CN103327957B - 亮肤组合物 - Google Patents
亮肤组合物 Download PDFInfo
- Publication number
- CN103327957B CN103327957B CN201180062278.6A CN201180062278A CN103327957B CN 103327957 B CN103327957 B CN 103327957B CN 201180062278 A CN201180062278 A CN 201180062278A CN 103327957 B CN103327957 B CN 103327957B
- Authority
- CN
- China
- Prior art keywords
- skin
- composition
- ketoconazole
- sulforaphen
- compositions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Abstract
期望的皮肤颜色是亚洲大多数消费者未被满足的需求。消费者特别期望均匀的皮肤颜色、无老年斑(日光性着色斑)和较浅的整体肤色。一个解决办法是使用能降低皮肤中黑素细胞活性的生物活性物质。存在于表皮的基底层中的这些细胞生成暗黑色色素黑色素并在被称为黑素体的小输出囊将其输出至临近的角化细胞。在文献中充分描述了减少黑色素合成的化合物当局部施用于皮肤时可减轻随时间经过的皮肤暗沉。本发明涉及一种用于亮肤的包含酮康唑和萝卜硫素增效组合的组合物。本发明基于的事实在于酮康唑和萝卜硫素的组合已被发现协同抑制B16单层培养物中色素的产生。因此该组合物,当局部施用或经过适当时长的体内吸收时,可期望使皮肤提亮,或减少瑕疵和/或色斑和/或日光性着色斑,从而改善皮肤颜色和均匀度。
Description
期望的皮肤颜色是亚洲大多数消费者未被满足的需求。消费者特别期望均匀的皮肤颜色、无老年斑(日光性着色斑)和较浅的整体肤色。一个解决办法是使用能降低皮肤中黑素细胞活性的生物活性物质。存在于表皮的基底层中的这些细胞生成暗黑色色素黑色素并在被称为黑素体的小输出囊将其输出至临近的角化细胞。在文献中充分描述了减少黑色素合成的化合物当局部施用于皮肤时可减轻随时间经过的皮肤暗沉。
本发明涉及一种用于亮肤的包含酮康唑和萝卜硫素增效组合的组合物。本发明基于的事实在于酮康唑和萝卜硫素的组合已被发现协同抑制B16单层培养物中色素的产生。因此该组合物,当局部施用或经过适当时长的体内吸收时,可期望使皮肤提亮,或减少瑕疵和/或色斑和/或日光性着色斑,从而改善皮肤颜色和均匀度。
酮康唑(例如Johnson&Johnson Inc.的NizoralTM和Janssen PharmaceuticaNV的DaktarinTMGold)以局部和口服非处方(OTC)制剂的形式销售用于治疗真菌疾病。
WO2007/072216A2公开了一个包括具有增强溶解性的治疗性唑类的治疗套装。该套装包括一个气雾剂包装组合,其具有一个容纳加压产品的容器和一个能够以泡沫的形式释放产品的出口。该加压产品是起泡组合物,其中含有治疗性唑类。在示例性的实施方案中,该治疗性唑类为选自包括酮康唑的组的咪唑或***。在一个或多个实施方案中,该起泡组合物还包含至少一种选自包括皮肤增白剂的组的附加的治疗剂。
在WO02/053108A2中,视黄酸被公开已用于治疗各种皮肤病包括老年斑和变色。抑制酰基辅酶A(CoA):视黄醇酰基转移酶/卵磷脂视黄醇酰基转移酶(ARAT/LRAT)、视黄醛还原酶、细胞视黄酸结合蛋白II(cellular retinoic acidbinding protein II(CRAB Pll))和视黄酸氧化(后者被细胞色素P450体系催化)的化合物,和其它增强视黄醇脱氢酶的化合物统称为“促进剂(booster)”。单独或相互结合的促进剂通过增加可用于转化为视黄酸的视黄醇的量并抑制视黄酸的降解来增强类维生素A的作用。酮康唑确认为视黄酸氧化抑制剂。
在Mun等(Biol.Pharm.Bull.,27(6),806-809(2004))中,公开了咪康唑对B16黑素瘤细胞中的黑素生成的抑制效应。与未处理的细胞相比,酪氨酸酶活性和黑色素含量因唑类而剂量依赖性降低,但是这也伴随着细胞活力的降低。
发明概述
在本发明的第一方面,提供了一种亮肤组合物,该组合物包含酮康唑和萝卜硫素。酮康唑具有下列结构:
酮康唑
而萝卜硫素具有下列结构:
萝卜硫素从十字花科蔬菜例如花椰菜获得。当植物受到损伤(例如由于咀嚼)时,酶-芥子酶将萝卜硫苷(glucoraphanin)(一种硫代葡萄糖苷)转化成萝卜硫素。花椰菜和菜花的嫩芽特别富含萝卜硫苷。
该亮肤组合物可包含0.001-2,优选0.005-0.5%w/w的酮康唑。该亮肤组合物可包含0.001-2,优选0.01-1%w/w的萝卜硫素。
萝卜硫素可以是L-异构体的形式,优选只是L-异构体的形式。
该亮肤组合物可以是口服或局部组合物的形式。
在本发明的第二方面,提供第一方面的组合物用于亮肤。在本方面的一个实施方案中,提供第一方面的组合物用于亮肤,其中使用该组合物使得酮康唑的每日口服剂量为50-200mg,优选50-100mg;萝卜硫素的每日口服剂量为50-600mg,优选200-400mg。
在替代方案中,提供了酮康唑和萝卜硫素用于制备用于亮肤的第一方面的组合物的用途。在该替代方案的另一实施方案中,提供了酮康唑和萝卜硫素用于制备用于亮肤的第一方面的组合物的用途,其中给予该组合物使得酮康唑的每日口服剂量为50-200mg,优选50-100mg;萝卜硫素的每日口服剂量为50-600mg,优选200-400mg。
在另一替代方案中,提供了一种提亮人体皮肤的方法,该方法包括有此需求的人吸收第一方面的组合物的步骤。在该另一替代方案的另一实施方案中,提供了一种提亮人体皮肤的方法,该方法包括有此需求的人吸收第一方面的组合物的步骤,使得酮康唑的每日剂量为50-200mg,优选50-100mg;萝卜硫素的每日剂量为50-600mg,优选200-400mg。
附图说明
参考下列附图说明本发明,其中:
图1显示与DMSO对照(左手边)相比,用1μM酮康唑处理14天的暗黑色的MelanoDermTM培养物(右手边),用Masson-Fontana染色显现黑色素的含量;
图2显示与DMSO对照(左手边)相比,用1μM酮康唑处理14天的暗黑色的MelanoDermTM培养物(右手边),用MART-免疫染色显现黑素细胞;和
图3显示与DMSO对照(左手边)相比,源自用1μM酮康唑处理5天后的深肤色捐献者的正常人黑素细胞的光学显微图像(右手边)。
发明详述
局部组合物
应该理解,商业上可接受的常规的媒介物可用于本发明的局部组合物,作为稀释剂、分散剂和/或载体用于本文所述的亮肤剂以及用于任何其它任选的但常常优选的成分。因此,适用于本发明的化妆品上可接受的媒介物可以是水基的、无水的或乳剂,其中一般优选油包水或水包油的乳剂。如果需要使用水,水通常补足组合物的余量,优选占该局部组合物的大约5-大约99重量%,最优选大约40-大约80重量%,包括其中纳入的所有范围。
除了水之外,可任选包括有机溶剂来作为本发明组合物中的载体或来辅助载体。适用于本发明的有机溶剂种类的说明性且非限制性的实例包括烷醇例如乙醇和异丙醇,及其混合物等。
其它适用的任选的添加剂包括酯油例如肉豆蔻酸异丙酯、肉豆蔻酸鲸蜡酯、肉豆蔻酸2-辛基十二烷基酯、鳄梨油、杏仁油、橄榄油、新戊二醇二癸酸酯及其混合物等。通常,这样的酯油有助于乳化本发明的组合物,且经常使用有效量以生成稳定乳剂,最优选油包水乳剂。
如果需要的话,也可以使用润肤剂作为本发明组合物中的载体。通常需要使用醇例如1-十六醇(即鲸蜡醇)以及一般归类为硅油和合成酯的润肤剂。适用的硅油包括含有3-9,优选4-5个硅原子的环状或直链聚二甲基硅氧烷。本文所述的本发明组合物中用作润肤剂物质的非挥发性硅油包括聚烷基硅氧烷、聚烷基芳基硅氧烷和聚醚硅氧烷共聚物。本文有用的基本不挥发的聚烷基硅氧烷包括例如聚二甲基硅氧烷。
可任选使用的酯类润肤剂为:
(1)具有10-20个碳原子的脂肪酸的烯基或烷基酯。其实例包括新戊酸异二十烷基酯、异壬酸异壬酯(isononyl isonanonoate)、肉豆蔻酸油烯基酯、硬脂酸油烯基酯和油酸油烯基酯。
(2)醚酯例如乙氧基化脂肪醇的脂肪酸酯。
(3)多元醇酯。乙二醇单和二脂肪酸酯、二甘醇单和二脂肪酸酯、聚乙二醇(200-6000)单和二脂肪酸酯、丙二醇单和二脂肪酸酯、聚丙二醇2000单油酸酯、聚丙二醇2000单硬脂酸酯、乙氧基化丙二醇单硬脂酸酯、甘油单和二脂肪酸酯、聚甘油多脂肪酸酯、乙氧基化甘油单硬脂酸酯、1,3-丁二醇单硬脂酸酯、1,3-丁二醇二硬脂酸酯、聚氧乙烯多元醇脂肪酸酯、失水山梨糖醇脂肪酸酯和聚氧乙烯失水山梨糖醇脂肪酸酯是令人满意的多元醇酯。
(4)蜡酯例如蜂蜡、鲸蜡油、硬脂酸十八烷基酯和山嵛酸二十烷基酯。
(5)甾醇酯,其中实例为胆固醇脂肪酸酯。
使用时,润肤剂通常占组合物的大约0.1-大约50重量%,包括其中纳入的所有范围。
也可以包含具有10-30个碳原子的脂肪酸作为本发明组合物中可接受的载体。这样的脂肪酸的说明性实例包括壬酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、异硬脂酸、油酸、亚油酸、花生酸、山嵛酸或芥子酸,及其混合物。据信增强皮肤渗透力的化合物,例如二甲亚砜,也可用作任选的载体。
多元醇类型的保湿剂也可用于本发明的组合物。保湿剂经常有助于增强润肤剂的有效性,减少起皮,促进积累的污垢的去除,并改善皮肤触感。典型的多元醇包括甘油、聚(亚烷基)二醇且更优选烷撑多元醇及其衍生物,包括丙二醇、二丙二醇、聚丙二醇、聚乙二醇及其衍生物、山梨糖醇、羟丙基山梨糖醇、己二醇、1,3-丁二醇、1,2,6-己三醇、乙氧基化甘油、丙氧基化甘油及其混合物。为达到最好的效果,保湿剂优选为丙二醇或透明质酸钠。以组合物的总重量计,保湿剂的量可以是组合物的0.2-25重量%,优选大约0.5-大约15重量%的范围内的任意值,包括其中纳入的所有范围。
增稠剂也可用作本发明组合物中可接受载体的一部分。典型的增稠剂包括交联的丙烯酸酯(例如Carbopol982)、疏水改性的丙烯酸酯(例如Carbopol1382)、纤维素衍生物和天然树胶。有用的纤维素衍生物中包括羧甲基纤维素钠、羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素和羟甲基纤维素。适用于本发明的天然树胶包括瓜尔胶、黄原胶、菌类植物胶、卡拉胶(carrageenan)、果胶以及这些树胶的组合。增稠剂的量可以是组合物的0.0-5重量%,通常0.001-1重量%,最优为0.01-0.5重量%。
水、溶剂、硅酮、酯、脂肪酸、保湿剂和/或增稠剂共同构成组合物的1-99.9重量%,优选80-99重量%的量的可接受的载体。
表面活性剂也可存在于本发明的组合物中。表面活性剂的总浓度为组合物的大约0-大约40重量%,优选大约0-大约20重量%,最优为大约0-大约5重量%。表面活性剂可选自阴离子型、非离子型、阳离子型和两性的活性物。特别优选的非离子表面活性剂是具有C10-C20脂肪醇或酸疏水物(每摩尔疏水物与2-100摩尔的环氧乙烷或环氧丙烷缩合)的那些;乙二醇的单和二脂肪酸酯;脂肪酸单甘油酯;失水山梨糖醇,单和二C8-C20脂肪酸;嵌段共聚物(环氧乙烷/环氧丙烷)和聚氧乙烯失水山梨糖醇及其组合。烷基多糖苷和糖脂肪酰胺(例如甲基葡糖酰胺)也是适合的非离子表面活性剂。
优选的阴离子表面活性剂包括皂、烷基醚硫酸盐和磺酸盐、烷基硫酸盐和磺酸盐、烷基苯磺酸盐、烷基和二烷基磺基琥珀酸盐、C8-C20酰基羟乙基磺酸盐、酰基谷氨酸盐、C8-C20烷基醚磷酸盐及其组合。
香料(perfume)可用于本发明的组合物。可用的香料类型的说明性非限制性实例包括包含萜烯和萜烯衍生物的那些,如Bauer,K.等人所著CommonFragrance and Flavor Materials,VCH Publishers(1990)中所述的那些。
可用于本发明的香料(fragrance)类型的说明性而非限制性的实例包括月桂烯、二氢月桂烯醇(dihydromyrenol)、柠檬醛、万寿菊酮、顺式香叶酸、香茅酸及其混合物等。
优选地,用于本发明组合物的香料的量为组合物的大约0.0%-大约10重量%,更优选大约0.00001%-大约5重量%,最优选大约0.0001%-大约2重量%。
各种类型的任选附加活性成分可用于本发明的组合物。活性物(actives)定义为除了润肤剂和除了仅改善组合物的物理特性的成分之外的皮肤有益剂。尽管不限于这种类型,通常实例包括滑石和二氧化硅以及α-羟基酸、β-羟基酸、锌盐和防晒剂。
β-羟基酸包括例如水杨酸。可用于本发明组合物的锌盐的一个实例为吡硫锌(Zinc pyrithione)。
防晒剂包括一般用于阻挡紫外线的那些材料。说明性的化合物是PABA的衍生物、肉桂酸酯和水杨酸酯。例如,可以使用avobenzophenone(Parsol)、甲氧基肉桂酸辛酯和2-羟基-4-甲氧基二苯甲酮(也称作氧苯酮)。甲氧基肉桂酸辛酯和2-羟基-4-甲氧基二苯甲酮分别以商标名Parsol MCX和Benzophenone-3市售。用于组合物的防晒剂的精确量可以根据希望对太阳的紫外辐射的防护程度而变化。也可以使用反射或散射太阳光线的添加剂。这些添加剂包括氧化物,如氧化锌和二氧化钛。
许多组合物,尤其是含水的那些,应该防止潜在有害微生物的生长。抗微生物化合物(例如三氯生)和防腐剂因此通常是必需的。适合的防腐剂包括对羟基苯甲酸的烷基酯、乙内酰脲衍生物、丙酸盐和各种季铵化合物。本发明特别优选的防腐剂是对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯氧乙醇和苯甲醇。防腐剂通常用量为组合物的大约0.1%-2重量%。
可以与本发明组合物一起使用的另外的其他任选成分包括二酸(例如丙二酸和癸二酸)、抗氧化剂例如维生素E、类维生素A,包括视黄酸、视黄醛、视黄醇和视黄酯、共轭亚油酸、岩芹酸及其混合物,以及任何已知用于减少皱纹、消除痤疮和降低皮脂影响的其他常规成分。
当制备本发明的组合物时,所需成分通常在大气压下在大约70-大约80℃的温度下按照非特定的顺序混合。
本发明组合物的包装可以是贴片、瓶子、管、滚珠施用器、推进剂驱动的气雾剂装置、挤压容器或带盖的罐子。
口服组合物
本发明的口服组合物可以是胶囊、丸剂、片剂、颗粒剂、溶液、混悬液或乳剂的形式。
如果组合物是水基的,即包含至少70%w/w的水,其具有常规水基产品的感觉并因此可经常作为消费者的正常饮食的一部分被食用。例如其可取代通常在早餐食用的果汁。水基组合物优选在1s-1剪切速率和25摄氏度下具有2-100厘泊的粘度。
该组合物可包含0.2-10%,优选0.4-5%w/w的油。该油可包含至少12,优选至少20%w/w的二十碳五烯酸(EPA)和二十二碳六烯酸(DHA),二者都是ω-3多不饱和酸并且称为鱼油。增加EPA的摄入已经表明有益于冠心病、高血压和炎症性疾病例如类风湿性关节炎。
为了防止或减慢鱼油的天然氧化降解,抗氧化剂是必需的。尽管非排他性的,适合的抗氧化剂可以选自下面的列表(单独或组合):叔丁基对苯二酚(TBHQ)、抗坏血酸酯例如棕榈酸抗坏血酸酯、抗坏血酸、生育酚、迷迭香提取物、水果浓缩物或提取物、红茶或绿茶提取物、没食子酸丙酯、精油或含油树脂、丁基羟基茴香醚(BHA)、二丁基羟基甲苯(BHT)、柠檬酸或酯、辅酶Q10、生育三烯酚(tocotrienols)、多酚、酚类化合物和黄酮类化合物。特别优选的抗氧化剂是维生素C和E。这些不仅是有效的抗氧化剂,而且当被食用时,也已经显示可带来皮肤益处。
应加入足量的抗氧化剂以防止鱼油在通常6个月的货架期内发臭。显然抗氧化剂的量将取决于所用的抗氧化剂的种类和活性。然而,该产品优选具有1∶10-1∶100的抗氧化剂与油的比例(基于维生素C的抗氧化活性)。为此,利用适当的试验测定抗氧化活性例如Trolox等价抗氧化能力。
已经发现,至少0.01%,优选0.05-3%,更优选0.1-1%w/w的磷脂乳化剂,例如卵磷脂,适于乳化大量的鱼油。
该组合物还可包含0.01-0.5%,优选0.01-0.3%w/w的大豆异黄酮。大豆异黄酮是大豆内的组分,具有与***相似的生物功能,包括促进真皮基质蛋白合成。此外,它们也已经显示具有消炎的特性并能刺激透明质酸(皮肤中的蛋白聚糖,其可保持水分并因此影响皮肤的紧致度)的合成。大豆异黄酮优选选自染料木素和大豆苷元。
该组合物还可包含0.0005-0.1%,优选0.002-0.04%w/w的类胡萝卜素。油溶性的类胡萝卜素可在油相内占主要部分。极为优选的类胡萝卜素是β-胡萝卜素和番茄红素。这些类胡萝卜素提供对引起红斑的紫外的适度防护,据信是由于它们的抗氧化功能包括清除活性氧族。
该组合物由分离的水相和油相制得。一般来说,水溶性的成分结合在一起来形成水相,而油溶性的成分结合在一起来形成油相。接着两相混合在一起来形成均质的稳定的乳剂。然后该稳定的乳剂可包装在密封的容器例如金属、带有涂层的纸板例如销售的Tetra PakTM或塑料容器中。然后该容器优选被密封从而没有顶部空间或没有气体(例如氮气或二氧化碳)填充顶部空间。这还有助于防止鱼油氧化。或者该乳剂可以被冷冻并包装并作为冷冻消费品销售。
酮康唑的亮肤效果的体外研究
材料
MelanoDermTM培养物
MatTek MelanoDermTM培养物(有色3D-活体皮肤等效(LSE)模型)购自MatTek Corporation。在用于良好色素生成同时保持可接受的组织学的长期维持培养基(EPI-100-LLMM,获自MatTek Corporation)中制备用于评价亮肤潜力的Dark培养物(MEL-300-B)。
得到样品后,将其放回生长培养基并在施行测试项目前在37℃下保持2小时来恢复。通过添加至生长培养基来将受试活性物施用于样品。只含有二甲基亚砜(DMSO)或受试活性物的新鲜生长培养基每2-3天替换,培养物在收获和分析之前以这种方式生长14天。在提取或固定之前,利用WST-1细胞增殖试验分析培养物。
B16单层培养物
在37℃,5%CO2下,在T175组织培养瓶中,在添加有10%胎牛血清(FCS)和2mM L-谷氨酰胺的伊格尔最小必需培养基(Eagle′s minimal essential medium(EMEM))中培养B16小鼠黑素瘤细胞,并利用EDTA中的胰蛋白酶每周两次继代培养。为了分析,将25000细胞/孔(500μl体积)接种到48孔板并粘附整晚。第二天早上用EMEM取代标准培养基,加入10%FCS,4mM L-谷氨酰胺(500μl)和受试活性物。接着将细胞培养72小时。72小时之后上清液被移除并通过光谱法在450nm依据参考标准曲线分析黑色素含量。在4℃下将B16细胞单层溶解在TritonTM/PBS中20分钟,在4℃和13000rpm下离心5分钟并利用标准二喹啉甲酸试验(bicinchoninic acid assay(BCA))分析依据参考标准曲线分析总蛋白含量。黑色素结果规范化为总蛋白。
正常人体黑素细胞
主要人体黑素细胞从Invitrogen Cascade Biologics(HEMn-DP)获得并根据生厂商的说明在Cascade黑素细胞培养基(M-254CF-500+人黑素细胞生长添加剂(HMGS)添加剂含有佛波醇肉豆蔻酸酯乙酸酯(PMA))中生长。一旦建立,培养物在T175组织培养瓶中常规生长并且通常可传代使用达6(P6)或7(P7)次。一旦细胞达到大约70%融合,将其用胰蛋白酶处理,旋转减慢并重新悬浮于适当体积的培养基中准备用于平板接种。细胞以每孔2×105细胞接种于6孔板并在每孔2ml培养基中培养。在进行处理之前,使细胞经过16小时来沉降在盖片上。用DMSO媒介物或溶解在DMSO中的受试活性物处理细胞5天并拍摄光学显微图像。
唑类
酮康唑、氟康唑、咪唑、噁唑和噻唑获自SigmaAldrich Company Limited。
方法
黑色素定量
根据由MatTek推荐的(可溶物提取方案)用称作SolvableTM(获自Perkin-Elmer)的专利溶剂作为提取溶剂来测定培养物的黑色素含量。如前所述提取蛋白质并用BCA分析定量。
组织学分析
后处理和WST-1分析培养物在中性缓冲***(NBF)中固定4小时并组织处理以提供***固定的石蜡包埋(FFPE)的组织块。将各培养物对切并包埋在同一石蜡包埋块中,从而当切片时,一个石蜡切片提供两个非连续的培养物切片。切割FFPE组织以每块提供4个载玻片,每个载玻片上含有两个非连续的切片/载玻片。成套玻片经受用抗黑素细胞标记物MART-1(Abcam Plc)的抗体的免疫染色,或用Masson Fontana染色并捕获代表性的图像。
结果
B16单层培养物中的黑素生成
各受试活性物在DMSO中施用于培养物(n=3)。结果总结在表1中。
表1:获自B16单层培养物的规范化黑色素(每mg蛋白质)(第一个DMSO对照只涉及酮康唑结果,而第二个DMSO对照涉及剩余结果)
MelanoDermTM培养物中的黑素生成
将酮康唑在DMSO中施用于培养物(n=6)。各处理组中的三个培养物提取用于黑色素和蛋白质定量,将三个培养物固定,蜡包埋,切片并染色以显现组织的完整性(H&E)和黑色素(Fontana-Masson)。规范化的黑色素(每mg蛋白质)的结果总结在表2中。
表2:获自MelanoDermTM培养物的规范化黑色素(每mg蛋白质)
所有处理的总提取蛋白浓度相对一致(数据未显示),表明对培养物没有任何实质上的细胞毒性效应。
组织学分析
图1显示提取自用1μm酮康唑处理过的培养物的规范化的黑色素持续降低可提取黑色素的水平并对基底黑素细胞的黑色素含量具有明显的影响,如Masson-Fontana染色后所示。
图2采用抗黑素细胞标记物MART-1的抗体的免疫染色显示图1中没有Masson-Fontana染色的黑色素不是由于黑素细胞从这些培养物中消失。
酮康唑对单层培养物中正常人黑素细胞(NHM)的生长和形态学的评价
单层培养物中生长的NHMs用1μm酮康唑处理5天并用光学显微镜评估。图3所示的结果表明,没有证据表明处理对NHM形态或增殖具有不利的影响。特别是,可以看出对于用酮康唑处理过的NHMs,双极细胞(正常细胞)的比例几乎与对照相同。
结论
1μm的酮康唑非常有效地抑制B16单层培养物和MelanoDermTM培养物中的黑色素生成。而且在该剂量下对单层人黑素细胞或表皮培养物的活力没有可察觉的影响。令人惊奇地,其它唑类特别是氟康唑、咪唑、噁唑和噻唑没有有效抑制B16单层培养物中的黑色素性成。
体外递送酮康唑至人体皮肤
方法
该项研究量化了在施用含有2%(w/w)酮康唑(DaktarinTMGold)的乳膏制剂后的体外人体皮肤渗透性。准备8个扩散池(使用来自三个捐献者的女性腹部皮肤)和3个未给药的对照池(用于分析确认目的)。使用表皮膜并通过测量电阻评价其完整性。目标施用5 mg/cm2剂量后测定24小时内活性物的渗透。开发了适合的液相色谱分析试验,从源自制剂、皮肤和胶带条的峰中分离出活性物的峰。
通过测定角质层(胶带条)和表皮加上任何剩余的下角质层(胶带剥离后)中活性物的含量来确定24小时时在皮肤内的分布。在胶带剥离之前擦洗皮肤以除去表面上残留的活性物。同时测定供体室密封脂内和供体室上的含量(供体室清洗)。
结果
结果列于下列表3中。
表3:24小时后由体外递送至人体皮肤内回收的酮康唑(n=8)
还包括胶带剥离之后任何残留的角质层残留物
结论
表明酮康唑低量但充分递送至人体皮肤。
酮康唑和萝卜硫素的组合
方法
从ATCC获得B16F10细胞(小鼠黑色素瘤细胞系)并在Lonza BiowhittakerBE12-662F培养基中生长。使用乙二胺四乙酸(EDTA)中的胰蛋白酶(SigmaT3924)和杜氏磷酸盐缓冲盐水(Dulbecco′s Phosphate Buffered Saline(DPBS))(SigmaD8537)分离细胞。在无酚红培养基(Sigma D1145)中在48孔板中以2.5×104细胞每孔的浓度构建平板。
过夜培养后,移除培养基,加入培养基和DMSO中的萝卜硫素(获自Sigma-Aldrich Company Limited,至少95%的L-萝卜硫素)和DMSO中的酮康唑溶液。向48孔板的4个孔中添加500μl的培养基和溶液并将板在37℃再培养3天。此后测定黑色素浓度和细胞数量。
通过每天配制标准品并将100μl的各标准品(一式两份)移液到Greiner板上来测定黑色素浓度。对于空白板,使用无酚红的培养基。来自各孔的100μl也被移液(一式两份)到Greiner板上并在450nm在Dynex板读取器(Dynex platereader)上读取板。
通过用磷酸盐缓冲液(PBS)清洗孔两遍来测定细胞数量。然后将1mL以1∶10v/v的比例在PBS中稀释的胰蛋白酶EDTA添加到各孔并观察孔中的细胞分离。然后收集来自各孔的所有培养基,通过把100μl的培养基加入到9.9ml的Coulter Isoton II稀释液中来分析该培养基。用Z1Coulter Particle Counter评估细胞数量。
结果
结果总结在表5中。
表5:每个细胞的黑色素(μg)
结论
在该体外试验中,通过组合L-萝卜硫素和酮康唑,显示在降低每个细胞的黑色素含量方面具有明显的协同作用。
Claims (13)
1.亮肤组合物,其包含酮康唑和萝卜硫素。
2.如权利要求1所述的亮肤组合物,其包含0.001-2% w/w的酮康唑。
3.如权利要求1或权利要求2所述的亮肤组合物,其包含0.001-2% w/w的萝卜硫素。
4.如权利要求1或权利要求2所述的亮肤组合物,其中萝卜硫素是L-异构体的形式。
5.如权利要求1或权利要求2所述的亮肤组合物,其为口服组合物或局部组合物的形式。
6.如权利要求3所述的亮肤组合物,其为口服组合物或局部组合物的形式。
7.如权利要求4所述的亮肤组合物,其为口服组合物或局部组合物的形式。
8.用于亮肤的如权利要求1或权利要求2所述的组合物,其中使用所述该组合物使得酮康唑的每日口服剂量为50-200mg;而萝卜硫素的每日口服剂量为50-600mg。
9.用于亮肤的如权利要求3所述的组合物,其中使用所述该组合物使得酮康唑的每日口服剂量为50-200mg;而萝卜硫素的每日口服剂量为50-600mg。
10.用于亮肤的如权利要求4所述的组合物,其中使用所述该组合物使得酮康唑的每日口服剂量为50-200mg;而萝卜硫素的每日口服剂量为50-600mg。
11.用于亮肤的如权利要求5所述的组合物,其中使用所述该组合物使得酮康唑的每日口服剂量为50-200mg;而萝卜硫素的每日口服剂量为50-600mg。
12.用于亮肤的如权利要求6或权利要求7所述的组合物,其中使用所述该组合物使得酮康唑的每日口服剂量为50-200mg;而萝卜硫素的每日口服剂量为50-600mg。
13.酮康唑和萝卜硫素用于制备用于亮肤的如权利要求1-5中任一项所述的组合物的用途,其中给予所述组合物使得酮康唑的每日口服剂量为50-200mg;而萝卜硫素的每日口服剂量为50-600mg。
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WO2002058664A1 (fr) * | 2001-01-26 | 2002-08-01 | Lmd | Utilisation d'un isothiocyanate, d'un thiocyanate ou de leur melange en tant que depigmentant |
CN1482899A (zh) * | 2000-12-28 | 2004-03-17 | 在双室包装中含有类维生素a、类维生素a增效剂和植物***的皮肤护理产品 | |
CN101267804A (zh) * | 2003-12-16 | 2008-09-17 | 弗米克斯有限公司 | 含油的药物和化妆品泡沫 |
EP2163238A2 (de) * | 2008-09-15 | 2010-03-17 | Henkel AG & Co. KGaA | Zusammensetzung zur Hautaufhellung enthaltend Sulforaphan oder Sulforaphen oder deren Derivate |
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KR100432449B1 (ko) * | 2001-11-30 | 2004-05-22 | 우원홍 | 케토코나졸 함유 피부 미백용 외용제 조성물 |
US20050186142A1 (en) | 2002-10-25 | 2005-08-25 | Foamix Ltd. | Kit and composition of imidazole with enhanced bioavailability |
FR2902325B1 (fr) * | 2006-06-20 | 2009-12-04 | Oreal | Utilisation de 3h-1,2-dithiole-3-thione, d'anethole dithiomlethione, de sulforaphe, de phenethyl isothiocyanate, de 6-methyle-sulphinyl)hexyl isothiocyanate et d'allyl isothiocyanate pour le traitement de la canitie |
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WO2002058664A1 (fr) * | 2001-01-26 | 2002-08-01 | Lmd | Utilisation d'un isothiocyanate, d'un thiocyanate ou de leur melange en tant que depigmentant |
CN101267804A (zh) * | 2003-12-16 | 2008-09-17 | 弗米克斯有限公司 | 含油的药物和化妆品泡沫 |
EP2163238A2 (de) * | 2008-09-15 | 2010-03-17 | Henkel AG & Co. KGaA | Zusammensetzung zur Hautaufhellung enthaltend Sulforaphan oder Sulforaphen oder deren Derivate |
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