CN103327958A - 局部用棕榈酰基谷胱甘肽制剂 - Google Patents
局部用棕榈酰基谷胱甘肽制剂 Download PDFInfo
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- CN103327958A CN103327958A CN2012800013636A CN201280001363A CN103327958A CN 103327958 A CN103327958 A CN 103327958A CN 2012800013636 A CN2012800013636 A CN 2012800013636A CN 201280001363 A CN201280001363 A CN 201280001363A CN 103327958 A CN103327958 A CN 103327958A
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Abstract
本发明提供了应用于老化皮肤的局部用组合物，其包含：有效量的式(I)的S-酰基谷胱甘肽衍生物，其中R1选自不饱和的或饱和的C16基团且R2为氢、脂肪族或芳香族酰基；以及皮肤病学可接受的载体。优选的组合物包含约1.0%至约3.0重量%的S-棕榈酰基谷胱甘肽。
Description
发明领域
本发明涉及预防和治疗皮肤老化的包含S-酰基谷胱甘肽的局部用组合物。更具体地，本发明涉及包含谷胱甘肽的S-棕榈酰基衍生物的制剂，其用于改善皱纹和细纹的出现、皮肤的干燥、暗淡或缺乏光泽，或用于预防或治疗深纹和皱纹的出现、皮肤的下垂、褪色或发红和斑点，以及围绝经期，绝经期或绝经后皮肤的所有可见症状。
发明背景
还原型谷胱甘肽，通常称为谷胱甘肽或GSH，是一种动植物中发现的相对小分子，具有下式：
谷胱甘肽是一种水相正分子(orthomolecule)。它是最小的细胞内硫醇分子。由于其显著的给电子能力，是一种有效的还原型化合物。谷胱甘肽是有效的抗氧剂和酶辅因子，在调控细胞活性方面发挥着重要作用。
谷胱甘肽是L-谷氨酰胺、L-半胱氨酸和甘氨酸的链状三肽。学术上，N-L-γ-谷氨酰基-半胱氨酰甘氨酸或L-谷胱甘肽，该分子在半胱氨酰部分有巯基(SH)基团，赋予其强大的供电子性质。失电子后，分子变成氧化态，两个氧化态谷胱甘肽分子被二硫桥键连接（二聚）形成二硫化谷胱甘肽或氧化谷胱甘肽（GSSG）。此连接在再次还原时可逆转。谷胱甘肽在细胞内和细胞外均处于严格地稳态控制中。谷胱甘肽合成、其从GSSG/氧化谷胱甘肽再循环及其利用之间保持动态平衡。
谷胱甘肽合成涉及两步紧密相连的利用ATP的酶控反应。首先半胱氨酸和谷氨酸(glutamate)通过γ-谷氨酰基半胱氨酰合成酶结合。其次，谷胱甘肽合成酶使得甘氨酸与γ-谷氨酰基半胱氨酸结合产生谷胱甘肽。由于谷胱甘肽水平升高，它们自身限制了进一步的谷胱甘肽合成；另外，半胱氨酸利用度通常是限速的。空腹时，蛋白能量营养不良或其他食物氨基酸缺乏限制了谷胱甘肽合成。
谷胱甘肽再循环受二硫化谷胱甘肽还原酶催化，其利用来自NADPH的还原等效物将GSSG复原为2GSH。抗坏血酸盐的还原能力有助于保全全身谷胱甘肽。谷胱甘肽用作辅助因子，其通过（1）多种过氧化物酶，以解毒由氧自由基攻击生物分子产生的过氧化物；（2）转氢酶，以减少DNA、蛋白质及其他生物分子上的氧化中心；和（3）谷胱甘肽S-转移酶（GST）以将谷胱甘肽与内源性物质（例如雌激素）和外源性亲电试剂（例如芳香烃氧化物、不饱和羰基物、有机卤化物）和不同的外源物缀合。
自由基和其他氧化剂可以消耗谷胱甘肽。当其被消耗时，稳态的谷胱甘肽氧化还原循环试图维持谷胱甘肽水平。食物中可利用的量有限（少于150mg/天），氧化消耗速度会超过合成速度。
肝脏是谷胱甘肽最大的储存器。实质细胞合成谷胱甘肽以备P450缀合和多种其他代谢需要，然后输出谷胱甘肽作为SH/还原能力的全身的源。谷胱甘肽随着胆汁被运送到肠腔室。肾小管、肠内衬和肺的上皮组织具有显著的P450活性和适度输出谷胱甘肽的能力。
谷胱甘肽等效物主要以胱氨酸、氧化型和更稳定形式的胱氨酸在血液中循环。细胞从血液中吸收胱氨酸，将其复原为半胱氨酸（很可能利用抗坏血酸盐作为辅助因子）并由此合成谷胱甘肽。相反地，细胞内谷胱甘肽有助于将其他抗氧剂如抗坏血酸和α-生育酚的氧化形式再还原。
谷胱甘肽是一种极其重要的细胞保护剂。它直接淬灭反应性羟自由基、其他氧中心自由基和DNA及其他生物分子上的自由基中心。谷胱甘肽保护皮肤、晶状体、角膜和视网膜免受辐射损伤，且保护P450解毒作用在肝、肾、肺、肠上皮细胞和其他器官的生化基础。
谷胱甘肽是许多需硫醇还原等效物的酶必不可少的辅助因子，并有助于保持酶上的氧化还原敏感活性位点在必要的还原态。高阶硫醇细胞系统-金属硫蛋白、硫氧还蛋白和其他氧化还原调控剂蛋白-最终受GSH水平和GSH/GSSG氧化还原比值调控。
谷胱甘肽及其代谢物还通过几种主要代谢途径干扰能量学和神经递质合成。谷胱甘肽利用度下调白三烯类和其他类花生酸类的促炎症可能性。
人体组织中谷胱甘肽水平正常范围为0.1-10毫摩尔（mM），主要集中在肝脏（高达10mM）和脾、肾、晶状体、红细胞和白细胞。血浆浓度在微摩尔范围（约4.5μM）。可以消耗谷胱甘肽的氧化应激源包括紫外线和其他辐射；病毒感染；环境毒素、室内化学物质和重金属；手术、炎症、烧伤；脓毒性休克；食物缺乏谷胱甘肽前体和酶辅因子。
许多公开知识教导人们通过服用不同谷胱甘肽衍生物来提高谷胱甘肽细胞水平。美国专利No.5,464,825(Anderson)公开了利用N-酰基单烷基谷胱甘肽单酯提高肝和肾细胞的细胞水平来治疗艾滋病和其它病毒性感染。美国专利No.5,624,955(Nagasawa)公开了由谷氨酰基半胱氨酸衍生物组成的谷胱甘肽前药来提高晶状体中谷胱甘肽水平和预防白内障发生。美国专利No.7,029,695(Redelmeier)公开了提高造血调控中所用谷胱甘肽类似物生物利用度的脂质制剂。Neuroscience 138:1161-1170(2006)(Perlugig等人)公开了利用三环癸烷-9-基-黄原酸盐获得神经元细胞内谷胱甘肽水平的增加用以治疗阿尔茨海默病。WO 2009/047728(Liguri)公开了谷胱甘肽的亲脂性衍生物可能对治疗阿尔茨海默病和亨廷顿舞蹈病有用。
谷胱甘肽衍生物的局部应用已经公开。美国专利No.3,948,569(Kalopissis)公开了S-取代的谷胱甘肽直链和支链烷基和烯基衍生物用于各种头皮和头发的应用并抑制皮脂过度分泌。美国专利No.5,516,507(N’Guyen)公开了谷胱甘肽单烷基酯用于局部治疗皮肤老化。这些谷胱甘肽单烷基酯在甘氨酸残基上被取代，并采用只有1-10个碳原子的烷基链。美国专利申请2004/0147452(Yu)建议非两性N-酰基谷胱甘肽衍生物对多种症状局部施用。谷胱甘肽非两性衍生物的建议基于谷胱甘肽的单和二酯前药的水性药物制剂的不稳定性，其随时间延长迅速变质。
美国专利No.6,011,067(Hersh)公开了包括几种协同抗氧化剂作为辅助物的组合物局部治疗脱屑炎症性疾病如牛皮藓，该组合物包含活性成分L-谷胱甘肽和硒化合物。Hersh的披露强调了这两种成分的存在对要求保护的组合物抗牛皮癣有效性的重要性。
申请人的公开申请、美国专利公开No.20050192229、20060063718和20060069036公开了高谷胱甘肽浓度的组合物局部用于治疗牛皮癣。
发明概述
本发明包含应用于皮肤老化的局部用组合物，其包含有效量的式(I)的S-酰基谷胱甘肽衍生物和皮肤病学可接受的载体：
其中R1选自不饱和的或饱和的C16基团且R2为氢、脂肪族或芳香族酰基。
在一些实施方案中，R1为棕榈酰基。在其中一些实施方案中，所述S-棕榈酰基谷胱甘肽衍生物以约0.01%至约20重量%存在。在其中某些实施方案中，所述S-棕榈酰基谷胱甘肽衍生物以约0.1%至约5重量%存在。在尤其优选的实施方案中，所述S-棕榈酰基谷胱甘肽衍生物以约1.0%至约3.0重量%存在。
在一些实施方案中，该载体包括硬脂酸的脂肪酸衍生物。
在某些实施方案中，该组合物还包含一种或多种附加成分，其选自：抗坏血酸和抗坏血酸衍生物，硫辛酸，神经肽，α-羟基酸，镁、锌和铜的盐，生育三烯酚，生育三烯酚衍生物和富含生育三烯酚、生育三烯酚衍生物的维生素E组分，以及它们的混合物。在其中一些实施方案中，所述附加成分包括天冬氨酸镁、葡萄糖酸锌和葡萄糖酸铜的混合物。
在某些实施方案中，所述组合物包括水包油乳剂。在其他实施方案中，所述组合物包括乳膏剂。
本发明还提供应用于老化皮肤的局部用组合物，其包含约0.01%至约20重量%的S-棕榈酰基谷胱甘肽，约0.01%至约15重量%的至少一种乳化剂，和水。
在一些实施方案中，所述S-棕榈酰基谷胱甘肽以约0.1%至约5重量%存在。在其中一些实施方案中，所述S-棕榈酰基谷胱甘肽以约1.0%至约3.0重量%存在。
在某些实施方案中，所述乳化剂包括硬脂酸的脂肪酸衍生物。
在一些实施方案中，所述组合物还包含一种或多种附加成分，其选自：抗坏血酸和抗坏血酸衍生物；硫辛酸，α-羟基酸；以及生育三烯酚和生育三烯酚衍生物和富含生育三烯酚或生育三烯酚衍生物的维生素E组分。在其中一些实施方案中，所述附加成分包括天冬氨酸镁、葡萄糖酸锌和葡萄糖酸铜的混合物。
在某些实施方案中，所述组合物包括水包油乳剂。
在一些实施方案中，所述组合物包括乳膏剂。
在某些实施方案中，所述组合物还包含棕榈酸异丙酯。
本发明还提供应用于老化皮肤的局部用组合物，其包含约1.0%至约3.0重量%的S-棕榈酰基谷胱甘肽，约1.5%至约15重量%的至少一种硬脂酸的脂肪酸衍生物，约1.0%至5.0重量%的棕榈酸异丙酯，和水。
发明详述
皮肤细胞老化通常与皮肤细胞中蛋白质的糖化作用有关，其引起皮肤失去弹性和胶原瓦解。糖化蛋白表现症状如炎症，皱纹和褐色斑点或脂褐质。
皮肤老化还经常由与绝经相关的雌激素损失或雌激素降低引起。雌激素受体主要富集在脸部、生殖器区域和下肢。本发明认识到这些过程并提供了将与绝经期雌激素和雌二醇损失相关的预期和现有的老化状况和皮肤状况最小化的组合物和方法。
术语“皮肤”意指角质表面的皮肤、毛发和指甲。用于此处的术语“皮肤”泛指脸部、身体、颈部和嘴唇的皮肤。
本发明包含局部用S-酰基谷胱甘肽(GSH)组合物，用于预防皮肤老化并解决与绝经相关的皮肤状况。所述组合物有助于解决严重皮肤干燥、暗淡、失去弹性、缺乏光泽、深纹和皱纹、蜘蛛状血管或红色斑点。特别是，使用本发明的组合物可改善”木偶”纹，笑纹，鼻唇沟深线，鱼尾纹，细纹/皱纹，眉毛之间的垂直纹、额头水平纹、皮肤薄/薄弱下垂、皮肤发红和暗淡。这些组合物还可使用IUPAC命名法称为S-烷酰基谷胱甘肽组合物。所述治疗由下式的S-酰基谷胱甘肽衍生物构成：
其中R1选自饱和或不饱和脂肪族C12-C24基团，优选C16-C24基团，最优选饱和C16基团；R2为氢、脂肪族或芳香族酰基基团，最优选氢。在优选实施方案中，R1选自亚油酰基、油酰基或棕榈酰基，但最优选为棕榈酰基。本发明尤其优选的实施方案为S-棕榈酰基谷胱甘肽。
本发明的一个具体目的是提供具有酰基基团的S-酰基谷胱甘肽组合物以提高皮肤渗透和透皮吸收而改善皮肤状况。与谷胱甘肽巯基结合的非极性酰基的烃链的存在使得本发明化合物可有效作为局部应用，其可轻易通过表皮和真皮细胞细胞膜的脂质双层。S-酰基谷胱甘肽具有亲脂性结构，使得其可溶于脂肪且允许其通过细胞膜并直接吸收进入细胞。
在不希望被任何理论所束缚的情况下，据信棕榈酰基团尤其增强疏水性并促进膜结合，类似于蛋白中观测到的S-棕榈酰化。该脂肪酸链的结合是可逆的(因为棕榈酸与谷胱甘肽之间的键是硫酯键)，允许该化合物被细胞膜吸收。
本发明的S-酰基谷胱甘肽化合物可以通过本领域技术人员所熟知的多种途径购买或制备。例如，可通过谷胱甘肽与适当的辅酶A（CoA）的酰基酯反应，随后从水相通过HPLC纯化，或通过谷胱甘肽与相应酰卤化学反应实现酶促硫酯交换(enzymatic transthioesterification)。见上文的WO 2009/047728，其纳入此处作为参考。另一种合成可通过在真空条件下，相应羧酸的卤化物与L-谷胱甘肽在三氟乙酸中的溶液反应，加入乙酸乙酯，并收集沉淀盐而进行。见上文的美国专利No.3,984,569，其纳入此处作为参考。
根据本发明含有S-酰基谷胱甘肽的局部用组合物将局部施加于皮肤组织并被其吸收。S-酰基谷胱甘肽激活转酮醇酶，使其活性增加300%，并预防蛋白质糖化和AGE形成。建议治疗期后，预计将观察到皮肤炎症、刺激和红斑减少，同时皮肤弹性和柔软度增加。尤其是减少了”木偶”纹，笑纹，鼻唇沟深线，鱼尾纹，细纹/皱纹，眉毛之间的垂直纹、额头水平纹、皮肤薄/薄弱下垂、皮肤发红和暗淡。因此预计本发明将改善皮肤外观，预防和治疗皮肤老化、干燥、暗淡、失去弹性和缺乏光泽。尤其，治疗可用于预防或延迟与绝经期皮肤相关的蜘蛛状血管或红斑的出现。另一个实施方案中，治疗可用于预防或延迟过大的细纹和皱纹。
仅需要有效量的含有S-酰基谷胱甘肽的局部用组合物来实现上述益处并预防皮肤绝经期和老化的典型作用。一般地，皮肤组织的局部施用结合皮肤病学上可接受的载体，尤其是S-酰基谷胱甘肽本身在其中可溶或可有效被增溶的载体（例如乳剂或微乳剂）来实现。使用时，载体为惰性的，即不导致谷胱甘肽衍生的活性成分失活或氧化，并对施加部位的皮肤无任何不良作用。
发明的一个优选实践中，一种或多种S-酰基谷胱甘肽衍生物与皮肤病学可接受载体或介质（例如洗剂、乳膏剂、软膏剂、皂、棒状物(stick)等）混合一起施加，以促进局部施加，并在某些情况下，提供额外治疗效果，例如通过润湿受影响皮肤区域而带来的效果。尽管局部用组合物的载体可由相对简单的溶剂或分散剂如水组成，但一般优选该载体包含更有助于局部施用的组分，尤其是将在应用的皮肤上形成薄膜或层，而使得施用局部化并预防在被水浸泡或排汗后洗掉，和/或帮助活性剂经皮递送。许多制剂为该领域熟知，包括含有油和/或醇和润滑植物油的洗剂、烃油和蜡、硅酮油、动物或海洋脂肪或油、甘油酯衍生物、脂肪酸或脂肪酸酯、或醇或醇醚、卵磷脂、羊毛脂及衍生物、多元醇或酯、蜡酯、甾醇、磷脂等，一般还有乳化剂（非离子型、阳离子型或阴离子型），尽管一些润滑剂本身具有乳化性质。在优化实施方案中，载体为水包油乳剂。
如上所述，通过利用不同比例的成分和/或加入增稠剂例如胶质或其他形式的亲水性胶体，这些成分可以配制成乳膏剂、洗剂或凝胶剂或固体棒(solidstick)。一个可能的实施方案是用溶液浸透用于擦拭患处的衬垫；另一个实施方案是清洁剂；其他的实施方案是洗剂、乳膏剂和凝胶剂，此处称为皮肤或皮肤病学可接受的载体，其用该领域普通技术人员熟知的传统技术配制。在最优选的实施方案中，所述成分配制成乳膏剂，其粘度为35,000至45,000cps(使用Brookfield LVT粘度计测量，其T/C主轴为5rpm)，比重为0.9990至1.100。
此处所用的术语“局部用组合物”应指包含S-酰基谷胱甘肽活性成分、载体和此处所述的应用于人皮肤的任何佐剂、增稠剂、赋形剂等的完整产品。
载体中S-酰基谷胱甘肽活性成分的量可依具体应用、具体化合物的有效性或所需浓度广泛改变或调整。一般地，S-酰基谷胱甘肽活性成分的量为局部用组合物的约0.01%至约20重量%，更优选为约0.1%至约5重量%。在一些应用中，S-酰基谷胱甘肽活性成分的量超过5%重量。一般地，载体中较低浓度的S-酰基谷胱甘肽活性成分是合适的，取决于应用方案和所采用的活性成分与辅助成分。在最优选的实施方案中，S-棕榈酰基谷胱甘肽以约1.00%至约3.00重量%存在。
一般在发明方法的实施中，局部用组合物以预定间隔局部施加于皮肤区域，比如脸部，经常作为湿润剂、洗剂或软膏剂。一般在每次连续应用后逐步改善。尽管可立即观察到效果，但当该局部用组合物每天施用两次，优选早晚各一次时，可观察到更强的效果。在目前已确定的临床研究中，未遇到不良副作用。本发明的一个优点是本发明组合物不需要药物处方。
本发明的局部用组合物可含有通常能在护肤组合物和化妆品中发现的其他成分，例如着色剂、柔润剂、皮肤调节剂、乳化剂、润湿剂、防腐剂、抗氧化剂、香料、螯合剂等等，条件是它们与此组合物的其他组分物理上或化学上相容。
防腐剂包括但不限于对羟基苯甲酸C1-C3烷基酯和苯氧乙醇，其含量范围以全部组合物计典型地为约0.1％至约2.0重量%。优选的防腐剂为ISP的OptiphenTM Plus，其为一种防腐剂制剂，特征是其为苯氧乙醇、山梨酸和柔润剂基质的混合物。
柔润剂，其含量范围典型地为全部组合物的约0.01％至10％，包括但不限于脂肪酯、脂肪醇、矿物油、聚醚硅氧烷共聚物、二十二碳六烯酸（DHA）以及它们的混合物。优选的柔润剂为Active Organics的
(水解葡糖氨基聚糖，丙二醇，水，苯氧乙醇)，以及角鲨烷，牛油树脂(shea butter)，白池花籽油，棕榈酸异丙酯和DHA。
润湿剂，其含量范围典型地为全部组合物的约0.1％至约5重量%，包括但不限于多元醇如甘油、聚亚烷基二醇(如丁二醇、丙二醇、二丙二醇、聚丙二醇及聚乙二醇)及它们的衍生物、亚烷基多醇及它们的衍生物、山梨醇、羟基山梨醇、己二醇、1,3-丁二醇、1,2,6-己三醇、乙氧基化甘油、丙氧基化甘油以及它们的混合物。优选的润湿剂为牛油树脂。
乳化剂，其典型含量为组合物的约1％至约15重量%，包括但不限于硬脂酸、鲸蜡醇、硬脂醇、硬脂醇聚醚-2、硬脂醇聚醚-20、丙烯酸酯/丙烯酸C10-30烷基酯交联聚合物、硅酮、二甲基乙醇胺（DMAE）、磷脂酰胆碱（PPC）、二十二碳六烯酸（DHA）及它们的混合物。优选的乳化剂为透明质酸钠，
(75%鲸蜡硬脂醇和25%乙氧基化鲸蜡硬脂醇的混合物，Amerchol Corp.销售)，ArlacelTM 165(硬脂酸甘油酯和PEG-100硬脂酸酯，Croda Inc.销售)，硅酮(Dow
200 Fluid，350 CST)，二甲基氨基乙醇（也已知为DMAE），和
90G (含10%脂肪酸的磷脂酰胆碱，Phospholipid GmbH销售)。
螯合剂，其典型含量范围为约0.01％至约2重量%，包括但不限于乙二胺四乙酸(EDTA)及其衍生物和其盐、二羟乙基甘氨酸、酒石酸及其混合物。
抗氧化剂，其典型含量范围为组合物的约0.01％至约0.75重量%，包括但不限于丁基化的羟基甲苯(BHT)；维生素C和/或维生素C衍生物，例如抗坏血酸的脂肪酸酯，特别是抗坏血酸棕榈酸酯；丁基羟基茴香醚(butylatedhydroanisole，BHA)；苯基-α-萘胺；对苯二酚；没食子酸丙酯；去甲二氢愈创木酸(nordihydroquiaretic acid)；维生素E和/或维生素E的衍生物，包括生育三烯酚(tocotrienol)和/或生育三烯酚衍生物；泛酸钙；绿茶萃取物；混合多酚；以及这些的任何混合物。特别优选的抗氧化剂为对皮肤提供额外益处的那些，如抗坏血酸棕榈酸酯、芝麻籽油、α-硫辛酸和
50(棕榈油、生育三烯酚类、生育酚)。
许多组合物中使用缓冲剂。优选地，缓冲剂的量使得组合物具有约4.0至约8.5、更优选约4.5至约7.0、最优选约5.0至约6.0的pH。典型缓冲剂为理化性质稳定的通常用于化妆品中的缓冲剂，并且可包括同时也是辅剂的化合物，如柠檬酸、苹果酸以及乙醇酸缓冲剂。
本发明的一些实施方式除了S-酰基谷胱甘肽之外还包括至少一种其它辅剂。辅剂成分存在的量为组合物的0.01%至约20重量%，其包括但不限于以下的一种或多种：异氰酸酯、咖啡因、维生素D3、硫辛酸；α-羟基酸，如乙醇酸或乳酸；抗坏血酸及其衍生物，尤其是抗坏血酸脂肪酸酯；或生育三烯酚和生育三烯酚衍生物以及富含生育三烯酚或生育三烯酚衍生物的维生素E组分；以及神经肽。优选的辅剂包括乙醇酸、柠檬酸、抗坏血酸棕榈酸酯、Seppic的SepitonicTM M3（其含天冬氨酸镁，葡萄糖酸锌和葡萄糖酸铜），
50，和寡肽-17和寡肽-49。
其他成分和方法公开于以下文献中：美国专利No.5,376,361；5,409,693；5,545,398；5,554,647；5,574,063；5,643,586；5,709,868；5,879,690；6,191,121；6,296,861；6,437,004；和6,979,459，其整体引入本文并作参考。
以下实施例进一步公开和描述了本发明的范围内的实施方案。这些实施例仅为示意性目的给出，不作为对本发明的限制，因为其在不偏离本发明的精神和范围的前提下可以有很多变化。
实施例
制剂：使用常规混合技术将以下成分混合而制备水包油乳剂制剂。
| 原料 | 级别 | 重量% |
| 纯水 | USP | 55-65 |
| S-棕榈酰基谷胱甘肽 | 化妆品 | 1.0-3.0 |
| 无机(镁、铜、锌)盐 | 化妆品 | 6-10 |
| 硬脂酸的脂肪酸衍生物 | 化妆品 | 1.5-11 |
| 棕榈酸异丙酯 | NF | 1.0-5.0 |
| 四己基癸醇抗坏血酸酯 | NF,FCC | 1.0-5.0 |
| 水解葡糖氨基聚糖 | 化妆品 | 0.5-3.5 |
| DMAE | 化妆品 | 0.25-3.5 |
| 磷酯酰胆碱 | 化妆品 | 1.0-3.0 |
| L-酪氨酸 | 化妆品 | 1.0-3.0 |
| 角鲨烷 | 化妆品 | 0.5-1.5 |
| 乙醇酸 | 化妆品 | 0.5-1.5 |
| 芝麻籽油/白池花籽油 | 化妆品 | 0.25-1.5 |
| 寡肽 | 化妆品 | 0.5-3.0 |
| 甘油 | USP | 0.25-0.75 |
| 基于苯氧乙醇的防腐剂 | 化妆品 | 0.25-0.75 |
| 二甲基硅油 | 化妆品 | 0.25-0.75 |
| DHA | 化妆品 | 0.25-0.75 |
| 生育三烯酚 | 化妆品 | 0.125-0.50 |
| EDTA二钠 | 化妆品 | 0.05-0.50 |
| 柠檬酸 | 化妆品 | 0.05-0.50 |
| α-硫辛酸 | 化妆品 | 0.005-0.150 |
| 抗坏血酸棕榈酸酯 | 化妆品 | 0.005-0.150 |
| 香料 | 化妆品 | 0.005-0.50 |
临床研究：在对于上述水包油制剂(“产品”)进行的家用试验研究中，收集了43位年龄为44-56岁、健康良好的女性受试者。所有受试者均感觉到自己有”木偶”纹，笑纹，鼻唇沟深线，鱼尾纹，细纹/皱纹，眉毛之间的垂直纹、额头水平纹、皮肤薄/薄弱下垂、皮肤发红和暗淡。用Visia
数字成像系统对各受试者拍摄基线照片。在基线随访时对受试者涂敷该产品。涂敷该产品后，受试者填写了调查问卷并再次拍照。对受试者给予该产品，并指示其在每天早晚在干净的面部和颈部上使用该产品4周后返回。在4周的随访结束时，患者填写了调查问卷并进行了最后一次拍照。
结果：在细纹和皱纹的表现、外观、感觉和皮肤的表现方面，受试者在首次涂敷后随即报告了38%至73%的改善。在细纹和皱纹的表现、外观、感觉和皮肤的表现方面，4周的涂敷结束后，受试者报告了80%至95%的改善。具体的改善见于：”木偶”纹、“11”纹（“eleven”lines）、额头水平纹、皮肤薄纸质外观、面颊圆形和肿胀、自然光泽、绷紧度和强度、平滑度和柔软度、色调、弹性和回弹力、湿度和水润、发红/斑点、褪色、毛孔大小、下垂，以及皮肤的总体年轻程度。
上面的描述是为了教导本领域普通技术人员如何实施本发明，它不意图详细描述其各种改进和变动，这些改进和变动对于熟练的技术人员在阅读了这一描述后将是显而易见的。但是，它意图将全部的各种改进和变动包括在本发明的任何顺序的范围内，除非上下文中特别地指出相反情况，那么这一范围对想要达到的目的是能有效满足的。
Claims (20)
1.应用于老化皮肤的局部用组合物，其包含：
有效量的式(I)的S-酰基谷胱甘肽衍生物
其中R1选自不饱和的或饱和的C16基团且R2为氢、脂肪族或芳香族酰基；和
皮肤病学可接受的载体。
2.权利要求1的组合物，其中R1为棕榈酰基。
3.权利要求2的组合物，其中所述S-棕榈酰基谷胱甘肽衍生物以约0.01%至约20重量%存在。
4.权利要求3的组合物，其中所述S-棕榈酰基谷胱甘肽衍生物以约0.1%至约5重量%存在。
5.权利要求4的组合物，其中所述S-棕榈酰基谷胱甘肽衍生物以约1.0%至约3.0重量%存在。
6.权利要求1、2、3、4或5的组合物，其中所述载体包含硬脂酸的脂肪酸衍生物。
7.权利要求1、2、3、4或5的组合物，其还包含一种或多种附加成分，其选自：抗坏血酸和抗坏血酸衍生物，硫辛酸，神经肽，α-羟基酸，镁、锌和铜的盐，生育三烯酚，生育三烯酚衍生物和富含生育三烯酚、生育三烯酚衍生物的维生素E组分，以及它们的混合物。
8.权利要求7的局部用组合物，其中所述附加成分包含天冬氨酸镁、葡萄糖酸锌和葡萄糖酸铜的混合物。
9.权利要求1、2、3、4或5的组合物，其中所述组合物包括水包油乳剂。
10.权利要求1、2、3、4或5的组合物，其中所述组合物包括乳膏剂。
11.应用于老化皮肤的局部用组合物，其包含：
约0.01%至约20重量%的S-棕榈酰基谷胱甘肽；
约0.01%至约15重量%的至少一种乳化剂；和水。
12.权利要求11的组合物，其中所述S-棕榈酰基谷胱甘肽以约0.1%至约5重量%存在。
13.权利要求12的组合物，其中所述S-棕榈酰基谷胱甘肽以约1.0%至约3.0重量%存在。
14.权利要求11、12或13的组合物，其中所述乳化剂包括硬脂酸的脂肪酸衍生物。
15.权利要求11、12或13的组合物，其还包含一种或多种附加成分，其选自：抗坏血酸和抗坏血酸衍生物；硫辛酸，α-羟基酸；以及生育三烯酚和生育三烯酚衍生物和富含生育三烯酚或生育三烯酚衍生物的维生素E组分。
16.权利要求15的局部用组合物，其中所述附加成分包括天冬氨酸镁、葡萄糖酸锌和葡萄糖酸铜的混合物。
17.权利要求11、12或13的组合物，其中所述组合物包括水包油乳剂。
18.权利要求11、12或13的组合物，其中所述组合物包括乳膏剂。
19.权利要求11、12或13的组合物，其还包含棕榈酸异丙酯。
20.应用于老化皮肤的局部用组合物，其包含：
约1.0%至约3.0重量%的S-棕榈酰基谷胱甘肽；
约1.5%至约15重量%的至少一种硬脂酸的脂肪酸衍生物；
约1.0%至5.0重量%的棕榈酸异丙酯；和
水。
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| US13/072,277 US8609618B2 (en) | 2011-03-25 | 2011-03-25 | Topical palmitoyl glutathione formulations |
| PCT/US2012/028234 WO2012134758A2 (en) | 2011-03-25 | 2012-03-08 | Topical palmitoyl glutathione formulations |
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| CN103327958A true CN103327958A (zh) | 2013-09-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012800013636A Pending CN103327958A (zh) | 2011-03-25 | 2012-03-08 | 局部用棕榈酰基谷胱甘肽制剂 |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US8609618B2 (zh) |
| EP (1) | EP2547316A2 (zh) |
| JP (1) | JP5843853B2 (zh) |
| KR (1) | KR101445182B1 (zh) |
| CN (1) | CN103327958A (zh) |
| AU (1) | AU2012238087B2 (zh) |
| CA (1) | CA2795557C (zh) |
| WO (1) | WO2012134758A2 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112137911A (zh) * | 2019-06-26 | 2020-12-29 | 强生消费者公司 | 含有n-酰基二肽衍生物和乙醇酸的局部用组合物 |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8609604B2 (en) * | 2009-12-28 | 2013-12-17 | N.V. Perricone Llc | Methods of improving the appearance of aging skin |
| US8580742B2 (en) * | 2010-03-05 | 2013-11-12 | N.V. Perricone Llc | Topical glutathione formulations for menopausal skin |
| JP6360437B2 (ja) * | 2011-12-20 | 2018-07-18 | ユニリーバー・ナームローゼ・ベンノートシヤープ | アミノペプチド混合物を含む保湿組成物 |
| IL260028B2 (en) * | 2015-12-16 | 2023-10-01 | Mattityahu Avshalomov | Baby care products |
| WO2020123306A1 (en) | 2018-12-14 | 2020-06-18 | Mary Kay Inc. | Cosmetic compositions |
| IT202000013393A1 (it) | 2020-06-05 | 2021-12-05 | Francesco Sestito | Composizioni fitoterapiche per uso topico |
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- 2012-03-08 CN CN2012800013636A patent/CN103327958A/zh active Pending
- 2012-03-08 JP JP2013515592A patent/JP5843853B2/ja not_active Expired - Fee Related
- 2012-03-08 AU AU2012238087A patent/AU2012238087B2/en active Active
- 2012-03-08 WO PCT/US2012/028234 patent/WO2012134758A2/en active Application Filing
- 2012-03-08 CA CA2795557A patent/CA2795557C/en active Active
- 2012-03-08 EP EP12710614A patent/EP2547316A2/en not_active Withdrawn
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| CN1424900A (zh) * | 1999-11-24 | 2003-06-18 | 通达商业集团国际公司 | 局部皮肤用组合物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112137911A (zh) * | 2019-06-26 | 2020-12-29 | 强生消费者公司 | 含有n-酰基二肽衍生物和乙醇酸的局部用组合物 |
| CN112137911B (zh) * | 2019-06-26 | 2024-05-17 | 强生消费者公司 | 含有n-酰基二肽衍生物和乙醇酸的局部用组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012134758A2 (en) | 2012-10-04 |
| KR101445182B1 (ko) | 2014-09-29 |
| US20140045767A1 (en) | 2014-02-13 |
| CA2795557A1 (en) | 2012-10-04 |
| US9023801B2 (en) | 2015-05-05 |
| KR20120130300A (ko) | 2012-11-30 |
| CA2795557C (en) | 2016-06-21 |
| AU2012238087A1 (en) | 2012-11-08 |
| US8609618B2 (en) | 2013-12-17 |
| US20120245098A1 (en) | 2012-09-27 |
| JP5843853B2 (ja) | 2016-01-13 |
| WO2012134758A3 (en) | 2013-01-17 |
| AU2012238087B2 (en) | 2014-07-31 |
| JP2013528662A (ja) | 2013-07-11 |
| EP2547316A2 (en) | 2013-01-23 |
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