CN101184532A - 减少毛发生长 - Google Patents
减少毛发生长 Download PDFInfo
- Publication number
- CN101184532A CN101184532A CNA2006800188989A CN200680018898A CN101184532A CN 101184532 A CN101184532 A CN 101184532A CN A2006800188989 A CNA2006800188989 A CN A2006800188989A CN 200680018898 A CN200680018898 A CN 200680018898A CN 101184532 A CN101184532 A CN 101184532A
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- Prior art keywords
- ester
- agonist
- acid
- hair growth
- buddhist nun
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Abstract
本发明涉及通过施用法尼酯X受体激动剂来减少哺乳动物的毛发生长。
Description
发明背景
本发明涉及减少哺乳动物的毛发生长，尤其是为了美容的目的。
哺乳动物毛发的主要功能是提供环境保护。然而，人类已经在很大程度上丧失了那种功能。对人类来说，保留毛发或从身体的多个部位去除毛发基本上是出于美容的原因。例如，通常优选在头皮上留有毛发，而不在脸上蓄有毛发。
人们已经使用了多种方法来移除多余的毛发，这些方法包括剃刮、电蚀除毛、脱毛膏或洗剂、热蜡、拔除和使用治疗性的抗雄激素。这些常规方法通常具有相关缺点。例如，剃刮会引起割伤和切口，并且会产生毛发再生速度增大的感觉。剃刮也会留下令人不悦的硬茬。另一方面，电蚀除毛会使已处理区域在很长的一段时间内没有毛发，但是电蚀除毛不仅会很昂贵和痛苦，而且有时还会留下疤痕。脱毛膏尽管很有效，但是由于它们具有高的潜在刺激性，因此典型地不建议频繁使用。用热蜡除去毛发和拔除毛发会引起疼痛和不适，并且对短毛发的脱除效果较差。最后，已用于治疗女性多毛症的抗雄激素会产生有害的副作用。
先前已经公开通过将某些酶的抑制剂涂敷到皮肤上来改变毛发生长的速度和特征。这些抑制剂包括抑制剂5-α还原酶(参见例如Breuer等人的美国专利4,885,289)、鸟氨酸脱羧酶(参见例如Shander的美国专利4,720,489)、S-腺苷甲硫氨酸脱羧酶(参见例如Shander的美国专利5,132,293)；腺苷酸琥珀酸合酶(参见例如Ahluwalia的美国专利5,095,007)；天冬氨酸盐转氨甲酰酶(参见例如Ahluwalia的美国专利5,095,007)；γ-谷酰基转肽酶(参见例如Ahluwalia等人的美国专利5,096,911)；谷氨酰胺转移酶(参见例如Shander等人的美国专利5,143,925)；L-天冬酰胺合成酶(参见例如Ahluwalia的美国专利5,444,090)；5-脂氧合酶(参见例如Ahluwalia等人的美国专利6,239,170)；环加氧酶(参见例如Ahluwalia等人的美国专利6,248,751)；一氧化一氮合酶(参见例如Ahluwalia等人的美国专利5,468,476)；鸟氨酸氨基转移酶(参见例如Shander等人的美国专利5,474,763)半胱氨酸合成路径酶，包括L-甲硫氨酸S-腺苷转移酶。L-巯基丁氨酸S-甲基转移酶、S-腺苷巯基丁氨酸水解酶、丙氨酸丁氨酸硫醚合酶和胱硫醚酶(参见例如Ahluwalia等人的美国专利5,455,234)；胆固醇合成路径酶包括HMGCoA还原酶和角鲨烯合成酶(参见例如Henry等人的美国专利5840752)；蛋白质激酶C(参见例如Ahluwalia等人的美国专利5,554,608)；精氨酸酶(参见例如Shander等人的美国专利5,728,736)；基质金属蛋白酶(参见例如Styczynski等人的美国专利5,962,466)；DNA拓扑异构酶(参见例如Styczynski等人的美国专利6,037,326)；氨酰-tRNA合成酶(参见例如Henry等人的美国专利5,939,458)；羧腐胺赖氨酸生物合成路径酶包括脱氧羧腐胺赖氨酸合酶和脱氧羧腐胺赖氨酸羟化酶(参见例如Styczynski等人的美国专利6,060,471)；碱性磷酸酶(参见例如Styczynski等人的美国专利6,020,006)；和蛋白质酪氨酸激酶(参见例如Henry等人的美国专利6,121,269)。
美国专利5,908,867(Henry等人)描述了通过抑制糖蛋白、蛋白聚糖或糖胺聚糖的形成来减少哺乳动物的毛发生长的方法，例如通过使用N-乙酰基葡糖胺-焦磷酰基-多萜基、软骨素硫酸根、角蛋白硫酸根、皮肤素硫酸根、类肝素硫酸根、肝素、透明质酸合成抑制剂，Glc3Man9-(GlcNAc)2-PP-多萜醇或糖胺聚糖透明质酸形成抑制剂，Glc3Man9-(GlcNAc)2转移抑制剂，葡糖苷酶I、葡糖苷酶II、甘露糖苷酶I、甘露糖苷酶II，和β-半乳糖苷酶酶抑制剂以及影响蛋白聚糖胞泌作用的化合物。
美国专利5,652,273、5,824,665和6,218,435(均授予Henry等人)描述了通过抑制用于将葡萄糖转变成乙酰基-Co-A的代谢途径来减少哺乳动物的毛发生长的多种方法。这可通过特别是抑制己糖激酶、果糖磷酸激酶、醛缩酶、磷酸甘油酸酯激酶、烯醇酶、丙酮酸激酶或丙酮酸脱氢酶或通过葡萄糖传送的抑制剂起作用。
用于调节毛发生长的其它方法包括诱导或活化雄性激素共轭作用的化合物的使用，例如Styczynski等人在美国专利5,958,946中所述；增加细胞神经酰胺含量化合物的使用，例如Styczynski等人在美国专利6,235,737中所述；非甾族血管形成抑制剂的使用，例如Ahluwalia在美国专利6,093,748中所述；儿茶素化合物的使用，例如在美国专利5,674,477和5,776,442(Ahluwalia)中所述；巯基反应性化合物的使用，例如Shander等人在美国专利5,411,991中所述；以及泛酸或其类似物的使用，例如Ahluwalia等人在美国专利5,364,885中所述。PCT公布WO03086331(Ahluwalia等人)公开了哺乳动物的毛发生长可通过局部应用脂肪酸代谢抑制剂而减少。PCT公布WO 2005/051335(Hwang等人)描述了使用前列腺素DP受体激动剂用于减少毛发生长。
法尼酯X受体(也称为“FXR”、“RIP14”、“胆汁酸受体”、“BAR”、“HRR1”和“NR1H4”)是配体活化的转录因子家族中的一元，所述转录因子结合到它们目标基因的启动子上的具体的顺式作用调节单元并调节对配体相应的基因表达。一些这些受体以由相同受体的两个分子组成的二聚体(同型二聚体)结合到它们目标基因上，而其它的受体以由两个不同的受体每分子一个组成的二聚体(异型二聚体)结合到它们目标基因上。法尼酯X受体与所述类视色素X受体(RXR)形成异型二聚体并在其目标基因启动子中结合到被一种核苷酸间隔的反向六核苷酸重复序列上。法尼酯X受体通过与配体如法尼酯和胆汁酸交互作用被活化。此外，在所述配体活化的法尼酯X受体和所述基础转录工具之间桥接，和/或改变染色质结构的共激活剂(DRIP205/TRAP220、SRC-1和PGC-1alpha)，可提高法尼酯X受体的转录活性。
法尼酯X受体通过调节涉及胆汁酸合成和传送的基因表达将有助于保持胆汁酸内稳态。胆汁酸是胆固醇分解代谢的最终产物。胆汁酸的合成是分泌过剩胆固醇的主要机理。人体内大多数胆汁酸是鹅去氧胆酸、胆酸、脱氧胆酸、胆烷和石胆酸。当胆汁酸含量增加时，法尼酯X受体被激活，并增量调节胆汁盐输出泵的表达，所述输出泵是形成胆汁酸分泌的原因。除了胆汁酸分泌，胆汁酸活化的法尼酯X受体抑制胆固醇7α-羟化酶(CYP7A1)的转录，其是在胆汁酸生物合成途径中的限速酶。
发明概述
在一个方面，本发明提供了一种减少哺乳动物(优选人类)多余的毛发生长的方法(典型为美容方法)。该方法通过向皮肤施用有效量的法尼酯X受体激动剂来减少毛发生长。优选地，所述激动剂与法尼酯X受体强烈地相互作用。从美容观点上看，多余的毛发生长是不受欢迎的。
在另一个方面，本发明提供了通过向所述皮肤上涂敷选自由胆汁酸、胆汁酸类似物和胆汁酸衍生物组成的组的化合物来减少哺乳动物多余的毛发生长的方法。
在另一个方面，本发明提供了通过向所述皮肤上涂敷选自由法尼酯、法尼酯类似物和法尼酯衍生物组成的组的化合物来减少哺乳动物多余的毛发生长的方法。
在另一个方面，本发明提供了通过向所述皮肤上涂敷增加FXR-RXR异型二聚体的形成，增加法尼酯X受体表达，或促进共激活剂补充并且促进与FXR-RXR异型二聚体交互作用的化合物，来减少哺乳动物多余的毛发生长的方法。
在另一个方面，本发明提供了一种通过施用任何上述激动剂/化合物来提供脱皮有益效果的方法。
在上述方法的实施中，所述激动剂/化合物通常连同皮肤病学或美容上可接受的载体一起被包含在局部用组合物中。因此，本发明还涉及包含皮肤病学或美容上可接受的载体和法尼酯X受体激动剂的局部用组合物。本发明还涉及局部用组合物，所述组合物包含皮肤病学或美容上可接受的载体和(a)选自由下列组成的组的化合物：胆汁酸、胆汁酸类似物或衍生物；(b)选自由下列组成的组的化合物：法尼酯、法尼酯类似物或衍生物；和/或(c)增加FXR-RXR异型二聚体的形成，增加法尼酯X受体表达，或促进共激活剂补充并且促进与FXR-RXR异型二聚体交互作用的化合物。
此外，本发明涉及使用法尼酯X受体激动剂来制备用于减少毛发生长的治疗性局部用组合物。此外，本发明涉及使用化合物来制备用于减少毛发生长的治疗性局部用组合物，其中所述化合物是(a)选自由下列组成的组的化合物：胆汁酸、胆汁酸类似物或衍生物；(b)选自由下列组成的组的化合物：法尼酯、法尼酯类似物或衍生物；和/或(c)增加FXR-RXR异型二聚体的形成，增加法尼酯X受体表达，或促进共激活剂补充并且促进与FXR-RXR异型二聚体交互作用的化合物。
在一些实施方案中，所述激动剂/化合物不是-二氟甲基鸟氨酸的氨基甲酸盐或酯。-二氟甲基鸟氨酸的氨基甲酸盐、酯和其它缀合物描述于U.S.S.N.10/397,132，其提交于2003年3月26日，由与本申请相同的所有者所拥有，并因此以引用的方式并入本文中。
如本文所用的“法尼酯X受体激动剂”的意思是活化法尼酯X受体的化合物。
与所述法尼酯X受体“强烈相互作用”的激动剂是用上述亲和力结合所述受体的那个。它引起响应，所述响应至少大约与由法尼酯引起的相当(在大小上)。
具体的化合物包括化合物本身和所述化合物在药理学上可接受的盐。
通过阅读发明详述和所述的权利要求，本发明其它的特点和优点是显而易见的。
发明详述
优选的组合物的实例包括至少一种在美容和/或皮肤病学可接受的载体中的法尼酯X受体激动剂。所述组合物可以为固体、半固体或液体。所述组合物可以为例如油膏剂、洗剂、泡沫、霜膏、凝胶或溶液形式的美容的和皮肤病学的产品。所述组合物也可是剃须制品、须后水或止汗剂的形式。载体本身可以是惰性的，或者它可以拥有它自己的美容、生理学和/或制药学有益效果。
法尼酯X受体激动剂的实例包括胆汁酸、法尼酯、它们的类似物和衍生物、以及其它化合物。
胆汁酸的衍生物和类似物是已知的。例如，J.Med.Chem.(2004年)，第47卷，第4559至4569页描述了胆汁酸衍生物。J.Biol.Chem.(2004年)，第279(10)卷，第8856至8861页描述了不同的胆汁酸。法尼酯的衍生物和类似物是已知的。例如，美国专利6187814描述了法尼酯衍生物。法尼酯X受体激动剂的其它实例描述于WO2004007521、WO03015771、WO2004048349、WO03076418、WO2004046162、WO03060078、WO02072598、WO03080803、WO2003086303、WO2004046068、美国专利20030187042、美国专利0040176426、美国专利20040180942、美国专利6452032、美国专利2003203939、美国专利2005004165、J.med.Chem.(2000年)，第43(6)卷，2971至2974页，Mol.Gen.Met.(2004年)，第83卷，第184至187页、Drugs for the future(1999年)，第24(4)卷，第431至438页，Current Pharmaceutical Design(2001年)，第7卷，第231至259页。包含在FXR-RXR异型二聚体中的共激活剂的实例描述于Genes&Dev.(2004年)，第18卷，第157至169页和J.Biol.Chem.(2004年)，第279(35)卷，第36184至36191页。所有这些文献均以引用的方式并入本文中。
法尼酯X受体激动剂具体的实例提供于表I中。
表I：
法尼酯X受体激动剂实例
所述组合物可包含不止一种法尼酯X受体激动剂。此外，所述组合物可包括一种或多种其它类型的毛发生长减少剂，例如在美国专利4,885,289、美国专利4,720,489、美国专利5,132,293、美国专利5,096,911、美国专利5,095,007、美国专利5,143,925、美国专利5,328,686、美国专利5,440,090、美国专利5,364,885、美国专利5,411,991、美国专利5,648,394、美国专利5,468,476、美国专利5,475,763、美国专利5,554,608、美国专利5,674,477、美国专利5,728,736、美国专利5,652,273、WO 94/27586、WO 94/27563和WO98/03149中所描述的那些，这些专利均以引用的方式并入本文中。
组合物中激动剂的浓度可以在最大为饱和溶液的宽范围内变化，按重量计优选为0.1％至30％，或甚至更多；毛发生长的减少随着每单位面积皮肤上所应用的激动剂量的增加而增大。有效应用的最大量仅受到激动剂渗入皮肤的速度的限制。有效量可以在例如每平方厘米皮肤10至3000微克或更多的范围内变化。
载体可以是惰性的，或者它可以拥有它自己的美容、生理学和/或制药学有益效果。载体可以与液体或固体润肤剂、溶剂、增稠剂、湿润剂和/或粉末一起配制。润肤剂包括硬脂醇、貂油、鲸蜡醇、油醇、月桂酸异丙酯、聚乙二醇、石油凝胶、棕榈酸、油酸和肉豆蔻酸十四烷基酯。溶剂包括乙醇、异丙醇、丙酮、二甘醇、乙二醇、二甲基亚砜和二甲基甲酰胺。
所述组合物任选地可包括增强激动剂渗透入皮肤和/或渗透至作用位置的组分。渗透增强剂的实例包括脲、聚氧乙烯醚(例如，Brij-30和月桂基聚氧乙烯醚-4)、3-羟基-3，7，11-三甲基-1，6，10-十二碳三烯、萜烯、顺式脂肪酸(例如，油酸、棕榈油酸)、丙酮、月桂氮卓酮、二甲基亚砜、2-吡咯烷酮、油醇、3-硬脂酸甘油酯、2-丙醇、肉豆蔻酸异丙酯、胆固醇和丙二醇。可以例如按重量计0.1％至20％或0.5％至5％的浓度添加渗透增强剂。
也可以配制所述组合物以提供皮肤表面内或上的贮存器，来为激动剂持续不断的缓慢释放做准备。也可以将所述组合物配制成从皮肤上慢慢地蒸发，从而使激动剂有额外的时间来渗入皮肤。
包含法尼酯X受体激动剂的局部用霜膏组合物可通过将水和所有水溶性组分在混合容器A中混合在一起制得。将所述pH调节到约3.5至8.0的所需范围。为了获得成分完全溶解，所述容器温度可升至最高45℃。pH和温度的选择将取决于激动剂。将除防腐剂和芳香剂以外的油溶性成分在另一个容器(B)中混合，并加热至最多70℃至熔融，并混合所述组分。在快速搅拌下，将容器B中加热后的内容物倒入水相(容器A)中。继续搅拌约20分钟。在约40℃的温度下加入防腐剂组分。继续搅拌直至温度达到约25温度以产生一种软霜膏，该软霜膏具有8Pa.s(8,000cps)至12Pa.s(12,000cps)的粘度或所需的粘度。在仍混合所述内容物并且粘度还未增大至所需范围内的时候，在约25℃至30℃加入芳香剂组分。如果想要增大所得乳液的粘度，可使用常规的匀化器(例如具有方孔高剪切筛网的Silverson L4R匀化器)施加剪切。可通过在制剂制备期间向水相中加入激动剂或可在制剂(载体)制备完成后加入激动剂，加工所述局部用组合物。还可在载体制备的任何步骤期间加入激动剂。以下实施例描述了所述霜膏制剂的组分。
实施例#1
(霜膏)：
| INCI名称 | W/w(％) |
| 去离子水 | 61.00-75.00 |
| 法尼酯X受体激动剂 | 1.00至15.00 |
| 矿物油 | 1.90 |
| 硬脂酸甘油酯 | 3.60 |
| PEG 100硬脂酸酯 | 3.48 |
| 十六/十八醇 | 2.59 |
| 鲸蜡硬脂基聚氧乙烯醚-20 | 2.13 |
| 聚二甲基硅氧烷，100ct | 0.48 |
| Lipidure PMBa | 3.00 |
| 高级滋润复合物b | 5.00 |
| 硬脂醇 | 1.42 |
| 防腐剂、芳香剂和有色颜料 | 适量 |
| 总计 | 100.00 |
a聚季铵盐-51(Collaborative Labs，NY)；
b甘油和水和PCA钠和尿素和海藻糖和聚季铵盐-51和透明质酸钠(Collaborative Labs，NY)
实施例#2
(霜膏)：
| INCI名称 | w/w(％) |
| 法尼酯X受体激动剂 | 0.5至15.00 |
| 甘油(丙三醇) | 0至5 |
| 异十六烷基聚氧乙烯醚-20 | 3至7 |
| 异硬脂酸甘油酯 | 1.5至5 |
| 二辛酰基醚 | 3至15 |
| 三醋酸甘油酯(甘油三乙酸酯) | 0.5至10 |
| 防腐剂、芳香剂和有色颜料 | 适量 |
| 水 | 适量至100.00 |
实施例#3
(霜膏)：
| INCI名称 | w/w(％) |
| 法尼酯X受体激动剂 | 0.5至15.00 |
| 甘油(丙三醇) | 0至5 |
| 异十六烷基聚氧乙烯醚-20 | 3至7 |
| 异硬脂酸甘油酯 | 1.5至5 |
| 二辛酰基醚 | 3至15 |
| 1-十二烷基-2-吡咯烷酮 | 0.5至10 |
| 防腐剂、芳香剂和有色颜料 | 适量 |
| 水 | 至100.00 |
实施例#4
(霜膏)：
| INCI名称 | w/w(％) |
| 水 | 70 |
| 硬脂酸甘油酯 | 4 |
| PEG-100 | 4 |
| 十六/十八醇 | 3 |
| 鲸蜡硬脂基聚氧乙烯醚-20 | 2.5 |
| 矿物油 | 2 |
| 硬脂醇 | 2 |
| 聚二甲基硅氧烷 | 0.5 |
| 防腐剂 | 0.43 |
| 1-十二烷基-2-吡咯烷酮 | 1至10 |
| 总计 | 100.00 |
将法尼酯X受体激动剂添加至所述实施例4制剂中并混合至溶解。
实施例5
(霜膏)：
| INCI名称 | w/w(％) |
| 水 | 70至80 |
| 硬脂酸甘油酯 | 4 |
| PEG-100 | 4 |
| 十六/十八醇 | 3 |
| 鲸蜡硬脂基聚氧乙烯醚-20 | 2.5 |
| 矿物油 | 2 |
| 硬脂醇 | 2 |
| 聚二甲基硅氧烷 | 0.5 |
| 防腐剂 | 0.43 |
| 单辛酸酯/癸酸酯(Estol 3601，Uniquema，NJ) | 1至10 |
| 总计 | 100.00 |
将法尼酯X受体激动剂添加至所述实施例5制剂中并混合至溶解。
实施例6
(霜膏)：
| INCI名称 | w/w(％) |
| 水 | 70至80 |
| 硬脂酸甘油酯 | 4 |
| PEG-100 | 4 |
| 十六/十八醇 | 3 |
| 鲸蜡硬脂基聚氧乙烯醚-20 | 2.5 |
| 矿物油 | 2 |
| 硬脂醇 | 2 |
| 聚二甲基硅氧烷 | 0.5 |
| 防腐剂 | 0.43 |
| 顺式脂肪酸 | 1至10 |
| 总计 | 100.00 |
将法尼酯X受体激动剂添加至所述实施例6制剂中并混合至溶解。
实施例7
(霜膏)：
| INCI名称 | w/w(％) |
| 水 | 70至80 |
| 硬脂酸甘油酯 | 4 |
| PEG-100 | 4 |
| 十六/十八醇 | 3 |
| 鲸蜡硬脂基聚氧乙烯醚-20 | 2.5 |
| 矿物油 | 2 |
| 硬脂醇 | 2 |
| 聚二甲基硅氧烷 | 0.5 |
| 防腐剂 | 0.43 |
| 萜烯 | 1至10 |
| 总计 | 100.00 |
将法尼酯X受体激动剂添加至所述实施例7制剂中并混合至溶解。
实施例8
(霜膏)：
| INCI名称 | w/w(％) |
| 水 | 70至80 |
| 硬脂酸甘油酯 | 4 |
| PEG-100 | 4 |
| 十六/十八醇 | 3 |
| 鲸蜡硬脂基聚氧乙烯醚-20 | 2.5 |
| 矿物油 | 2 |
| 硬脂醇 | 2 |
| 聚二甲基硅氧烷 | 0.5 |
| 防腐剂 | 0.43 |
| 聚氧乙烯脱水山梨糖醇(吐温) | 1至10 |
| 总计 | 100.00 |
将法尼酯X受体激动剂添加至所述实施例8制剂中并混合至溶解。
包含法尼酯X受体激动剂的水醇的制剂通过在混合容器中混合所述制剂组分制得。将所述制剂的pH调节至在3.5至8.0范围内所需的值。也可进行所述pH调节以促使所述制剂成分完全溶解。此外，可应用加热至最高45℃，或甚至最高70℃(取决于激动剂的稳定性)以使制剂成分达到完全溶解。两种水醇的制剂的组分列于下文。
实施例#9
(水醇的)
| INCI名称 | w/w(％) |
| 水 | 48.00-62.50 |
| 法尼酯X受体激动剂 | 0.5至15.00 |
| 乙醇 | 16.00 |
| 丙二醇 | 5.00 |
| 双丙甘醇 | 5.00 |
| 苄醇 | 400 |
| 碳酸亚丙酯 | 2.00 |
| Captex-300a | 5.00 |
| 总计 | 100.00 |
a辛酸/癸酸甘油三酯(Abitec Corp.，OH)。
实施例#10
(水醇的)
| INCI名称 | w/w(％) |
| 水 | 53.00-67.9 |
| 法尼酯X受体激动剂 | 0.1-15.00 |
| 乙醇 | 16.00 |
| 丙二醇 | 5.00 |
| 双丙甘醇二甲基醚 | 5.00 |
| 苄醇 | 4.00 |
| 碳酸亚丙酯 | 2.00 |
| 总计 | 100.00 |
实施例#11
(水醇的)
| INCI名称 | w/w(％) |
| 乙醇(醇) | 80 |
| 水 | 17.5 |
| 二壬酸丙二醇酯 | 2.0 |
| 丙二醇 | 0.5 |
| 总计 | 100.00 |
将法尼酯X受体激动剂添加至所述实施例11制剂中并混合至溶解。
应将所述组合物局部施用到所需身体选择的区域以减少毛发生长。例如，可将所述组合物施用至脸部，尤其是施用至脸部有胡须的区域，即面颊、脖子、上嘴唇和下巴。所述组合物还可用作其它毛发脱除方法的辅助，所述其它方法包括剃刮、用热蜡除去毛发、机械拔除、化学脱毛和电蚀除毛和激光辅助毛发脱除。其它使其概念显现的作用是除了毛发减少以外同时的皮肤有益效果。
所述组合物还可涂敷到腿部、手臂、躯干或腋窝。所述组合物适用于例如减少女性身上多余毛发的生长。对人类而言，应每天一次或两次、或甚至更频繁地施用该组合物，以达到可察觉的毛发生长的减少。毛发生长减少的感觉可以早在使用后24小时或48小时(例如，在正常的剃刮间隔之间)发生，或可能在长达例如三个月后察觉到。毛发生长的减少的指示标记是例如毛发生长速度减慢、减少了移除的必要、受试者感觉被处理区域上具有较少毛发，或定量地，脱除的毛发重量(即，毛发团)减少。
人类毛囊生长检测分析：
在解剖镜下使用解剖刀和表匠用的镊子，由整形组织(得自整形外科医生)分离出生长阶段(生长期)的人类毛囊。将皮肤切成外露2至3排易于剥离的毛囊的细条。将毛囊放入0.5mL William E介质(LifeTechnologies，Gaither sburg，MD.)中。补充以2mM L-谷氨酰胺、10μg/mL胰岛素、10ng/mL氢化可的松、100单位的青霉素、0.1mg/mL链霉素和0.25μg/mL两性霉素B。在5％CO2和95％空气的大气条件下，于37℃在24孔培养板(1个毛囊/孔)中培养毛囊。将化合物溶解于二甲基亚砜形成100倍储备溶液。用不合前列腺素的二甲基亚砜处理对照毛囊。在解剖镜下，以10倍的倍率为24孔培养板中的毛囊照相。典型地，在第0天(将毛囊放入培养器中的那天)记录图像，并且在第7天再记录。使用图象分析软件体系评估毛囊的长度。通过将第7天测定的毛囊长度减去第0天的毛囊长度来计算毛发纤维的生长。
仓鼠毛发团试样：
仓鼠毛发团使用类似于描述于上文专利(US2004/0198821)中的方法确定。
法尼酯X受体激动剂显示显著的人毛发毛囊生长的减少。所测试的所有六个法尼酯X受体激动剂显著减少毛发生长。表II中列出了这些结果。发现依据所述法尼酯X受体激动剂的所述毛发生长抑制特征图是倚赖剂量的。表III中列出了这些结果。
表II。
依据所述法尼酯X受体激动剂的人毛发毛囊生长抑制
| 剂量 | 毛囊长度增加(mm) | |||
| FXR激动剂 | (μM) | 处理过的 | Control＝对照物 | ％抑制率 |
| 脱氧胆酸 | 100 | 0.06±0.05 | 1.07±0.14 | 94.3±4.7 |
| 熊脱氧胆酸 | 200 | 0.20±0.11 | 1.07±0.14 | 81.3±10.3 |
| 鹅脱氧胆酸 | 100 | 0.05±0.06 | 1.07±0.14 | 95.3±5.6 |
| 石胆酸 | 50 | 0.02±0.02 | 1.07±0.14 | 98.1±1.9 |
| 金合欢醇 | 100 | 0.04±0.07 | 0.87±0.23 | 95.4±8.0 |
| 保幼激素III | 100 | 0.21±0.15 | 0.87±0.23 | 75.9±17.2 |
表III。
依据所述法尼酯X受体激动剂的计量控制的人毛发毛囊生长减少
| 剂量 | 毛囊的生长(mm) | |||
| FXR激动剂 | (μM) | 处理过的 | Control＝对照物 | 减少％ |
| 脱氧胆酸 | 10 | 1.20±0.49 | 1.76±0.36 | 31.8±18.1 |
| 50 | 0.54±0.34 | 1.76±0.36 | 69.3±13.6 | |
| 100 | 0.54±0.34 | 1.76±0.36 | 69.3±13.6 | |
| 熊脱氧胆酸 | 50 | 1.12±0.24 | 1.76±0.36 | 36.3±13.6 |
| 100 | 0.86±0.20 | 1.76±0.36 | 51.1±11.4 | |
| 150 | 0.61±0.20 | 1.76±0.36 | 65.3±11.4 | |
| 鹅脱氧胆酸 | 5 | 1.53±0.29 | 1.55±0.02 | 1.3±18.7 |
| 25 | 0.79±0.27 | 1.55±0.02 | 49.0±17.4 | |
| 50 | 0.13±0.10 | 1.55±0.02 | 91.6±6.5 | |
| 石胆酸 | 2 | 0.82±0.14 | 1.24±0.23 | 33.9±11.3 |
| 10 | 0.44±0.16 | 1.24±0.23 | 64.5±12.9 | |
| 20 | 0.03±0.06 | 1.24±0.23 | 97.6±4.8 | |
此外，测试法尼酯X受体激动剂用于所述仓鼠毛发团试样。所述激动剂减少体内毛发团如表IV中所示。
表IV。
依据所述法尼酯X受体激动剂的仓鼠毛发团的减少
| 剂量 | 毛发团(mg) | ||||
| FXR激动剂 | (w/v) | 赋形剂* | 处理过的 | 对照物 | ％抑制率 |
| 石胆酸 | 4％ | 乙醇 | 1.01±0.12 | 1.96±0.19 | 46.4±6.0 |
| 鹅脱氧胆酸 | 5％ | 乙醇 | 0.54±0.08 | 2.28±0.19 | 76.4±2.6 |
| 脱氧胆酸 | 5％ | 乙醇 | 0.92±0.14 | 2.66±0.28 | 63.6±6.0 |
| 熊脱氧胆酸 | 5％ | 乙醇 | 1.02±0.16 | 2.43±0.31 | 56.8±3.8 |
*所述载体包含90％乙醇和10％丙二醇。
因此，其它实施方案在以下权利要求的范围之内。
Claims (36)
1.一种减少哺乳动物毛发生长的美容方法，所述方法包括选择希望减少毛发生长的皮肤区域；并向所述皮肤区域施用皮肤病学可接受的组合物，所述组合物包含可有效减少毛发生长的量的法尼酯X受体激动剂，
其中所述激动剂不是
-二氟甲基鸟氨酸和金合欢醇的氨基甲酸盐或酯。
2.如权利要求1所述的方法，其中所述激动剂为胆汁酸。
3.如权利要求1所述的方法，其中所述激动剂为胆汁酸类似物。
4.如权利要求1所述的方法，其中所述激动剂为胆汁酸衍生物。
5.如权利要求1所述的方法，其中所述激动剂与所述法尼酯X受体强烈相互作用。
6.如权利要求1所述的方法，其中所述激动剂选自石胆酸、胆酸、脱氧胆酸、鹅脱氧胆酸、熊脱氧胆酸、6-α-乙基-鹅脱氧胆酸或它们中的两种或更多种的混合物。
7.如权利要求1所述的方法，其中所述激动剂为法尼酯。
8.如权利要求1所述的方法，其中所述激动剂为法尼酯类似物。
9.如权利要求1所述的方法，其中所述激动剂为法尼酯衍生物。
10.如权利要求1所述的方法，其中所述激动剂选自金合欢醇、金合欢醛、乙酸法尼酯、麝油酸、甲基法尼基醚、麝油酸甲酯、乙基法尼基醚、麝油酸乙酯、或它们中的两种或更多种的混合物。
11.如权利要求1所述的方法，其中所述激动剂为7-甲基-9-(3，3-二甲基环氧乙烷基)-3-甲基-2，6-壬二烯酸甲酯(保幼激素III)。
12.如权利要求1所述的方法，其中所述激动剂为7-甲基-9-(3，3-二甲基环氧乙烷基)-3-甲基-2，6-壬二烯酸乙酯。
13.如权利要求1所述的方法，其中所述激动剂为3α，7α-二羟基-6α-乙基-5p-胆烷-24-酸。
14.如权利要求1所述的方法，其中所述激动剂为3α，7α-二羟基-6α-丙基-5p-胆烷-24-酸。
15.如权利要求1所述的方法，其中所述激动剂为3α，7α-二羟基-6α-烯丙基-5p-胆烷-24-酸。
16.如权利要求1所述的方法，其中所述激动剂为苯磺酰胺，N-(2，2，2-三氟乙基)-N-[4-[2，2，2-三氟-1-羟基-1-(三氟甲基)乙基]苯基]-。
17.如权利要求1所述的方法，其中所述激动剂为苯甲酸，3-[2-[2-氯-4-[[3-(2，6-二氯苯基)-5-(1-甲基乙基)-4-异噁唑基]甲氧基]苯基]乙烯基]-。
18.如权利要求1所述的方法，其中所述激动剂为膦酸，[[3，5-双(1，1-二甲基乙基)-4-羟基苯基]亚乙烯基]二乙酯、四乙酯。
19.如权利要求1所述的方法，其中所述激动剂为膦酸，[2-[3，5-双(1，1-二甲基乙基)-4-羟基苯基]亚乙基]二(1-甲基乙基)酯、四(1-甲基乙基)酯。
20.如权利要求1所述的方法，其中所述激动剂为膦酸，[2-[3，5-双(1，1-二甲基乙基)-4-羟基苯基]亚乙基]二乙酯、四乙酯。
21.如权利要求1所述的方法，其中所述激动剂为膦酸，[[3，5-双(1，1-二甲基乙基)-4-羟基苯基]亚乙烯基]二(1-甲基乙基)酯、四(1-甲基乙基)酯。
22.如前述任一项权利要求所述的方法，其中所述激动剂在所述组合物中的浓度介于0.1％和30％之间。
23.如权利要求1至21中任一项所述的方法，其中当在人的毛发毛囊试样中测试时，所述组合物减少至少30％的毛发生长。
24.如权利要求1至21中任一项所述的方法，其中所述激动剂在所述皮肤上的涂敷量为每平方厘米皮肤10至3000微克所述激动剂。
25.如权利要求1至21中任一项所述的方法，其中所述皮肤区域位于人的脸部。
26.如权利要求25所述的方法，其中在剃刮的同时将所述组合物施用到所述皮肤区域。
27.如权利要求1至21中任一项所述的方法，其中所述皮肤区域位于人的腿部或臂部。
28.如权利要求1至21中任一项所述的方法，其中所述皮肤区域位于人的腋窝处。
29.如权利要求1至21中任一项所述的方法，其中所述皮肤区域位于人的躯干上。
30.如权利要求1至21中任一项所述的方法，其中所述毛发生长包括雄性激素刺激的毛发生长。
31.如权利要求1至21中任一项所述的方法，其中所述组合物还包含同样引起毛发生长减少的第二组分。
32.一种减少哺乳动物毛发生长的美容方法，所述方法包括选择希望减少毛发生长的包含毛囊的皮肤区域；和
向所述皮肤区域施用皮肤病学可接受的组合物，所述组合物包含可有效地减少毛发生长的量的化合物，所述化合物选自由下列组成的组：胆汁酸、胆汁酸类似物、以及胆汁酸衍生物。
33.一种减少哺乳动物毛发生长的美容方法，所述方法包括选择希望减少毛发生长的包含毛囊的皮肤区域；和
向所述皮肤区域施用可有效减少毛发生长的量的皮肤病学可接受的组合物，所述组合物包含不同于
-二氟甲基鸟氨酸和金合欢醇的
氨基甲酸盐或酯的化合物，所述化合物选自由下列组成的组：增加FXR-RXR异型二聚体的形成的化合物、促进共激活剂补充并且促进与FXR-RXR交互作用的化合物、以及增加法尼酯X受体表达的化合物。
34.一种处理皮肤剥落区域的方法，所述方法包括向所述皮肤剥落区域施用法尼酯X受体激动剂。
35.如权利要求34所述的方法，其中所述皮肤剥落区域在施用法尼酯X受体激动剂之前已被剃刮。
36.法尼酯X受体激动剂在制备用于抑制涂敷了药物的区域内的毛发生长的所述药物中的用途。
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| US11/141,798 US7618956B2 (en) | 2005-05-31 | 2005-05-31 | Reduction of hair growth |
| US11/141,798 | 2005-05-31 |
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| US (2) | US7618956B2 (zh) |
| EP (1) | EP1888176A2 (zh) |
| JP (1) | JP4801150B2 (zh) |
| KR (1) | KR20080010444A (zh) |
| CN (1) | CN101184532A (zh) |
| AU (1) | AU2006252877B2 (zh) |
| BR (1) | BRPI0611490A2 (zh) |
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| CN1681469B (zh) * | 2002-09-09 | 2010-06-16 | 雀巢技术公司 | 用于改善毛发和皮毛质量的口服施用组合物 |
| AU2003290796A1 (en) | 2002-11-14 | 2004-06-15 | The Scripps Research Institute | Non-steroidal fxr agonists |
| EP1562915A1 (en) | 2002-11-22 | 2005-08-17 | SmithKline Beecham Corporation | Farnesoid x receptor agonists |
| US7015349B2 (en) | 2003-03-26 | 2006-03-21 | The Gillette Company | Reduction of hair growth |
| JP3913718B2 (ja) * | 2003-06-27 | 2007-05-09 | 花王株式会社 | 発毛抑制皮膚外用剤 |
-
2005
- 2005-05-31 US US11/141,798 patent/US7618956B2/en not_active Expired - Fee Related
-
2006
- 2006-05-15 CA CA2729440A patent/CA2729440A1/en not_active Abandoned
- 2006-05-15 JP JP2008514674A patent/JP4801150B2/ja not_active Expired - Fee Related
- 2006-05-15 CA CA2729437A patent/CA2729437A1/en not_active Abandoned
- 2006-05-15 MX MX2007015060A patent/MX2007015060A/es active IP Right Grant
- 2006-05-15 KR KR1020077027693A patent/KR20080010444A/ko not_active Application Discontinuation
- 2006-05-15 CA CA2729438A patent/CA2729438A1/en not_active Abandoned
- 2006-05-15 CA CA002608053A patent/CA2608053A1/en not_active Abandoned
- 2006-05-15 WO PCT/US2006/018663 patent/WO2006130330A2/en active Application Filing
- 2006-05-15 CN CNA2006800188989A patent/CN101184532A/zh active Pending
- 2006-05-15 CA CA2729431A patent/CA2729431A1/en not_active Abandoned
- 2006-05-15 BR BRPI0611490-3A patent/BRPI0611490A2/pt not_active IP Right Cessation
- 2006-05-15 EP EP06759810A patent/EP1888176A2/en not_active Withdrawn
- 2006-05-15 AU AU2006252877A patent/AU2006252877B2/en not_active Ceased
-
2009
- 2009-10-02 US US12/572,564 patent/US20100021412A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103068786A (zh) * | 2010-08-05 | 2013-04-24 | 考格尼斯知识产权管理有限责任公司 | 化妆品制剂 |
| CN103068786B (zh) * | 2010-08-05 | 2016-01-20 | 考格尼斯知识产权管理有限责任公司 | 化妆品制剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4801150B2 (ja) | 2011-10-26 |
| US7618956B2 (en) | 2009-11-17 |
| JP2008542372A (ja) | 2008-11-27 |
| US20100021412A1 (en) | 2010-01-28 |
| MX2007015060A (es) | 2008-01-28 |
| CA2729438A1 (en) | 2006-12-07 |
| CA2729440A1 (en) | 2006-12-07 |
| US20060269496A1 (en) | 2006-11-30 |
| WO2006130330A3 (en) | 2007-03-22 |
| AU2006252877B2 (en) | 2011-05-26 |
| WO2006130330A2 (en) | 2006-12-07 |
| CA2608053A1 (en) | 2006-12-07 |
| AU2006252877A1 (en) | 2006-12-07 |
| EP1888176A2 (en) | 2008-02-20 |
| KR20080010444A (ko) | 2008-01-30 |
| CA2729431A1 (en) | 2006-12-07 |
| BRPI0611490A2 (pt) | 2010-09-08 |
| CA2729437A1 (en) | 2006-12-07 |
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