CN104105473B - 皮肤美白组合物 - Google Patents
皮肤美白组合物 Download PDFInfo
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- CN104105473B CN104105473B CN201380009238.4A CN201380009238A CN104105473B CN 104105473 B CN104105473 B CN 104105473B CN 201380009238 A CN201380009238 A CN 201380009238A CN 104105473 B CN104105473 B CN 104105473B
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Abstract
本发明涉及皮肤美白组合物和皮肤美白方法。使用siRNA寡核苷酸实现皮肤美白，所述siRNA寡核苷酸能用比已知化学活性剂低得多的浓度实现这一点。
Description
技术领域
本发明涉及皮肤美白组合物和皮肤美白方法。
发明背景
已经报道了许多皮肤美白方法和组合物。已知用于皮肤美白的活性剂可以合成制备或可以使用或萃取自天然来源。这些活性剂通常可用于皮肤美白，以及用于治疗、预防或改善皮肤外观以对抗色素沉着过度、老年斑、瑕疵等。
肤色取决于黑色素在表皮细胞内的量、类型和分布。角化细胞是皮肤表皮中的主要细胞(群体的>90%)，而成纤维细胞位于真皮中，黑素细胞(总表皮细胞的~5%)存在于真皮:表皮接合处。这三种类型的细胞通过各种分泌的因子互相交流以调节皮肤色素沉着。
皮肤中的黑素细胞合成黑色素(生物聚合色素)并将其转移到相邻的角化细胞，以使黑色素分布在皮肤上层内。在专门的溶酶体相关的细胞器(被称作黑素体)内合成黑色素。肤色受若干因素影响，包括(a) 生成并转移到角化细胞中的黑色素的量和类型，和(b)其随后在角化细胞内的并入、聚集和降解。调节皮肤色素沉着的其它因素包括由影响黑素细胞的角化细胞和成纤维细胞分泌的因子、来自供血的内分泌因子以及神经因子和炎症相关因子；影响皮肤色素沉着的外在因素包括紫外线(UV)辐射。已经报道了利用siRNA调节这些因素中的一些。
siRNA是短双链的小干扰RNA分子。大多数siRNA的长度为20-25个核苷酸。siRNA参与RNA干扰并在转录后调节(干扰 - 沉默)基因表达。可以使用适当的转染程序将合成siRNA引入细胞中并通常表现出瞬态效应。这导致相应的靶基因表达的基于序列互补的敲低。上述特征长度看起来使靶基因特异性最大化(超过非特异性效应)。当特定的靶基因是已知的时，整个过程包括选择性设计一些siRNA序列以靶向该基因的各种部分并凭实验测试，以确定该集合内最有效的siRNA序列(基因表达的最高抑制)。可以使用针对该基因的siRNA测试给定基因对于特定细胞现象的相关性。siRNA因此既充当基因功能研究中的检测工具，又充当调节基因表达并经此调节细胞生物学的技术手段。
例如在US 7 087 743、US 7 504 385和US 2007/0134188中公开了用于皮肤脱色素的寡核苷酸。在上述公开或任何其它公开文献中尚未公开掺入施加在皮肤上的组合物中的本发明中要求保护的寡核苷酸。
在EP1752536、EP2213738、WO2009/001359和WO2010/080452中报道了有可能用于医药用途的用于基因表达抑制的非常大量的siRNA分子。但是，它们都没有教导或指导本领域技术人员为皮肤美白益处而使用任何那些寡核苷酸用于在皮肤上施用。
因此本发明的一个目的是提供增强皮肤美白效力的新型寡核苷酸。
发明概述
根据本发明的第一方面，提供了包含siRNA的皮肤美白组合物，其包含
(a) 寡核苷酸，其包含选自下列之一的序列
它们的包含至少19个核苷酸的部分；和
(b) 化妆品可接受的载体；
其中寡核苷酸大小为19至30个核苷酸。
根据本发明的另一方面，提供了皮肤美白组合物，其包含：
(a) 包含寡核苷酸的siRNA，所述寡核苷酸包含选自下列的序列
它们的包含至少19个核苷酸的部分；和
(b) 化妆品可接受的载体，其选自乳液、洗液、霜、泡沫、凝胶、皂条、棒、面膜、棉片或贴剂；
其中寡核苷酸大小为19至30个核苷酸。
根据本发明的另一方面，提供了皮肤美白方法，其包括在皮肤上施加本发明的组合物。
发明详述
本领域普通技术人员在阅读下列详述和所附权利要求时容易看出这些和其它方面、特征和优点。为避免疑问，本发明的一个方面的任何特征可用于本发明的任何其它方面。词语“包含”意在表示“包括”但不一定“由...组成”或“由...构成”。换言之，所列步骤或选项不需要是穷举的。要指出，下列描述中给出的实例意在阐明本发明而无意将本发明限于这些实例本身。类似地，除非另行指明，所有百分比为重量/重量百分比。除了在实施例和对比例中或在另行明示之处外，本说明书和权利要求中指示材料量或反应条件、材料物理性质和/或用途的所有数值应被理解为用词语“大约”修饰。以“x至y”格式表示的数值范围被理解为包括x和y。当对特定特征而言，以“x至y”格式描述多个优选范围时，要理解的是，还考虑组合不同端点的所有范围。
本文所用的“皮肤美白组合物”意在包括局部施加到皮肤上以增白天然肤色的组合物。这种组合物通常可分类为免洗或洗除型，并包括施加到人体上以还有改善外观、清洁、气味控制或一般美观的任何产品。本发明的组合物可以是液体、洗液、霜、泡沫、磨砂膏、凝胶、皂条或化妆水形式，或用工具或经面膜、棉片或贴剂施加。这种组合物的非限制性实例包括免洗护肤液、霜、止汗剂、除臭剂、粉底和洗除型洗发水、护发素、沐浴凝胶和皂条。本发明的组合物优选是免洗组合物。本文所用的“皮肤”意在包括面部和身体(例如颈、胸、背、手臂、腋下、手、腿、臀部和头皮)上的皮肤，尤其是其暴露在阳光下的部分。
本发明的组合物包含配制到用于皮肤美白用途的化妆品可接受的基质中的siRNA(双链核苷酸)，其包含长度为19至30个核苷酸的所选寡核苷酸。用于本发明的寡核苷酸是在这一领域中的广泛研究后选择的，下面描述选择过程。
皮肤中存在的角化细胞、黑素细胞和成纤维细胞通过各种分泌的因子互相交流以调节皮肤色素沉着。本发明人已经研究了这些因子中的一些，仔细挑选以使它们对黑素生成的影响最大化，即干细胞因子(SCF)、内皮素(EDN)、α-黑素细胞刺激激素(α-MSH)和Wnt，它们分别结合到它们的同源受体c-Kit酪氨酸激酶、内皮素受体A和B(EDNRA和EDNRB)、黑皮质素1和Frizzled 1(Fz1)上。这样的相互作用引发调节皮肤色素沉着的多种下游信号传导通路。本发明人已经分析了最可能在基因表达水平下抑制所述受体的核酸序列并得出可能调节皮肤美白的大量这样的序列。然后使用黑色素含量体外检测法实验测试这些大量的寡核苷酸序列(存在于双链siRNA中)作为皮肤美白剂的潜力并获得本发明，其包括利用十种这样的寡核苷酸提供皮肤美白益处。
这十种寡核苷酸是：
它们的包含至少19个核苷酸的部分。
根据一个优选方面，包含至少19个核苷酸的部分是连续核苷酸(contiguousnucleotides)。
根据本发明，寡核苷酸大小为19至30个核苷酸长。用于提供本发明的益处的siRNA可以小至19个核苷酸长，在这种情况下，所需核苷酸可以是本发明中要求保护的序列(1)至(10)的任何部分。或者，所需寡核苷酸可以长达30个核苷酸长，其包含这十个序列中的任一整个，并另外包含连接在一个或两个末端上的几个核苷酸。
根据本发明的一个优选方面，该寡核苷酸为至少20个核苷酸长，优选至少22个，更优选至少25个核苷酸长。根据再一优选方面，该寡核苷酸为最多30个，更优选最多27个，再更优选最多25个核苷酸长。该寡核苷酸最优选为19至25个核苷酸长。根据本发明的再一优选方面，该寡核苷酸选自
该寡核苷酸优选是下列之一
该寡核苷酸更优选是下列之一
使用其中寡核苷酸的糖组分已化学修饰的siRNA在本发明的范围内。
根据本发明的一个优选方面，提供了皮肤美白组合物，其包含：
(a) 包含寡核苷酸的siRNA，所述寡核苷酸包含选自下列的序列
它们的包含至少19个核苷酸的部分；和
(b) 化妆品可接受的载体；
其中寡核苷酸大小为19至30个核苷酸。
根据本发明的再一优选方面，提供了皮肤美白组合物，其包含：
(a) 包含寡核苷酸的siRNA，所述寡核苷酸包含选自下列的序列
它们的包含至少20个核苷酸的部分；和
(b) 化妆品可接受的载体；
其中寡核苷酸大小为20至30个核苷酸。
在上述优选方面中，该寡核苷酸为至少20个核苷酸长，优选至少22，更优选至少25个核苷酸长。
根据本发明的另一方面，提供了皮肤美白组合物，其包含：
(a) 包含寡核苷酸的siRNA，所述寡核苷酸包含选自下列的序列
它们的包含至少19个核苷酸的部分；和
(b) 化妆品可接受的载体，其选自乳液、洗液、霜、泡沫、凝胶、皂条、棒、面膜、棉片或贴剂；
其中寡核苷酸大小为19至30个核苷酸。
该寡核苷酸优选以更安全和有效的量存在于该组合物中以便能明显改进皮肤美白效力。该寡核苷酸更优选以该组合物的0.00001至1重量%，更优选0.0001至0.01重量%存在。
该化妆品可接受的载体优选是乳液、洗液、霜、泡沫、凝胶、皂条、棒、面膜、棉片或贴剂，更优选是霜、凝胶或洗液。
当本发明的组合物是霜时，其优选包含3至25%脂肪酸。当本发明的组合物是洗液时，其优选包含1至20%脂肪酸。更优选的形式是霜，再更优选是雪花膏。雪花膏基质是包含1至25%，更优选5至20%脂肪酸的基质。该脂肪酸可以是饱和或不饱和的脂肪酸。该基质优选包含0.1至10%，更优选0.1至3%皂。C12至C20脂肪酸在雪花膏基质中尤其优选，再更优选的是C14至C18脂肪酸。在霜中，脂肪酸优选基本是硬脂酸和棕榈酸的混合物。雪花膏基质中的皂包括脂肪酸的碱金属盐，如钠或钾盐。该皂优选是脂肪酸混合物的钾盐。雪花膏基质中的脂肪酸通常使用hystric酸(其基本(通常大约90至95%)是硬脂酸和棕榈酸的混合物)制备。因此，包括hystric酸及其皂以制备雪花膏基质在本发明的范围内。该化妆品可接受的基质通常为该组合物的10至99.9重量%，优选50至99重量%。该化妆品可接受的基质优选包括水。优选以该组合物的35至90重量%，更优选50至85重量%，再更优选50至80重量%包括水。
本发明的组合物优选包含UV-A和/或UV-B防晒剂。这两种类型的有机防晒剂通常可获自下列主要类别：二苯甲酮、邻氨基苯甲酸酯、二苯甲酰甲烷、水杨酸酯、肉桂酸酯、樟脑和三嗪。
本发明的组合物优选包含UV-A防晒剂，其是二苯甲酰甲烷或其衍生物。最优选的二苯甲酰甲烷衍生物是4-叔丁基-4'-甲氧基二苯甲酰甲烷。
在本发明的组合物中优选包括油溶性的UV-B有机防晒剂。油溶性的UV-B防晒剂优选选自肉桂酸、水杨酸、二苯基水杨酸或其衍生物。可购得并可用于包含在本发明的组合物中的几种优选的油溶性UV-B防晒剂是OctisalateTM、HomosalateTM、NeoHelipanTM、OctocryleneTM、OxybenzoneTM或Parsol MCXTM。或者，在本发明的组合物中优选包括水溶性有机UVB防晒剂。优选的水溶性有机UVB防晒剂是苯基苯并咪唑磺酸。
本发明的组合物优选包含占该组合物总重量的按重量计0.1至5%，更优选0.2至5%，再更优选0.4至3%的UV-A和/或UV-B防晒剂，并包括其中包含的所有范围。
在本发明的组合物中可以包括光稳定剂。合适的光稳定化合物是二苯基丙烯酸酯、亚苄基樟脑、萘二甲酸酯(napthalate)、三嗪、芴或二芳基丁二烯类型的。
在本发明中可优选使用其它可用的防晒剂，例如无机防晒剂。这些包括例如氧化锌、氧化铁、二氧化硅如锻制二氧化硅，或二氧化钛。优选并入本发明的组合物中的防晒剂的总量为该组合物的0.1至5重量%。
本发明的组合物可另外包含皮肤美白剂。该皮肤美白剂优选选自维生素B3化合物或其衍生物，例如烟碱酸、烟酸、烟酰胺或其它公知的皮肤美白剂，例如芦荟提取物、乳酸铵、壬二酸、曲酸、柠檬酸酯、鞣花酸、乙醇酸、绿茶提取物、氢醌、柠檬提取物、亚油酸、抗坏血酸磷酸镁、维生素如维生素B6、维生素B12、维生素C、维生素A、二羧酸、间苯二酚衍生物、羟基羧酸如乳酸和它们的盐，例如乳酸钠，及其混合物。维生素B3化合物或其衍生物，例如烟碱酸、烟酸、烟酰胺是根据本发明更优选的皮肤美白剂，最优选的是烟酰胺。烟酰胺在使用时优选以该组合物的0.1至10重量%，更优选0.2至5重量%范围的量存在。
本发明的组合物还可包含其它稀释剂。稀释剂充当该组合物中存在的其它材料的分散剂或载体，以便在将该组合物施加到皮肤上时利于它们的分布。除了水以外的稀释剂可包括液体或固体润肤剂、溶剂、保湿剂、增稠剂和粉末。
本发明的组合物可包含常规除臭剂基质作为化妆品可接受的载体。除臭剂是指为个人除臭益处使用的、例如施加在腋下或任何其它区域的、可能含有或不含止汗活性剂的在棒、滚涂或推进剂介质中的产品。
除臭剂组合物通常可以是紧实固体、软固体、凝胶、霜和液体形式并使用适合该组合物的物理特性的涂施器分配。
本发明的组合物可包含多种其它任选组分。全文经此引用并入本文的CTFACosmetic Ingredient Handbook, 第2版, 1992描述了适用在本发明的组合物中的在护肤工业中常用的多种非限制性化妆品和药物成分。实例包括：抗氧化剂、粘合剂、生物添加剂、缓冲剂、着色剂、增稠剂、聚合物、收敛剂、香料、湿润剂、乳浊剂、调理剂、去角质剂、pH调节剂、防腐剂、天然提取物、香精油、皮肤感觉剂(skin sensates)、皮肤舒缓剂和皮肤愈合剂。
根据本发明的另一方面，提供了皮肤美白方法，其包括将本发明的皮肤美白组合物施加到皮肤的预期表面上的步骤。
本发明的组合物针对化妆品和护肤用途，因此优选不用于治疗/医疗用途。
现在借助下列非限制性实施例进一步描述本发明。
实施例
实施例1至10：用于量化siRNA序列的皮肤美白效力的黑色素含量检测
合成制备十种siRNA双链，其中一个链具有如下给出的寡核苷酸，并用来使用黑色素含量体外检测法评估作为皮肤美白剂的潜力。本领域技术人员清楚的是，规定单链就足以完全定义该双链siRNA。该体外检测如下进行：
检测包含下列寡核苷酸序列的siRNA：
。
siRNA转染
将原代人黑素细胞培养24小时。在培养基中用Mirus Trans IT-TKO转染试剂和双链体寡聚物转染细胞。细胞在增湿的CO2培养箱中在37℃下培养并在转染后96-144小时收获以进行黑色素含量和存活力检测。
存活力：在转染96、120、144或168小时后，除去培养基并将中性红(在黑素细胞培养基中50µg/ml)添加到细胞中并在CO2培养箱中在37℃下培养3小时。在培养结束时，细胞用1 x磷酸盐缓冲溶液(PBS)洗涤，使用解吸溶液(乙醇:水:冰醋酸，50:49:1)提取染料，并在540纳米下测量吸光度。
黑色素含量：在转染96、120、144或168小时后，除去培养基并将细胞溶解在200微升10% DMSO/1N NaOH中。在60℃下1小时后，在400纳米下测量吸光度。
计算：黑色素含量表示为与扰乱(scramble)处理细胞相比的%黑色素含量。
进行实验，关于黑色素含量的数据(作为对照样品的百分比)作为3个读数的平均值概括在表1中。已知曲酸在72小时内作用完全。
表1
| 实施例 | 浓度 (nM) | 时间点(小时) | %对照 黑色素 | 标准偏差 |
| SEQ ID:1 | 20 | 144 | 76 | 10 |
| SEQ ID:2 | 20 | 144 | 75 | 3 |
| SEQ ID:3 | 20 | 144 | 80 | 8 |
| SEQ ID:4 | 20 | 96 | 62 | 1 |
| SEQ ID:5 | 20 | 144 | 77 | 5 |
| SEQ ID:6 | 50 | 168 | 81 | 4 |
| SEQ ID:7 | 50 | 168 | 85 | 4 |
| SEQ ID:8 | 20 | 144 | 81 | 8 |
| SEQ ID:9 | 20 | 144 | 84 | 15 |
| SEQ ID:10 | 10 | 120 | 83 | 5 |
| 曲酸(对照) | 105 | 72 | 76 | 7 |
表1中的数据表明，本发明的组合物(SEQ ID:1至SEQ ID:10)提供良好的黑色素含量降低，与公知活性剂之一，即曲酸相当。本发明的优点在于siRNA可以以量级低于该化学活性剂的浓度使用。
Claims (6)
1.siRNA在制备用于美白皮肤的方法中的皮肤美白组合物的用途，所述方法包括将所述皮肤美白组合物施加到皮肤的预期表面上的步骤，其中所述siRNA包含寡核苷酸，所述寡核苷酸由选自下列的序列构成：
其中所述组合物进一步包含化妆品可接受的载体。
2.siRNA在制备用于美白皮肤方法中的皮肤美白组合物的用途，所述方法包括将皮肤美白组合物施加到皮肤的预期表面上的步骤，其中所述siRNA包含寡核苷酸，所述寡核苷酸由选自下列的序列构成：
SEQ ID：6 CAAUUCACCCACACUGUTC；
SEQ ID：8 GUUCAUGAUGCCAAAGGCCTG；
SEQ ID：9 UUCAUUGCUGUGAUCAUUCGC；和
其中所述组合物进一步包含化妆品可接受的载体，其选自乳液、洗液、霜、泡沫、凝胶、皂条、棒、面膜、棉片或贴剂。
3.如权利要求1中所述的用途，
其中所述寡核苷酸由选自下列的序列构成
SEQ ID：1 UCAAUGACCACAUAGAUAAGGUCUC；
SEQ ID：4 UAACAGCCGGACAAGAAGAUGAUGG；
SEQ ID：5 AAGAGGUUGAAGUUCUUGAAGAUGC；
或
其中所述寡核苷酸由选自下列的序列构成
SEQ ID：2 UACUCAUUAGUACUAUCGCUGCAGG；
SEQ ID：3 UUAGAAUCAUUCUUGAUGUCUCUGG；
SEQ ID：7 UUUAUUAAAGAUGCCACGUGG；
SEQ ID：10 UAGAAUCCCACCUUUACUCTG。
4.皮肤美白组合物，其包含：
(a1)包含寡核苷酸的siRNA，所述寡核苷酸由选自下列的序列构成
SEQ ID：1 UCAAUGACCACAUAGAUAAGGUCUC；
SEQ ID：4 UAACAGCCGGACAAGAAGAUGAUGG：
SEQ ID：5 AAGAGGUUGAAGUUCUUGAAGAUGC；
或
(a2)包含寡核苷酸的siRNA，所述寡核苷酸由选自下列的序列构成
SEQ ID：2 UACUCAUUAGUACUAUCGCUGCAGG：
SEQ ID：3 UUAGAAUCAUUCUUGAUGUCUCUGG；
SEQ ID：7 UUUAUUAAAGAUGCCACGUGG；
SEQ ID：10 UAGAAUCCCACCUUUACUCTG；和
(b)化妆品可接受的载体。
5.如权利要求4中所述的皮肤美白组合物，其中所述化妆品可接受的载体是霜、凝胶或洗液。
6.如权利要求4或5中所述的皮肤美白组合物，其中所述siRNA以所述组合物的0.00001至1重量％存在。
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| CN101917846B (zh) | 2007-11-06 | 2014-06-25 | 圣诺制药公司 | 用于皮肤伤口无疤痕愈合的多靶标RNAi治疗 |
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