St. Louis,MO的Sigma-Aldrich商购可得。
在本发明的另一个特定实施方案中,白藜芦醇衍生物含有一个或多个含糖保护基团,例如葡萄糖、半乳糖、甘露糖、果糖、蔗糖、乳糖、麦芽糖、海藻糖等。例如,可以通过从植物或植物材料例如虎杖(polygonum
cuspidatum)组织或葡萄(vitis vinifera)细胞的体外培养物中提取获得的白藜芦醇葡糖苷在本发明的美容组合物中使用。
D.
白藜芦醇的含氮衍生物
在本发明的组合物中使用的白藜芦醇衍生物还可以含有一个或多个含氮官能团,即上式中A、B和C中的一个或多个选自酰胺、胺、亚胺、脒和甲脒(carboxamidines)。下述是特别适合于本发明实践的示例性白藜芦醇醚的列举:
3-酰胺-5,4’-二羟基茋
5-酰胺-3,4’-二羟基茋
4’-酰胺-3,5-二羟基茋
3,5-二酰胺-4’-羟基茋
3,4’-二酰胺-5-羟基茋
4’,5-二酰胺-3-羟基茋
3,5,4’-三酰胺茋
3-氨基-5,4’-二羟基茋
5-氨基-3,4’-二羟基茋
4’-氨基-3,5-二羟基茋
3,5-二氨基-4’-羟基茋
3,4’-二氨基-5-羟基茋
4’,5-二氨基-3-羟基茋
3,5,4’-三氨基茋
3-亚氨基-5,4’-二羟基茋 5-亚氨基-3,4’-二羟基茋
4’-亚氨基-3,5-二羟基茋 3,5-二亚氨基-4’-羟基茋
3,4’-二亚氨基-5-羟基茋 4’,5-二亚氨基-3-羟基茋
3,5,4’-三亚氨基茋
3-脒基-5,4’-二羟基茋
5-脒基-3,4’-二羟基茋
4’-脒基-3,5-二羟基茋
3,5-二脒基-4’-羟基茋
3,4’-二脒基-5-羟基茋
4’,5-二脒基-3-羟基茋
3,5,4’-三脒基茋。
优选但不一定地,当存在时,将本发明的白藜芦醇衍生物单独或与DNA修复酶和/或一种或多种另外的皮肤护理活性物组合装入脂质体中,用于其更有效递送到皮肤的真皮内。白藜芦醇衍生物可以以按总组合物的总重量计范围约0.001%- 约95%、优选约0.005%- 约90%、更优选约0.1%- 约20%的量存在于本发明的美容组合物中。
DNA
修复酶
本发明的组合物任选含有至少一种DNA修复酶。这不像US
11/837,658,其中需要至少一种DNA修复酶并且不考虑sirt1激活物的使用。任选DNA修复酶的建议浓度是相对于最终组合物的总重量约0.00001
- 约35%、优选约0.00005
- 约30%、更优选约0.0001
- 约25%。
如美国专利号5,077,211、5,190,762、5,272,079和5,296,231中公开的DNA修复酶适合于在本发明的组合物和方法中使用,所有所述专利在此整体引入作为参考。此类DNA修复酶的一个例子可以在商品名Roxisomes®下购自AGI/Dermatics,并且具有INCI名称拟南芥(ArabidopsisThaliana)提取物。它可以单独或与卵磷脂和水混合存在。这种DNA修复酶已知在修复8-氧代-二鸟嘌呤碱基突变损伤中是有效的。
可以使用的另一类DNA修复酶是已知在修复06-甲基鸟嘌呤碱基突变损伤中有效的酶。它通过AGI/Dermatics在商品名Adasomes®下出售,并且具有INCI名称乳杆菌属(Lactobacillus)发酵物,其可以单独或与卵磷脂和水混合加入本发明的组合物中。
可以使用的另一类DNA修复酶是已知在修复T-T二聚体中有效的酶。该酶存在于生物学或植物材料的混合物中。此类成分的例子通过AGI/Dermatics在商品名Ultrasomes®或Photosomes®下出售。Ultrasomes®包含微球菌属(Micrococcus)裂解物(微球菌属的各个物种的控制裂解的最终产物)、卵磷脂和水的混合物。Photosomes®包含浮游生物提取物(其为海洋生物质的提取物,所述海洋生物质包括下述生物中的一种或多种:海洋浮游生物、绿色微藻、硅藻、绿蓝和固氮海藻)、水和卵磷脂的混合物。
另一类DNA修复酶可以是各种灭活的细菌裂解物的组分,例如双歧杆菌(Bifida)裂解物或双歧杆菌发酵裂解物,后者是来自双歧杆菌细菌的裂解物,其含有代谢产物和细胞质级分——当双歧杆菌细菌进行培养、灭活且随后分解时。这种材料具有INCI名称双歧杆菌发酵裂解物。
其他合适的DNA修复酶包括内切核酸酶V,其可以通过噬菌体T4的denV基因产生。还合适的是T4内切核酸酶;O6-甲基鸟嘌呤-DNA甲基转移酶;光解酶例如尿嘧啶和次黄嘌呤-DNA糖基化酶;脱嘧啶/脱嘌呤内切核酸酶;DNA外切核酸酶、损伤碱基糖基化酶(例如3-甲基腺嘌呤-DNA糖基化酶);单独或在复合物中的校正内切核酸酶(例如大肠杆菌(E. coli)uvrA/uvrB/uvrC内切核酸酶复合物);APEX核酸酶,这是通常称为“APE”的多功能DNA修复酶;二氢叶酸还原酶;末端转移酶;拓扑异构酶;O6苄基鸟嘌呤;DNA糖基化酶。
其他类型的合适DNA修复酶可以通过促进的修复类型进行分类,并且包括BER(碱基切除修复)或BER因子酶例如尿嘧啶-DNA糖基化酶(UNG);单链选择性单功能尿嘧啶DNA糖基化酶(SMUG1);3,N(4)-亚乙烯基胞嘧啶糖基化酶(MBD4);胸腺嘧啶DNA-糖基化酶(TDG);A/G-特异性腺嘌呤DNA糖基化酶(MUTYH);8-氧鸟嘌呤DNA糖基化酶(OGG1);内切核酸酶III-样(NTHL1);3-甲基腺嘌呤DNA糖苷酶(MPG);DNA糖基化酶/AP裂解酶(NEIL1或2);AP内切核酸酶(APEX 1和2)、DNA连接酶(LIG3)、连接酶辅助因子(XRCC1);DNA 5'-激酶/3'-磷酸酶(PNKP);ADP-核糖基转移酶(PARP1或2)。
另一个类别的DNA修复酶包括认为直接逆转损伤的那些,例如O6-MeG烷基转移酶(MGMT); 1-meA双加氧酶(ALKBH2或ALKBH3)。
可作用于修复DNA/蛋白质交联的另外一个类别的酶包括Tyr-DNA磷酸二酯酶(TDP1)。
还合适的是MMR(错配切除修复)DNA修复酶,例如MutS蛋白质同系物(MSH2);错配修复蛋白质(MSH3);mutS同系物4(MSH4);mutS同系物5(MSH5);或G/T错配结合蛋白(MSH6);DNA错配修复蛋白质(PMS1、PMS2、MLH1、MLH3);减数***后分离增加的2-样蛋白质(PMS2L3);或减数***后分离增加的2-样4假基因(PMS2L4)。
还合适的DNA修复酶是称为核苷酸切除修复(NER)酶的那些,且包括那些例如着色性干皮病C组-互补蛋白质(XPC); RAD23(酿酒酵母(S. cerevisiae))同系物(RAD23B);钙牵蛋白同种型(CETN2);RFA蛋白质1、2或3(RPA1、2或3);3’至5’ DNA解旋酶(ERCC3);5’至3’ DNA解旋酶(ERCC2);碱性转录因子(GTF2H1、GTF2H2、GTF2H3、GTF2H4、GTF2H5); CDK激活激酶(CDK7、CCNH);细胞周期蛋白G1相互作用蛋白质(MNAT1);DNA切除修复蛋白质ERCC-5l;切除修复交叉互补1(ERCC1);DNA连接酶1(LIG1);ATP-依赖性解旋酶(ERCC6);等。
还合适的可以是在促进同源重组的类别中的DNA修复酶,并且包括但不限于DNA修复蛋白质RAD51同系物(RAD51、RAD51L1、RAD51B等);DNA修复蛋白质XRCC2;DNA修复蛋白质XRCC3;DNA修复蛋白质RAD52;ATP酶(RAD50);3’外切核酸酶(MRE11A);等等。
其为DNA聚合酶的DNA修复酶也是合适的,并且包括DNA聚合酶β亚单位(POLB);DNA聚合酶γ(POLG);DNA聚合酶亚单位δ(POLD1);DNA聚合酶II亚单位A(POLE);DNA聚合酶δ辅助蛋白质(PCNA);DNA聚合酶ζ(POLZ);MAD2同系物((REV7);DNA聚合酶η(POLH): DNA聚合酶κ(POLK);等等。
通常称为“编辑和加工核酸酶”的各种类型的DNA修复酶包括3’-核酸酶;3’-外切核酸酶;5’-外切核酸酶;内切核酸酶;等。DNA修复酶的其他例子包括DNA解旋酶,包括例如ATP DNA解旋酶等等。DNA修复酶可以作为植物提取物、细菌裂解物、生物学材料等的组分存在。例如,植物提取物可以含有DNA修复酶。
实例
1: Sirt1
激活物(
Orsirtine
™和白藜芦醇)协同改善角化细胞存活
就有丝***延迟试剂Orsirtine™((SEQ
ID No. 8) G - L - Y - D - N - L- E)和白藜芦醇改善受UVB照射的人角化细胞的存活的能力进行测试。
方法:
正常人角化细胞在具有人角化细胞生长补充物的Epilife培养基中培养。将细胞传代培养到96孔板(Costar)内。用单独的白藜芦醇(25µM)和Orsirtine(1%, 3%)以及白藜芦醇(25µM)和Orsirtine™(3%)的复合物预处理角化细胞。用未稀释的复合物以及用1:2、1:4和1:8(复合物 : Epilife培养基) 的稀释物处理角化细胞。
使角化细胞与这些处理一起在37℃、5%CO2下温育过夜。在24小时后,抽吸处理并且使角化细胞在D-PBS中洗涤1次。加入100µl D-PBS用于照射。对细胞实施以0、45、90和135 mJ/cm2 UVB的UVB照射。在照射后,去除D-PBS。角化细胞适当地进行后处理,并且在37℃、5%CO2下温育过夜。第二天,利用MTS试剂(CellTiter96,Promega)就活力测定细胞。在37℃、5%CO2下大约2小时温育后,在SpectraMax190分光光度计(Molecular Devices)上在490nm获得吸光度读数。
结果和结论:
参考图2,在低UV照射(45 mJ/cm2)下,已证明细胞不显示出强烈损伤,因此生存性中的改善预期是可忽略不计的。然而,我们的确观察到的是仅用白藜芦醇处理的细胞显示20%减少的存活率,并且仅用Orsitine™ 3%处理的细胞显示8%减少的存活率。然而,用1:2稀释的复合物(白藜芦醇25µM和Orsirtine™ 3%)或用未稀释的复合物处理的细胞测试与对照相同。此外,当复合物稀释至1:4且随后1:8时,生存性减少。因此单独的白藜芦醇和单独的3% Orsirtine减少细胞存活。然而,白藜芦醇和3% Orsirtine的组合不减少细胞存活。但组合可以相对于对照改善细胞存活率吗?
在90 mJ/cm2 UV照射下,未处理细胞的存活率是47%。相比之下,用未稀释和稀释的复合物(白藜芦醇25µM和3% Orsirtine™)处理的细胞的生存性遵循剂量依赖性关系,如下:
复合物的稀释 | 1:8 | 1:4 | 1:2 | 未稀释的 |
在90 mJ/cm2 UV后增加的存活 | 28% | 34% | 60% | 64% |
而关于仅用Orsirtine™或仅用白藜芦醇处理的细胞的生存性如下:
Orsirtine™ 3% | Orsirtine™ 1% | 白藜芦醇25µM | |
在90 mJ/cm2 UV后增加的存活 | 11% | -17% | -15% |
在135 mJ/cm2 UV照射下,未经处理的细胞的存活率是19%。相比之下,关于用未稀释和稀释的复合物处理的细胞的生存性遵循准剂量依赖性关系,如下:
复合物的稀释 | 1:8 | 1:4 | 1:2 | 未稀释的 |
在135 mJ/cm2 UV后增加的存活 | 11% | 5% | 56% | 131% |
而关于仅用Orsirtine™或仅用白藜芦醇处理的细胞的生存性如下:
Orsirtine™ 3% | Orsirtine™ 1% | 白藜芦醇25µM | |
在135 mJ/cm2 UV后增加的存活 | 26% | 5% | 22% |
可以推断,复合物(白藜芦醇25µM和Orsirtine™ 3%)提供针对UVB诱导的细胞毒性的显著保护和相对于单独的白藜芦醇和Orsirtine™增加的细胞存活。
这些数字看起来还暗示Orsirtine™和白藜芦醇的组合对角化细胞生存性的作用是协同的。例如,单独的3%Orsirtine™使生存性增加11%(对于90 mJ/cm2的UVB)和26%(对于135 mJ/cm2的UVB)。单独的25µM白藜芦醇使生存性减少15%(对于90 mJ/cm2的UVB)且使其增加22%(对于135 mJ/cm2的UVB)。然而,未稀释的组合3%Orsirtine™和25µM白藜芦醇使角化细胞生存性大量和未预期地增加64%(对于90 mJ/cm2的UVB)和131%(对于135 mJ/cm2的UVB)。即使当稀释下至1:8时,组合仍使角化细胞生存性增加28%(对于90 mJ/cm2的UVB)和11%(对于135 mJ/cm2的UVB)。这是完全未预料到的。因为Orsirtine™是已知的sirtuin激活物,并且白藜芦醇是怀疑的sirtuin激活物,所以角化细胞生存性中的巨大改善是本领域普通技术人员不会预期的。最多,可能已预期叠加作用,但不是协同作用。
(SEQ ID No. 8) G -
L - Y - D - N - L- E和白藜芦醇的何种相对浓度将产生对角化细胞存活的大量协同作用?这个问题可以通过常规实验得到回答,现在该作用已得到鉴定。“sirt1激活物和白藜芦醇的协同组合”意指(SEQ ID No. 7)(AA)n- G -
L - Y - D - N - L- E -(AA)n和白藜芦醇或其衍生物的组合,其增加角化细胞存活比率(像这样比率通过本领域已知的方法测量)超过每种材料个别作用的总和的量。
实例
2: SIRT1
激活物以正确浓度改善昼夜节奏激活物和
DNA
修复酶面对
UVB
暴露的表现
根据实例1中所述的方法,就其对在UV暴露后角化细胞存活的作用,2种复合物以各种稀释度进行测试。复合物I由具有人角化细胞生长补充物和Chronolux(0.1%)、双歧杆菌提取物(12.4%)、Adasome(0.05%)和Roxisome(0.05%)的Epilife培养基组成。复合物II由复合物I加上Orsirtine™(0.08%)和白藜芦醇(25µM)组成。复合物I未稀释以及以1:2和1:4(复合物 : Epilife培养基)的稀释度进行测试。复合物II未稀释以及以1:2、1:4和1:8的稀释度进行测试。培养基用作对照。角化细胞暴露于100、150和200 mL/cm2水平的UVB。
结果和结论:
参考图3,且在相同UVB暴露内比较复合物II与复合物I,
在除了2种外的所有情况下,与单独的昼夜节奏基因激活物比较,Orsirtine™和白藜芦醇改善在UVB暴露后的角化细胞存活。然而,将前2列(100 mJ/cm2)向下移,这些数据看起来暗示与昼夜节奏基因激活物组合的sirt1激活物越少,则越佳。然而,该模式在第2和3列(150 mJ/cm2和200
mJ/cm2)中被破坏,暗示sirt1和昼夜节奏基因激活物的最佳组合取决于角化细胞暴露于其的UVB量。事实上,从左到右跨越过第3行(未稀释的),数据暗示Orsirtine™和白藜芦醇的添加对于更大量的UVB暴露是有保证的。该模式在1:2稀释样品中也可见,但在1:4稀释样品中逆转,暗示在更低UVB暴露时,需要更少的sirt1激活。因此,整个看来,这些实验的结果暗示昼夜节奏基因激活物和sirt1激活物的最佳相对浓度取决于UVB暴露的量。然而,所有复合物II测试样品(昼夜节奏激活物加上sirt1激活物)显示角化细胞生存性相对于对照的改善。测定昼夜节奏基因激活物和sirt1激活物的最佳相对浓度可能仅需要常规实验,现在本领域普通技术人员了解该相对浓度是结果有效变量,这迄今为止是未知的。
组合物
本发明的组合物的形式一般不受限制。例如,本发明的组合物可以是乳液、水溶液或分散体、凝胶或无水***的形式。如果是乳液的形式,那么组合物可以是油包水或水包油乳液。如果是乳液的形式,那么组合物可以含有约1-99%、优选约5-90%、更优选约10-85%的水,和约1-99%、优选约5-90%、更优选约5-75%的油。如果是水性悬液或分散体的形式,那么组合物一般可以含有约1-99.9%、优选约5-95%、更优选约10-90%的水,其余成分是活性成分或其他配方成分。
优选地,组合物含有将提供美容或药学可接受的产物的其他成分。此类成分的类别可以包括保湿剂、UVA和UVB遮光剂、表面活性剂、植物提取物、生物学材料、水相结构试剂(即多糖、丙烯酸酯聚合物、高分子量PEG或聚甘油)、挥发性和非挥发性油(包括硅酮)、维生素和抗氧化剂。
昼夜节奏基因激活物和sirt1激活物在分开的组合物中也是可能的,所述分开的组合物可以接续应用于皮肤的相同区域,或可以通过分配每种组合物的有效量、混合组合物、且随后将混合物应用于皮肤来应用。
优选组合物
优选组合物是水溶液或乳液形式,并且含有至少一种非离子型有机表面活性剂、至少一种化学遮光剂、至少一种clock或per1基因激活物、至少一种肽sirt1激活物、和至少一种DNA修复酶。至少一种植物提取物和至少一种油也可为优选的。
更优选的是这样的组合物,其中非离子型有机表面活性剂是烷氧基化醇,化学遮光剂是UVB遮光剂,clock或per1角化细胞基因激活物是三肽-32,sirt1激活物是Orsirtine™-样分子和白藜芦醇的组合,DNA修复酶是拟南芥提取物、微球菌属裂解物、双歧杆菌细菌发酵裂解物、乳杆菌属发酵物和浮游生物提取物的混合物,并且至少一种油是有机酯或烃。
本发明的方法
本发明的方法主要涉及修复对于人角化细胞、优选面部角化细胞的损伤,所述损伤响应环境攻击物而发生。一种方法由对受损人皮肤应用一种或多种组合物组成,所述组合物包含至少一种角化细胞clock或per1基因激活物和至少一种sirt1激活物。任选地,该方法的一种或多种组合物可以包含至少一种DNA修复酶。通过在损伤已发生后应用组合物,正常昼夜节奏周期将更快速恢复。然而,在有丝***前的细胞周期停滞将允许更多时间用于DNA修复。通过这种方法,大量细胞损伤将被逆转和/或将被检查传递给子细胞。该方法还将改善角化细胞活力和寿命。
本发明还涉及预防或抑制对人角化细胞、优选面部角化细胞的损伤的方法,所述损伤将响应环境攻击物而发生。该方法由对处于经历环境损伤的危险中的人皮肤应用一种或多种组合物组成,所述组合物包含至少一种角化细胞clock或per1基因激活物和至少一种sirt1激活物。任选地,该方法的一种或多种组合物可以包含至少一种DNA修复酶。通过在损伤已发生前应用组合物,正常昼夜节奏周期可以得到更紧密地维持,并且正常细胞周期修复过程可以得到更紧密地维持。通过这种方法,大量细胞损伤将被预防和/或将被检查传递给子细胞。该方法也将改善角化细胞活力和寿命。
在本发明的方法中,一种或多种组合物可以每天一次或多次应用于皮肤。例如,一种或多种组合物可以在早晨在开始日常活动之前和/或在晚上在就寝之前立即应用于皮肤。这些时间是优选的,因为皮肤一般在最小量的环境袭击下,意味着在这些时间皮肤细胞修复可以达到最大。“在就寝之前立即”或“在夜间休息之前立即”意味着在上床1小时内,更优选在上床30分钟内。在早晨是更预防性的方法,而在就寝之前立即或在晚间是更修复性的方法。一种或多种组合物可以作为方案的一部分应用;即,皮肤被清洁且用化妆水(toner)处理,这之后应用本发明的一种或多种组合物。一种或多种组合物可以是试剂盒的一部分,所述试剂盒含有清洁剂、化妆水和本发明的一种或多种组合物。
优选地,一种或多种组合物在就寝之前立即应用于面部和/或颈部和胸颈部(décolletage)的皮肤,以修复DNA受损的角化细胞且提供皮肤的一般改善。使clock和per1基因激活物与sirt1激活物(和优选地,DNA修复酶)在晚上、在就寝之前立即用于处理面部皮肤的组合物中组合,使DNA损伤的角化细胞修复达到最大,并且还促进细胞活力、寿命和健康。
如上所述,昼夜节奏基因激活物和sirt1激活物在分开的组合物中也是可能的。在该情况下,本发明的方法包括将每种组合物连续应用于皮肤的相同区域,或分配每种组合物的有效量、混合组合物、且随后将混合物应用于皮肤的步骤。
实施例
本发明将与下述实施例结合进一步描述,所述实施例仅为了举例说明的目的而阐述。皮肤处理组合物可以如下制备。
实施例
1
成分 | w/w% | w/w% |
Oleth-3 磷酸酯 | 0.45 | 0.45 |
Oleth-3 | 0.35 | 0.35 |
Oleth-5 | 0.24 | 0.24 |
丁二醇 | 0.20 | 0.20 |
角鲨烷 | 0.50 | 0.50 |
BHT | 0.10 | 0.10 |
乙基己基甲氧基肉桂酸酯 | 0.10 | 0.10 |
Choleth-24/ceteth-24 | 0.10 | 0.10 |
三乙醇胺 | 0.11 | 0.11 |
视黄基棕榈酸酯/玉蜀黍(玉米) 油/BHT/BHA | 0.10 | 0.10 |
丁二醇 | 1.10 | 1.10 |
甘菊 | 0.03 | 0.03 |
红没药醇 | 0.10 | 0.10 |
对羟基苯甲酸甲酯 | 0.46 | 0.46 |
PEG-75 | 4.00 | 4.00 |
双-PEG-18甲醚二甲基硅烷 | 2.00 | 2.00 |
甘油聚醚-26(Glycereth-26) | 1.00 | 1.00 |
甲基葡糖醇聚醚-20(Methyl gluceth-20) | 4.00 | 4.00 |
EDTA三钠 | 0.10 | 0.10 |
泛硫乙胺(Pantethine) | 0.14 | 0.14 |
咖啡因 | 0.05 | 0.05 |
黄原胶 | 0.075 | 0.075 |
卡波姆 | 0.26 | 0.26 |
三乙醇胺 | 0.50 | 0.50 |
苯氧乙醇 | 0.70 | 0.70 |
苯甲醇 | 0.10 | 0.10 |
双歧杆菌发酵裂解物 | 9.40 | 9.40 |
水 / 双歧杆菌发酵裂解物 / 氢化卵磷脂 | 3.00 | 3.00 |
丁二醇/水/苏丹可乐果(Cola Acuminata)提取物 | 3.00 | 3.00 |
核糖核酸钠 | 0.01 | 0.01 |
水 / 丁二醇 / 三肽 -32 | 0.10 | 0.10 |
乳杆菌属发酵物 / 卵磷脂 / 水 | 0.05 | 0.05 |
水 / 拟南芥提取物 / 卵磷脂 | 0.05 | 0.05 |
Orsirtine 10x | 0.08 | 0.08 |
白藜芦醇 | ------- | 25µM |
苯氧乙醇 | 0.02 | 0.02 |
透明质酸钠 | 0.01 | 0.01 |
FD&C红编号4(含丁二醇的1%水溶液) | 0.04 | 0.04 |
FD&C黄编号5(含丁二醇的1%水溶液) | 0.09 | 0.09 |
D&C绿编号5(含丁二醇的0.1%溶液) | 0.001 | 0.001 |
水 | QS | QS |
实施例
2-4
含有clock基因激活物(Chronolux®,三肽-32)但不含一种或多种sirt1激活物的第一种皮肤处理组合物可以根据配方A(实施例2)进行制备。含有clock基因激活物(Chronolux®)和sirt1激活物(Orsirtine™和白藜芦醇)的第二种皮肤处理组合物可以根据配方B(实施例3)进行制备。含有sirt1激活物(Orsirtine™)但不含昼夜节奏基因激活物的第三种皮肤处理组合物可以根据配方C(实施例4)进行制备。通过使组分组合且充分混合以形成液体来制备组合物。组合物可以贮存于棕色玻璃瓶中。
组合物A包含昼夜节奏基因激活物和sirt1激活物Orsirtine™和白藜芦醇。因此,组合物A预期单独使用。组合物B包含Chronolux®(昼夜节奏基因激活物),但不含sirt1基因激活物。因此,组合物B预期与具有sirt1基因激活能力的单独组合物例如组合物C一起使用。
成分 | A(w/w%) | B(w/w%) |
Oleth-3 磷酸酯 | 0.45 | 0.45 |
Oleth-3 | 0.35 | 0.35 |
Oleth-5 | 0.24 | 0.24 |
丁二醇 | 0.20 | 0.20 |
角鲨烷 | 0.50 | 0.50 |
BHT | 0.10 | 0.10 |
乙基己基甲氧基肉桂酸酯 | 0.10 | 0.10 |
Choleth-24/ceteth-24 | 0.10 | 0.10 |
三乙醇胺 | 0.11 | 0.11 |
视黄基棕榈酸酯/玉蜀黍(玉米) 油/BHT/BHA | 0.10 | 0.10 |
丁二醇 | 1.10 | 1.10 |
甘菊 | 0.03 | 0.03 |
红没药醇 | 0.10 | 0.10 |
水 | QS | QS |
对羟基苯甲酸甲酯 | 0.46 | 0.46 |
PEG-75 | 4.00 | 4.00 |
双-PEG-18甲醚二甲基硅烷 | 2.00 | 2.00 |
甘油聚醚-26(Glycereth-26) | 1.00 | 1.00 |
甲基葡糖醇聚醚-20(Methyl gluceth-20) | 4.00 | 4.00 |
EDTA三钠 | 0.10 | 0.10 |
泛硫乙胺 | 0.14 | 0.14 |
咖啡因 | 0.05 | 0.05 |
黄原胶 | 0.075 | 0.075 |
卡波姆 | 0.26 | 0.26 |
三乙醇胺 | 0.50 | 0.50 |
苯氧乙醇 | 0.70 | 0.70 |
苯甲醇 | 0.10 | 0.10 |
双歧杆菌发酵裂解物 | 9.40 | 9.40 |
水/双歧杆菌发酵裂解物/氢化卵磷脂 | 3.00 | 3.00 |
丁二醇/水/苏丹可乐果提取物 | 3.00 | 3.00 |
核糖核酸钠 | 0.01 | 0.01 |
水 / 丁二醇 / 三肽 -32 ( Chronolux® ) | 0.20 | 0.20 |
水 / 丁二醇 / 水解的稻提取物( Orsirtine™ ) | 0.08 | ------ |
白藜芦醇 | 25µM | ------ |
乳杆菌属发酵物 / 卵磷脂 / 水 | 0.05 | 0.05 |
水 / 拟南芥提取物 / 卵磷脂 | 0.05 | 0.05 |
苯氧乙醇 | 0.02 | 0.02 |
透明质酸钠 | 0.01 | 0.01 |
FD&C红编号4(含丁二醇的1%水溶液) | 0.04 | 0.04 |
FD&C黄编号5(含丁二醇的1%水溶液) | 0.09 | 0.09 |
D&C绿编号5(含丁二醇的0.1%溶液) | 0.001 | 0.001 |
成分 | C(w/w%) |
肌酸 | 0.08 |
海藻糖 | 0.50 |
乙酰葡糖胺 | 0.50 |
咖啡因 | 0.20 |
卡波姆 | 0.15 |
丙烯酸酯/C10-30 烷基丙烯酸酯交联共聚物/苯氧乙醇 | 0.108 |
丙烯酰二甲基牛磺酸铵/VP共聚物 | 0.50 |
丁二醇 | 1.00 |
黄原胶 | 0.08 |
氢氧化钠 | 0.03 |
鲸蜡醇 | 2.00 |
C12-20酸PEG-8酯 | 3.00 |
辛酸/癸酸甘油三酸酯 | 5.90 |
二甲基硅氧烷 | 0.50 |
鲸蜡基磷酸钾 | 0.20 |
椰子(COCOS NUCIFERA)(椰子) 油/库拉索芦荟(ALOE BARBADENSIS)叶提取物 | 1.60 |
胆固醇/硫酸钾 | 0.05 |
PEG-100硬脂酸酯 | 0.75 |
植三醇 | 0.50 |
小麦(TRITICUM VULGARE)(麦麸) 提取物/橄榄(OLEA EUROPAEA)(橄榄) 果实提取物 | 0.20 |
石榴(PUNICA GRANATUM)(石榴) 固醇 | 0.50 |
戊二醇 | 1.00 |
苯氧乙醇 | 0.30 |
甘油 USP99%(蔬菜) | 2.00 |
乙基己基甘油 | 1.00 |
酵母发酵提取物(虎杖根提取物(白藜芦醇) / 啤酒花(HUMULUS LUPULUS)提取物 / 亚油酸 / 亚麻酸 / 葡萄籽提取物/ 迷迭香(ROSMARINUS OFFICINALIS)提取物/ 卷柏(SELAGINELLA TAMARISCINA)提取物/ 环糊精 /乙基双亚氨基甲基愈创木酚锰氯化物/ 柑橘(CITRUS RETICULATA)皮提取物/ 石榴汁提取物/去甲二氢愈创木酸/二甲基硅氧烷) | 0.50 |
西伯利亚落叶松(LARIX SIBIRICA)木材提取物 | 0.10 |
糖海带(LAMINARIA SACcharINA)提取物 | 0.50 |
酵母提取液(磷酸腺苷/苯氧乙醇/二甲基硅氧烷 | 0.50 |
六缩氨酸乙酸酯-8 | 0.50 |
PCA钠 | 0.50 |
豨莶草(SIGESBECKIA ORIENTALIS)(圣保罗草(ST. PAUL'S WORT))提取物 | 0.50 |
甘油/粉团扇藻(PADINA PAVONICA THALLUS)提取物 | 0.10 |
刺阿干树(ARGANIA SPINOSA)叶提取物 | 0.10 |
水/丁二醇/酸豆(TAMARINDUS INDICA)种子提取物 | 0.10 |
丙二醇二辛酸酯/葵花(HELIANTHUS ANNUUS)(向日葵) 油饼/大麦(HORDEUM VULGARE)(大麦) 提取物/黄瓜(CUCUMIS SATIVUS)(黄瓜) 果实提取物 | 0.50 |
丁二醇/ CENTAURIUM ERYTHRAEA(CENTAURIUM ERYTHRAEA)(矢车菊) 提取物 | 0.50 |
水 / 丁二醇 / 水解的稻提取物( Orsirtine™ ) | 0.08 |
透明质酸钠 | 2.50 |
透明质酸 | 0.02 |
香味(香料) | 0.125 |
丙烯酸钠/丙烯酰二甲基牛磺酸钠共聚物/氢化聚癸烯/LAURETH- 8 | 0.001 |
水 | Q.S. |
虽然本发明已与优选实施方案结合进行描述,但它不预期使本发明的范围限制于所述特定形式。相反,本说明书预期涵盖如可以包括在本发明的精神和范围内的此类替代方案、修饰和等价物,如由所附权利要求限定的。
序列表
<110> Maes, Daniel H.
Pernodet,
Nadine A.
Mammone,
Thomas
Slutsky, Lenny
Collins, Donald F.
Goldgraben,
Kerri
Pelle, Edward
McCarthy, James T.
<120> 包含昼夜节奏基因激活物和Sirt1基因激活物的协同组合的皮肤修复组合物
<130> 09.11
<160> 8
<170> PatentIn version
3.5
<210> 1
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CLOCK和/或PER1基因激活物
<220>
<221> misc_feature
<222> (1)..(4)
<223> Xaa可以是任何天然发生的氨基酸或无氨基酸
<220>
<221> misc_feature
<222> (5)
<223> Xaa可以是苏氨酸或丝氨酸或无氨基酸
<220>
<221> misc_feature
<222> (9)
<223> Xaa可以是异亮氨酸、亮氨酸、脯氨酸、缬氨酸、丙氨酸、甘氨酸或无氨基酸
<220>
<221> misc_feature
<222> (10)..(13)
<223> Xaa可以是任何天然发生的氨基酸或无氨基酸
<400> 1
Xaa Xaa Xaa Xaa Xaa Ser Thr
Pro Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 2
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CLOCK和/或PER1基因激活物
<400> 2
Tyr Val Ser Thr Pro Tyr Asn
1 5
<210> 3
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CLOCK和/或PER1基因激活物
<400> 3
Val Ser Thr
Pro Glu
1 5
<210> 4
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CLOCK和/或PER1基因激活物
<400> 4
Leu His Ser Thr Pro Pro
1 5
<210> 5
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CLOCK和/或PER1基因激活物
<400> 5
Arg His Ser Thr Pro Glu
1 5
<210> 6
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CLOCK和/或PER1基因激活物
<400> 6
His Ser Thr
Pro Glu
1 5
<210> 7
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> SIRT1基因激活物
<220>
<221> misc_feature
<222> (1)..(3)
<223> Xaa可以是任何天然发生的氨基酸或无氨基酸
<220>
<221> misc_feature
<222> (11)..(13)
<223> Xaa可以是任何天然发生的氨基酸或无氨基酸
<400> 7
Xaa Xaa Xaa Gly Leu Tyr
Asp Asn Leu Glu Xaa Xaa
Xaa
1 5 10
<210> 8
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> SIRT1基因激活物
<400> 8
Gly Leu Tyr Asp Asn Leu Glu
1 5
Claims (7)
1.皮肤护理组合物,其包含Ser-Thr-Pro-NH2以及白藜芦醇和下述肽的协同组合:
Gly-Leu-Tyr-Asp-Asn-Leu-Glu。
2.皮肤护理组合物,其包含:
相对于最终组合物的总重量为0.00001% - 25%的Ser-Thr-Pro-NH2;
相对于最终组合物的总重量为0.0001%- 5%的Gly-Leu-Tyr-Asp-Asn-Leu-Glu;和
相对于最终组合物的总重量为0.001%- 95%的白藜芦醇。
3.根据权利要求2的组合物,其进一步包含相对于最终组合物的总重量为0.0001%- 25%的至少一种DNA修复酶。
4.根据权利要求3的组合物,其中所述DNA修复酶选自碱基切除修复酶、核苷酸切除修复酶、DNA聚合酶、DNA解旋酶、错配修复酶及其混合物。
5.根据权利要求3的组合物,其中所述DNA修复酶选自拟南芥(ArabidopsisThaliana)提取物、乳杆菌属(Lactobacillus)发酵物、微球菌属(Micrococcus)裂解物、浮游生物提取物、双歧杆菌发酵裂解物及其混合物。
6.局部组合物,其为化学、热力学和光稳定的,且对于局部使用安全的,其包含白藜芦醇和下述肽的协同组合:
Gly-Leu-Tyr-Asp-Asn-Leu-Glu。
7.权利要求1的组合物,其进一步包括:
包含多糖、丙烯酸聚合物或其混合物的至少一种水相结构试剂;
至少一种非离子型有机表面活性剂,其为烷氧基化醇;和
至少一种保湿剂,其为C2-4烷撑二醇或甘油。
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US12/489,619 | 2009-06-23 | ||
PCT/US2010/037871 WO2011005406A2 (en) | 2009-06-23 | 2010-06-09 | Skin repair compositions comprising circadian gene activators and a synergistic combination of sirt1 gene activators |
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CA2761967A1 (en) | 2011-01-13 |
BRPI1015932B1 (pt) | 2019-10-22 |
RU2494756C1 (ru) | 2013-10-10 |
AU2010271088B2 (en) | 2012-08-02 |
HK1178798A1 (zh) | 2013-09-19 |
EP2445511B1 (en) | 2016-09-07 |
BRPI1015932A2 (pt) | 2016-08-16 |
EP2445511A2 (en) | 2012-05-02 |
CN102802656A (zh) | 2012-11-28 |
US8703161B2 (en) | 2014-04-22 |
CA2761967C (en) | 2019-01-08 |
AU2010271088A1 (en) | 2011-12-22 |
JP2015129138A (ja) | 2015-07-16 |
JP5715623B2 (ja) | 2015-05-07 |
KR20120024822A (ko) | 2012-03-14 |
US20100028317A1 (en) | 2010-02-04 |
EP2445511A4 (en) | 2015-04-08 |
KR101393960B1 (ko) | 2014-05-14 |
RU2012102050A (ru) | 2013-07-27 |
ES2605623T3 (es) | 2017-03-15 |
JP6117830B2 (ja) | 2017-04-19 |
WO2011005406A2 (en) | 2011-01-13 |
JP2012531414A (ja) | 2012-12-10 |
WO2011005406A3 (en) | 2011-03-03 |
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