CN101087583A - 用生存素抑制剂来减少毛发生长 - Google Patents
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Abstract
通过局部施用包含生存素抑制剂的组合物来减少哺乳动物的毛发生长。
Description
要求优先权
本申请依据35 U.S.C.§119(e)要求于2004年12月22日提交的美国专利申请序列号60/639,083的优先权,所述专利的全部内容引入本文以供参考。
发明背景
本发明涉及减少哺乳动物身上的毛发生长,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此功能。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为了美容的原因。例如,通常优选在头皮上而不是在脸上留有毛发。
人们已经使用了多种方法来去除多余的毛发,这些方法包括剃刮、电蚀除毛、使用脱毛膏或洗剂、使用热蜡、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的缺点。例如,剃刮不仅会引起割伤和切口,而且还给人一种毛发再生速度增大的感觉。剃刮也会留下令人不快的硬茬。另一方面,虽然电蚀除毛会使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,但是由于其具有高的潜在刺激性,典型地不推荐频繁使用。用热蜡去除毛发和拔除毛发会引起疼痛或不适并且对较短毛发的去除效果较差。最后,抗雄激素(已被用于治疗女性多毛症)会产生有害的副作用。
先前已经公开,可以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5-α还原酶、鸟氨酸脱羧酶、S-腺苷甲硫氨酸脱羧酶、γ-谷氨酰转肽酶和转谷氨酰胺酶的抑制剂。参见例如Breuer等人的美国专利4,885,289、Shander的美国专利4,720,489、Ahluwalia的美国专利5,095,007、Ahluwalia等人的美国专利5,096,911和Shander等人的美国专利5,132,293。
生存素具有控制细胞增殖和抑制细胞凋亡的作用。本文所用术语“生存素”是指由生存素基因表达的蛋白质。
生存素的表达非常有规律地以依赖细胞周期的方式进行,并且在细胞分裂期间需要生存素来进行胞质分裂和染色体移动。此外,生存素抑制由各种凋亡刺激诱导的细胞死亡。体内生存素的过量表达增加了细胞对凋亡的抵抗力。已经显示表皮角质细胞中生存素的转录表达,显著减少了暴露于紫外照射下后表皮中凋亡细胞的数量。相反,通过反义生存素低聚核苷酸的处理,不仅抑制了体外生存素的表达而且还增加了许多细胞株对凋亡的敏感度。已经提出生存素可通过直接或间接地抑制半胱氨酸天冬氨酸蛋白酶(caspase)-包括细胞凋亡的细胞死亡蛋白酶的活性,来抑制细胞凋亡。具体地讲,生存素的结构特征表明在生存素和半胱氨酸天冬氨酸蛋白酶-9之间有相互作用。生存素的去磷酸化导致有丝分裂器上免疫沉淀的生存素-半胱氨酸天冬氨酸蛋白酶-9复合物的解离,使得半胱氨酸天冬氨酸蛋白酶-9的活性依赖于细胞凋亡。此外,生存素可通过连接到源自第二线粒体的半胱氨酸天冬氨酸蛋白酶的活化剂(Smac/DIABLO)上,间接地抑制半胱氨酸天冬氨酸蛋白酶的活性,从而阻止Smac/DIABLO执行线粒体凋亡路径。在胚胎阻止和大多数的人类肿瘤中观察到了生存素的表达,但是在正常的成人组织中它的表达显示受到了限制。
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)。该方法包括向皮肤施用可有效减少毛发生长的量的生存素抑制剂。多余的毛发生长从美容的观点来看可能不受欢迎,或者多余的毛发生长可能是由例如疾病或反常情况(例如多毛症)产生的。
生存素抑制剂包括:通过与蛋白质强相互作用专一性抑制毛囊中生存素蛋白质功能的化合物;减少毛囊中生存素量的化合物;以及通过例如磷酸化生存素蛋白质抑制生存素活性的化合物。“强相互作用”是指所述化合物连接或优先连接在生存素上。
在上述方法的实行中,所述抑制剂典型地连同皮肤病学或美容上可接受的载体一起被包括在局部用组合物中。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生存素抑制剂的局部用组合物。
除此以外,本发明还涉及使用生存素抑制剂来制备一种治疗性局部用组合物以减少毛发生长。
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将显而易见。
发明详述
优选的组合物包括含于皮肤病学和/或美容上可接受的载体中的生存素抑制剂。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。所述组合物也可以采取剃刮制品或须后水的形式。载体本身可以是惰性的,或者它可以拥有它自己的美容的、生理学的和/或制药学上的有益效果。
某些已知的生存素抑制剂的实施例提供在表1中。
表1
抑制剂名称 | 化学名 | 功能 | 参考文献 |
G4N | 内消旋-1,4-二[(3,4-二甲基氨基乙酰氧基)苯基]-(2R,3S)-二甲基丁烷盐酸盐;四-N,N-二甲基氨基甜菜碱-NDGA酯; | 减少生存素含量 | Rhu Chih C.Huang和Jonathan D Heller,美国专利申请US2003/0171416 A1,2003年9月11日 |
M4N | 内消旋-1,4-二(3,4-二甲氧基苯基)-(2R,3S)-二甲基丁烷;四-邻-甲基-NDGA | 减少生存素含量 | Rhu Chih C.Huang和Jonathan D Heller,美国专利申请US2003/0171416A1,2003年9月11日 |
Roscovitine | (2R)-2-[[9-(1-甲基乙基)-6-[(苯基甲基)氨基]-9H-嘌呤-2-基]氨基]-1-丁醇(R)-2-[[9-(1-甲基乙基)-6-[(苯基甲基)氨基]-9H-嘌呤-2-基]氨基]-1-丁醇CYC 202 | 减少生存素含量 | Kim EH等人,“Oncogene”,2004年1月15日;23(2):446-56。 |
Silibinin | (2R,3R)-2-[(2R,3R)-2,3-二氢-3-(4-羟基-3-甲氧苯基)-2-(羟甲基)-1,4-苯并二噁烷-6-基]-2,3-二氢-3,5,7-三羟基-4H-1-苯并吡喃-4-酮3,5,7-三羟基-2-[3-(4-羟基-3-甲氧苯基)-2-(羟甲基)-1,4-苯并二噁烷-6-基]-4-苯并二氢吡喃-4-酮;[2R-[2α,3β,6(2R*,3R*)]]-2-[2,3-二氢-3-(4-羟基-3-甲氧苯基)-2-(羟甲基)-1,4-苯并二噁烷-6-基]-2,3-二氢-3,5,7-三羟基-4H-1-苯并吡喃-4-酮,Silybin;1,4-苯并二噁烷,4H-1-苯并吡喃-4-酮衍生物; | 减少生存素含量 | Tyagi AK等人,“Biochem Biophys ResCommun”,2003年;312(4):1178-84。 |
7C3MT;喜尔肝(Silliver);Silybin A;Silybin b1;Silybine;水飞蓟物质E6;Silymarin I;Silymarin MZ 80;Silymarine I | |||
白藜芦醇 | 5-[(1E)-2-(4-羟基苯基)乙烯基]-1,3-苯二酚(E)-5-[2-(4-羟基苯基)乙烯基]-1,3-苯二酚;3,4′,5-芪三酚;白藜芦醇;(E)-5-(对-羟基苯乙烯基)间苯二酚;(E)-白藜芦醇;3,4′,5-三羟基-反式-二苯乙烯;CA 1201;反式-白藜芦醇 | 减少生存素含量 | Hayashibara等人,“NutrCancer”,2002;44:193-201 |
牻牛儿基牻牛儿醇-转移酶I抑制剂(GGTIs) | GGTI-298;GGTI-2166;L-亮氨酸,N-[4-[[(2R)-2-氨基-3-巯基丙基]氨基]-2-(1-萘基)苯甲酰基]-,甲酯(9CI);L-亮氨酸,N-[4-[(2-氨基-3-巯基丙基)氨基]-2-(1-萘基)苯甲酰基]-,甲酯,(R)- | 生存素接合剂 | Dan等人,“Oncogene”,2004年;23(3):706-15 |
Flavopiridol | 2-(2-氯苯基)-5,7-二羟基-8-[(3S,4R)-3-羟基-1-甲基-4-哌啶基]-4H-1-苯并吡喃-4-酮顺式-(-)-2-(2-氯苯 | 抑制生存素第34位苏氨酸(Thr34)磷酸化 | Wall N等人,“CancerResearch”,(2003年),63(1),230-235。 |
基)-5,7-二羟基-8-(3-羟基-1-甲基-4-哌啶基)-4H-1-苯并吡喃-4-酮;AlvocidibHMR 1275;L 86-8275 | |||
生存素小干扰RNA(siRNA) | 通过RNA干扰沉默生存素基因的表达 | Ning S等人,“Int J Oncol”,2004年10月;25(4):1065-71。 | |
以生存素为靶标的反义分子 | 减少生存素表达并因此减少生存素的含量 | US6165788:生存素表达的反义调控 |
内消旋-1,4-二[(3,4-二甲基氨基乙酰氧基)苯基]-(2R,3S)-二甲
基丁烷盐酸盐(G4N)的合成
在25℃下使用活性酯方法将去甲二氢愈创木酸(NDGA)的全部四个苯氧基连接到N,N-二甲基氨基甜菜碱上(Rhu Chih C.Huang和Jonathan D Heller,美国公布申请US2003/0171416 A1,2003年9月11日)。所述产品(G4N)通过色谱法使用硅胶纯化并提供LCMS表征。通过加入稀盐酸就地制备质子化型产品。G4N具有以下结构:
具体地讲,向NDGA(0.342g,1.13mmol)和N,N-二甲基甜菜碱(0.7g,6.8mmol)的二氯甲烷(7mL)溶液中加入二环己基碳酰二亚胺(DCC,1.4g,6.8mmol)和N,N-二甲基氨基吡啶(DMAP,62mg,0.5mmol)。使该反应混合物在25℃在氩气氛下搅拌24小时。在滤去生成的二环己基脲之后,用饱和碳酸氢钠水溶液洗涤滤液。用无水硫酸钠干燥有机溶剂,随后蒸发得到粗产物混合物。通过色谱法在预处理过的(氯仿)硅胶层析管柱(BondElute10g)上使用甲醇-氯仿混合物(1%至5%)作为淋洗剂纯化所述粗产物残余物。将包含产品的部分(用薄层色谱法检测)合并,并在减压下蒸发得到纯的G4N(588mg),81%的收率,为粘稠清亮的油。中和10%(w/w)的5%甲醇-水溶液,就地得到G4N的质子化产品形式。LCMS(ESI+ve)m/z 665(M++1+Na)和643(M++1)。
所述组合物可包括不止-种生存素抑制剂。此外,所述组合物可包括一种或多种其它类型的毛发生长抑制剂,例如描述于美国专利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中的那些,这些专利均引入本文以供参考。
所述组合物中生存素抑制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抑制剂量的增加而增长。有效应用的最大量仅受到抑制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,或者它可以具有它自己的美容的、生理学的和/或制药学上的有益效果。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抑制剂渗透入皮肤和/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。
也可以通过配制所述组合物以提供皮肤表面内或上的贮存器来为抑制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,从而使抑制剂有额外的时间来渗入皮肤。
可通过在混合容器-A中将水和全部水溶性组分混合在一起来制备包含生存素抑制剂的基于霜膏的局部用组合物。将pH调节在约3.5至8.0的所需范围内。为了使成分完全溶解,容器的温度可升至最高45℃。pH和温度的选择将取决于生存素抑制剂的稳定性。将除防腐剂和芳香剂以外的油溶性成分在另一个容器(B)中混合并加热至最高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。继续混合约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)的粘度或所需粘度。当仍在混合所述内容物并且粘度还未增大至所需范围的时候,在约25℃至30℃加入芳香剂组分。如果想要增加所得乳液的粘度,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。可通过在上述制剂制备期间向水相中加入抑制剂或可在制剂(载体)制备完成后加入抑制剂,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抑制剂。以下实施例中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 |
生存素抑制剂a | 1.00-15.00 |
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 |
磷脂质(Lipidure)PMBb | 3.00 |
高级滋润复合物c | 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抑制剂可以从例如表1提供的目录中选择。
b聚季铵盐-51(Collaborative Labs,NY)。
c甘油、水、PCA钠、尿素、海藻糖、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(%) |
生存素抑制剂a | 0.5-15.00 |
甘油(丙三醇) | 0-5 |
异十六烷基聚氧乙烯醚-20 | 3-7 |
异硬脂酸甘油酯 | 1.5-5 |
二辛酰基醚 | 3-15 |
三醋酸甘油酯(甘油三乙酸酯) | 0.5-10 |
防腐剂、芳香剂和有色颜料 | 适量 |
水 | 适量至100.00 |
a抑制剂可以从例如表1提供的目录中选择。
实施例#3(霜膏)
INCI名称 | w/w(%) |
生存素抑制剂a | 0.5-15.00 |
甘油(丙三醇) | 0-5 |
异十六烷基聚氧乙烯醚-20 | 3-7 |
异硬脂酸甘油酯 | 1.5-5 |
二辛酰基醚 | 3-15 |
1-十二烷基-2-吡咯烷酮 | 0.5-10% |
防腐剂、芳香剂和有色颜料 | 适量 |
水 | 至100.00 |
a抑制剂可以从例如表1提供的目录中选择。
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 |
聚二甲聚硅氧烷 | 0.5 |
防腐剂 | 0.43 |
1-十二烷基-2-吡咯烷酮 | 1-10 |
总计 | 100.00 |
向实施例4的制剂中加入抑制剂并混合直至溶解。抑制剂可以从例如表1提供的目录中选择。
实施例#5(霜膏)
INCI名称 | w/w(%) |
水 | 70-80 |
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 |
聚二甲聚硅氧烷 | 0.5 |
防腐剂 | 0.43 |
单辛酸酯/癸酸酯(Estol 3601,Uniquema,NJ) | 1-10 |
总计 | 100.00 |
向实施例5的制剂中加入抑制剂并混合直至溶解。抑制剂可以从例如表1提供的目录中选择。
实施例#6(霜膏)
INCI名称 | w/w(%) |
水 | 70-80 |
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 |
聚二甲聚硅氧烷 | 0.5 |
防腐剂 | 0.43 |
顺式脂肪酸 | 1-10 |
总计 | 100.00 |
向实施例6的制剂中加入抑制剂并混合直至溶解。抑制剂可以从例如表1提供的目录中选择。
实施例#7(霜膏)
INCI名称 | w/w(%) |
水 | 70%-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 |
聚二甲聚硅氧烷 | 0.5 |
防腐剂 | 0.43 |
萜烯 | 1-10 |
总计 | 100.00 |
向实施例7的制剂中加入生存素抑制剂并混合直至溶解。抑制剂可以从例如表1提供的目录中选择。
实施例#8(霜膏)
INCI名称 | w/w(%) |
水 | 70%-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 |
聚二甲聚硅氧烷 | 0.5 |
防腐剂 | 0.43 |
聚氧乙烯脱水山梨糖醇(吐温) | 1-10 |
总计 | 100.00 |
向实施例8的制剂中加入生存素抑制剂并混合直至溶解。抑制剂可以从例如表-1提供的目录中选择。
通过在混合容器中混合制剂组分,来制备包含生存素抑制剂的水醇制剂。将所述制剂的pH调节至所需值,该值在3.5至8.0的范围内。进行pH调节也可以促成制剂成分的完全溶解。此外,可应用加热至最多45℃,或甚至最多70℃(取决于活性物质的稳定性)以使制剂成分达到完全溶解。以下列出了若干种水醇制剂。
实施例#9(水醇制剂)
INCI名称 | w/w(%) |
水 | 48.00-62.50 |
生存素抑制剂a | 0.5-15.00 |
乙醇 | 16.00 |
丙二醇 | 5.00 |
双丙甘醇 | 5.00 |
苄醇 | 400 |
碳酸丙烯酯 | 2.00 |
Captex-300b | 5.00 |
总计 | 100.00 |
a抑制剂可以从例如表1提供的目录中选择。
b辛酸/癸酸甘油三酯(Abitec Corp.,OH)。
实施例#10(水醇制剂)
INCI名称 | w/w(%) |
水 | 53.00-67.9 |
生存素抑制剂a | 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 |
碳酸丙烯酯 | 2.00 |
总计 | 100.00 |
a抑制剂可以从例如表1提供的目录中选择。
实施例#11(水醇制剂)
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 |
向所述制剂中加入生存素抑制剂并混合直至溶解。抑制剂可以从例如表1提供的目录中选择。
应将所述组合物局部施用至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、上唇和下巴。所述组合物还可用作例如剃须或机械脱毛的助剂。
所述组合物还可施用至腿部、手臂、躯干或腋窝。所述组合物尤其适用减少患有多毛症或其它病症的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。可通过已处理区域中减少的毛发长度、毛发直径、毛发色素沉着和/或毛发密度,定量地证明毛发生长的减少。可通过已处理区域中不易看见的毛发、较短的毛发硬茬、较细/较薄的毛发、较软的毛发和/或较持久的剃刮,在美容上证明毛发生长的减少。
人类毛囊生长检测分析
人的皮肤作为整形手术的副产物得自整形外科医生。皮肤样本通常由取自脸部区域的有毛发的和无毛发的区域组成。在移除后,将皮肤立即置于包含抗生素的Williams E介质中并保持冷冻。所述Williams E介质是市售购得的(Life Technologies,Gaithersburg,MD),并且已用基本营养物质配制以维持体外环境中毛囊的活力。
在解剖镜下使用解剖刀和表匠用的镊子,由整形组织分离出生长阶段(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介质中,该介质补充 2mML-谷氨酰胺、10ug/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%空气的气氛下,于37℃在24孔培养板(1个毛囊/孔)中培养毛囊。在解剖镜下,以20倍的倍率为24孔培养板中的毛囊照相。在第0天(将毛囊放入培养器中的那天)测量毛囊长度,并且在第6至7天再次测量。在该体系中,毛囊显示完全分化成毛发纤维,并且长度的增长率与人体内约0.3mm/天的速率相似。为了测试生存素抑制剂,从时间0开始将所述抑制剂包括在培养基中,并在整个实验过程中保留在所述介质中。
免疫组织化学检测分析
制备八微米的毛囊冷冻切片或快速冷冻皮肤切片,并置于-20℃的丙酮中10分钟。为了免疫检测生存素,使用酪胺放大的方法。简而言之,在阻断内源性过氧化物酶和非特异性亲合素/生物素(亲合素/生物阻断试剂盒,Vector Lab)后,将切片在TNB缓冲剂(0.1MTris-HCl,pH 7.5,0.15M NaCl,和0.5%阻断剂,Perkin Elmer,Boston,MA)中培养30分钟。然后应用兔抗人生存素多克隆抗体(ChemiconInt.;AB16532)(1∶1000,过夜),随后应用生物素化羊抗兔或羊抗兔抗血清,该抗血清稀释于TNB阻断缓冲剂(Perkin Elmer,Boston,MA,1∶200,30分钟)中。接下来,将切片培养在链霉亲和素-辣根过氧化物酶(1∶100的TNB溶液,30分钟)中。用TNT缓冲剂(0.1 MTris-HCl,pH 7.6,0.15M NaCl,0.05%Tween)洗涤三次,随后应用TRITC-酪胺(1∶50的放大稀释剂溶液,Perkin Elmer,Boston,MA)10分钟。接下来,用Hoechst 33342(1∶300,15分钟)进行切片复染色,以鉴定细胞核,并且使用VectaShield(Vector Laboratories)制作成标本。
为了同时检测增殖和生存素阳性细胞,将上述操作与使用兔抗Ki-67单克隆抗体(Dako;M 7187)的免疫荧光操作结合。在检测生存素之后,用抗Ki-67抗体在室温下培养皮肤切片过夜,随后用TRITC-标记的羊抗兔IgG(Jackson ImmunoResearch;45分钟,37℃)培养。使用HOECHST 33342染料(10mg/mL的PBS溶液;10分钟)进行复染色。在PBS中通过洗涤步骤(三次)分配每一相。最后,使用VectaShield(Vector Laboratories)将切片制作成标本。
所有切片均在Olympus BX 60荧光显微镜下观察,并使用数字图象分析系统(CoolSnapTM冷却的CCD照相机,Alpha Innotech)以照片形式存档。
通过ELISA(酶联免疫吸附测定法)测定毛囊生存素蛋白质含量
为了提取蛋白质,将5微米的毛囊冷冻切片收集在离心管中,随后用裂解液(BD Bioscience;CA;目录号#K 1848-1)进行短时间培养。在4℃以14,000xg将所述溶液离心30分钟并将上清液冷冻并储存在-80℃下。为了确定生存素蛋白的量,按照制造商的用法说明,使用市售的ELISA试剂盒(Assay Design Inc;Michigan;目录号#900-111)。通过使用二喹啉甲酸(BCA)蛋白质检测法(PierceChemical Company,Rockford;目录号#23225)测定提取物中总的蛋白质浓度。使用 EL340 Bio Kinetics微板读数计(Bio-TekInstruments Inc.)进行光密度的读取。使生存素的含量(以pg/mL计)对从毛囊提取出的蛋白质(以ug/mL计)总量归一化。
金黄叙利亚仓鼠检测分析
认为未经阉割的雄性金黄叙利亚仓鼠是用于人类胡须毛发生长的可接受的模型,因为它们显示有椭圆形的侧腹部器官,每侧一个,每个的主直径为约8mm。这些器官长出存在于躯体上的典型动物毛皮的纤细浅色毛发。所述侧腹部器官响应雄性激素,长出类似于男性人类胡须毛发的黑色粗毛发。为了评估组合物的有效性,通过应用基于硫基乙醇酸盐的化学脱毛剂(Surgex)为每组仓鼠的侧腹部器官脱毛和/或为其剃须。每天向每只动物的一个器官施用10μl的单独的载体,同时向每只动物的另一个器官施用等量的包含生存素抑制剂的产品。在施用十三次之后(每天施用一次,每星期五天),剃刮侧腹部器官并称取从每个器官收集的毛发的量(毛发质量)。对于某些实验,其中指明了该处理周期少于13次施用。该减少的处理周期使得能够确定起作用的起点。通过以下方法计算毛发生长的减少百分数:从载体处理侧的毛发质量值减去测试化合物处理侧的毛发质量(mg)值;然后将所得的Δ值除以载体处理侧的毛发质量值,并将所得数乘以100。通常在第8天、第15天和第19天进行视觉评估,比较药物处理点和载体对照点之间的毛发再生。这些观测提供对起作用(并因此起效)的起点确认。
结果
使用免疫组织化学方法,证明了体外源自人类头皮和胡须的毛囊中生存素的存在。在两个案例中,生存素蛋白的表达被限制于毛发基质的单独细胞,并且在沿外部根部外皮的不同细胞中被观察到。在胡须毛囊中,还可以在毛乳头中观察到少数的生存素阳性细胞。同时检测生存素和增殖标记Ki-67的双免疫组化染色显示只有增殖细胞表达生存素(参见图)。
在使用内消旋-1,4-二[(3,4-二甲基氨基乙酰氧基)苯基]-(2R,3S)-二甲基丁烷盐酸盐(G4N)时,观察到依赖于剂量的人类毛囊生长的减少(表2)。
表2
化合物 | 剂量 | 长度增加(mm) | %抑制率 | p< |
对照物*G4NG4N | -20uM50uM | 1.7±0.11.19±0.110.61±0.14 | 03064 | 0.0010.000001 |
*通过从第6天的总毛囊长度减去第0天总毛囊长度来确定毛发生长。抑制率%=100-(抑制剂处理过的毛囊的毛发生长/对照物的毛发生长)x 100。
在G4N(参见表3)和silibinin及silymarin(参见表4)的局部给药后,证明金黄叙利亚仓鼠检测分析中抑制了侧腹部器官的毛发生长。
表3
化合物 | 剂量 | 处理侧(mg) | 载体对照物侧(mg)* | %抑制率 |
G4N | 5% | 1.17±0.2 | 2.21±0.28 | 48±6 |
*所述载体为20%丙二醇的乙醇溶液。
表4
化合物名称 | 剂量 | 处理侧(mg) | 载体对照物侧(mg)* | %抑制率 |
SilibininSilymarin | 10%10% | 0.77±.141.15±.14 | 2.07±.242.51±.20 | 62.1+5.552.7+6.0 |
*所述载体为10%DMSO的乙醇、水、Emerest和丙二醇溶液。
表5显示了体外通过roscovitine的依赖于剂量的人类毛囊生长的减少。
表5
处理 | 以mm计的长度增加 | 毛发生长抑制 |
对照物10uM Roscovitine | 1.7+0.20.97+0.13 | 42% |
对照物15uM Roscovitine | 1.4±0.10.5±0.1 | 60% |
对照物20uM Roscovitine | 1.2±0.10.05±0.05 | 80% |
表6显示了当用ELISA检测法检测时,体外通过roscovitine的依赖于剂量的人类毛囊中生存素蛋白质含量的减少。
表6
处理 | 生存素蛋白质(pg/mg) | 抑制率 |
对照物15uM Roscovitine | 0.070.03 | 62% |
对照物20uM Roscovitine | 0.150.007 | 95% |
其它实施方案也在权利要求书的保护范围内。
Claims (22)
1.一种减少哺乳动物毛发生长的方法,所述方法包括选择需要减少毛发生长的皮肤区域;并且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生存素抑制剂。
2.如权利要求1所述的方法,其中所述抑制剂是内消旋-1,4-二[(3,4-二甲基氨基乙酰氧基)苯基]-(2R,3S)-二甲基丁烷盐酸盐。
3.如权利要求1所述的方法,其中所述抑制剂是内消旋-1,4-二(3,4-二甲氧基苯基)-(2R,3S)-二甲基丁烷。
4.如权利要求1所述的方法,其中所述抑制剂是(2R)-2-[[9-(1-甲基乙基)-6-[(苯基甲基)氨基]-9H-嘌呤-2-基]氨基]-1-丁醇。
5.如权利要求1所述的方法,其中所述抑制剂是2-(2-氯苯基)-5,7-二羟基-8-[(3S,4R)-3-羟基-1-甲基-4-哌啶基]-4H-1-苯并吡喃-4-酮。
6.如权利要求1所述的方法,其中所述抑制剂是(2R,3R)-2-[(2R,3R)-2,3-二氢-3-(4-羟基-3-甲氧苯基)-2-(羟甲基)-1,4-苯并二噁烷-6-基]-2,3-二氢-3,5,7-三羟基-4H-1-苯并吡喃-4-酮。
7.如权利要求1所述的方法,其中所述抑制剂是5-[(1E)-2-(4-羟基苯基)乙烯基]-1,3-苯二酚。
8.如权利要求1所述的方法,其中所述抑制剂抑制牻牛儿基牻牛儿醇转移酶I。
9.如权利要求1所述的方法,其中所述抑制剂是L-亮氨酸,N-[4-[[(2R)-2-氨基-3-巯基丙基]氨基]-2-(1-萘基)苯甲酰基]-,甲酯(9CI)。
10.如权利要求1所述的方法,其中所述抑制剂是L-亮氨酸,N-[4-[(2-氨基-3-巯基丙基)氨基]-2-(1-萘基)苯甲酰基]-,甲酯,(R)-。
11.如权利要求1所述的方法,其中所述抑制剂是2-(2-氯苯基)-5,7-二羟基-8-[(3S,4R)-3-羟基-1-甲基-4-哌啶基]-4H-1-苯并吡喃-4-酮。
12.如权利要求1所述的方法,其中所述抑制剂是以生存素mRNA为靶标的小干扰RNA化合物。
13.如权利要求1所述的方法,其中所述抑制剂是以编译生存素的核酸为靶标的反义化合物。
14.如权利要求1所述的方法,其中所述抑制剂是与毛囊细胞中生存素强烈相互作用的化合物。
15.如权利要求1所述的方法,其中所述抑制剂是减少毛囊中生存素含量的化合物。
16.如权利要求1所述的方法,其中所述抑制剂是减少毛囊中生存素mRNA表达的化合物。
17.如权利要求1所述的方法,其中所述抑制剂是抑制生存素磷酸化的化合物。
18.如权利要求1所述的方法,其中所述抑制剂在所述组合物中的浓度介于0.1%和30%之间。
19.如权利要求1所述的方法,其中所述抑制剂涂敷到皮肤上的量为每平方厘米皮肤10至3000微克所述抑制剂。
20.如权利要求1所述的方法,其中所述皮肤区域在人的脸部。
21.如权利要求1所述的方法,其中所述皮肤区域在人的腿部或手臂上、腋窝里、和/或躯干上。
22.如权利要求1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。
Applications Claiming Priority (2)
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US63908304P | 2004-12-22 | 2004-12-22 | |
US60/639,083 | 2004-12-22 |
Publications (1)
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CN101087583A true CN101087583A (zh) | 2007-12-12 |
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ID=36130012
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CNA2005800445288A Pending CN101087583A (zh) | 2004-12-22 | 2005-12-21 | 用生存素抑制剂来减少毛发生长 |
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Country | Link |
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US (1) | US20060135461A1 (zh) |
EP (1) | EP1841401A1 (zh) |
JP (1) | JP2008523159A (zh) |
KR (1) | KR20070086431A (zh) |
CN (1) | CN101087583A (zh) |
AU (1) | AU2005319166A1 (zh) |
BR (1) | BRPI0519217A2 (zh) |
CA (1) | CA2589762A1 (zh) |
MX (1) | MX2007007624A (zh) |
WO (1) | WO2006069192A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102793639A (zh) * | 2011-12-16 | 2012-11-28 | 百奥迈科生物技术有限公司 | 一种植物提取物介导的药物透皮导入系统及其透皮方法 |
CN107308451A (zh) * | 2017-06-08 | 2017-11-03 | 深圳培元生物科技有限公司 | 一种毛发生长抑制剂及其用途 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2932088B1 (fr) | 2008-06-06 | 2013-04-05 | Lvmh Rech | Utilisation d'un extrait de lepechinia caulescens comme agent cosmetique, et composition cosmetique le contenant |
FR2932086A1 (fr) | 2008-06-06 | 2009-12-11 | Lvmh Rech | Methode de soin cosmetique anti-age par stimulation de l'expression de la survivine |
FR2932089B1 (fr) | 2008-06-06 | 2012-12-28 | Lvmh Rech | Utilisation d'un extrait de limnophila comme agent cosmetique, et composition cosmetique le concernant |
FR2955112B1 (fr) | 2010-01-14 | 2012-01-20 | Isp Investments Inc | Nouveaux peptides anti-age modulateurs de la survivine et compositions les comprenant |
Family Cites Families (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3426137A (en) * | 1965-12-23 | 1969-02-04 | Olin Mathieson | Hair growth inhibiting by aminobenzophenones |
US4161540A (en) * | 1966-08-22 | 1979-07-17 | Schering Corporation | Antiandrogenic agents and methods for the treatment of androgen dependent disease states |
JPS5432773B2 (zh) * | 1972-05-09 | 1979-10-16 | ||
US3976049A (en) * | 1973-07-04 | 1976-08-24 | Asahi Kasei Kogyo Kabushiki Kaisha | Structure of warmer |
US4039669A (en) * | 1975-08-01 | 1977-08-02 | Sterling Drug Inc. | Composition for topical application and use thereof |
US4201873A (en) * | 1975-09-17 | 1980-05-06 | The Upjohn Company | 9-Deoxy-9,10-didehydro-PGD2 analogs |
US4203924A (en) * | 1976-01-08 | 1980-05-20 | The Upjohn Company | 2-Decarboxy-2-hydroxymethyl-deoxy-9,10-didehydro-PGD2 analogs |
US4139638A (en) * | 1976-09-23 | 1979-02-13 | Schering Corporation | Methods for the treatment of hirsutism |
FR2380775A1 (fr) * | 1977-02-22 | 1978-09-15 | Sederma Sarl | Composition " apres-epilation " favorisant un ralentissement progressif de la repousse des poils |
US4191775A (en) * | 1977-12-15 | 1980-03-04 | Imperial Chemical Industries Limited | Amide derivatives |
US4269831A (en) * | 1979-05-09 | 1981-05-26 | Sterling Drug Inc. | Topical dermatological method of use of an androstenopyrazole |
JP2519024B2 (ja) * | 1982-06-07 | 1996-07-31 | 花王株式会社 | 毛髪化粧料 |
JPS595154A (ja) * | 1982-06-30 | 1984-01-12 | Ono Pharmaceut Co Ltd | プロスタグランジンd類似化合物 |
US4508714A (en) * | 1983-11-14 | 1985-04-02 | Tihomir Cecic | Organic scalp lotion |
US4885289A (en) * | 1983-12-12 | 1989-12-05 | Breuer Miklos M | Alteration of character of male beard growth |
US4720489A (en) * | 1984-10-15 | 1988-01-19 | Douglas Shander | Hair growth modification with ornithine decarboxylase inhibitors |
US4935231A (en) * | 1985-08-28 | 1990-06-19 | Repligen Corporation | Use of thioredoxin, thioredoxin-derived, or thioredoxin-like dithiol peptides in hair care preparations |
US5096911A (en) * | 1990-06-25 | 1992-03-17 | Ahluwalia Gurpreet S | Alteration of rate and character of hair growth |
CA2088909C (en) * | 1990-08-14 | 2002-03-19 | Douglas Shander | Enzymic alteration of hair growth |
US5189212A (en) * | 1990-09-07 | 1993-02-23 | University Of Georgia Research Foundation, Inc. | Triarylethylene carboxylic acids with estrogenic activity |
US5095007A (en) * | 1990-10-24 | 1992-03-10 | Ahluwalia Gurpreet S | Alteration of rate and character of hair growth |
DE4038693A1 (de) * | 1990-12-05 | 1992-06-11 | Heverhagen Ulrich | Mittel zum reduzieren des wachstums bzw. zum entfernen der haare am menschlichen koerper |
US5143925A (en) * | 1990-12-20 | 1992-09-01 | Douglas Shander | Alteration of rate and character of hair growth |
DE4101122A1 (de) * | 1991-01-16 | 1992-07-23 | Betrix Cosmetic Gmbh & Co | Kosmetisches oder pharmazeutisches mittel |
GB9118979D0 (en) * | 1991-09-04 | 1991-10-23 | Unilever Plc | Cosmetic composition |
US5866595A (en) * | 1991-09-26 | 1999-02-02 | The Regents Of The University Of California | Calcium antagonists for treatment of vascular restenosis |
US5425728A (en) * | 1991-10-29 | 1995-06-20 | Tankovich; Nicolai I. | Hair removal device and method |
US5328686A (en) * | 1991-10-30 | 1994-07-12 | Douglas Shander | Treatment of acne or of pseudofolliculitis barbae |
AU670554B2 (en) * | 1991-11-05 | 1996-07-25 | Gillette Company, The | Alteration of rate and character of hair growth |
US6280438B1 (en) * | 1992-10-20 | 2001-08-28 | Esc Medical Systems Ltd. | Method and apparatus for electromagnetic treatment of the skin, including hair depilation |
US5364885A (en) * | 1992-11-13 | 1994-11-15 | Ahluwalia Gurpreet S | Reduction of hair growth |
US5411991A (en) * | 1992-12-22 | 1995-05-02 | Shander; Douglas | Method of reducing hair growth employing sulfhydryl active compounds |
US6743419B1 (en) * | 1992-12-22 | 2004-06-01 | The Gillette Company | Method of reducing hair growth employing sulfhydryl active compounds |
US5648394A (en) * | 1993-05-27 | 1997-07-15 | Boxall; Brian Alfred | Topical composition for inhibiting hair growth |
US6248751B1 (en) * | 1993-05-28 | 2001-06-19 | Gurpreet S. Ahluwalia | Inhibition of hair growth |
US6239170B1 (en) * | 1993-05-28 | 2001-05-29 | Gurpreet S. Ahluwalia | Inhibition of hair growth |
US6414017B2 (en) * | 1993-05-28 | 2002-07-02 | The Gillette Company | Inhibition of hair growth |
US6046222A (en) * | 1993-09-15 | 2000-04-04 | Warner-Lambert Company | Use of thiazolidinedione derivatives in the treatment of polycystic ovary syndrome, gestational diabetes and disease states at risk for progressing to noninsulin-dependent diabetes mellitus |
US5362748A (en) * | 1993-09-15 | 1994-11-08 | The Procter & Gamble Company | Methods of using diethyldithiocarbamic acid for the prevention of hair growth |
US5474763A (en) * | 1994-03-11 | 1995-12-12 | Shander; Douglas | Reduction of hair growth |
US5455234A (en) * | 1994-03-16 | 1995-10-03 | Ahluwalia; Gurpreet S. | Inhibition of hair growth |
US5468476A (en) * | 1994-03-16 | 1995-11-21 | Ahluwalia; Gurpreet S. | Reduction of hair growth |
US5594015A (en) * | 1994-06-22 | 1997-01-14 | Regents Of The University Of California | Thiazolidine derivatives for the treatment of psoriasis |
US5554608A (en) * | 1994-09-28 | 1996-09-10 | Ahluwalia; Gurpreet S. | Inhibition of hair growth |
US5735844A (en) * | 1995-02-01 | 1998-04-07 | The General Hospital Corporation | Hair removal using optical pulses |
DE69622154T2 (de) * | 1995-02-28 | 2003-02-13 | Gillette Co | Verwendung von angiogenese-suppressoren zur hemmung des haarwuchses |
US5674477A (en) * | 1995-02-28 | 1997-10-07 | Ahluwalia; Gurpreet S. | Reduction of hair growth |
US5660836A (en) * | 1995-05-05 | 1997-08-26 | Knowlton; Edward W. | Method and apparatus for controlled contraction of collagen tissue |
US5645825A (en) * | 1995-06-07 | 1997-07-08 | The Procter & Gamble Company | Depilatory compositions comprising sulfhydryl compounds |
US5728736A (en) * | 1995-11-29 | 1998-03-17 | Shander; Douglas | Reduction of hair growth |
US5652273A (en) * | 1995-11-30 | 1997-07-29 | Henry; James | Reduction of hair growth |
US5700835A (en) * | 1995-12-22 | 1997-12-23 | Alcon Laboratories, Inc. | 3-Oxa-D-prostaglandins for lowering IOP |
US5908867A (en) * | 1996-07-18 | 1999-06-01 | Henry; James P. | Reduction of hair growth |
EP0950103B1 (en) * | 1996-11-20 | 2008-11-12 | Yale University | Survivin, a protein that inhibits cellular apoptosis, and its modulation |
US5840752A (en) * | 1996-11-21 | 1998-11-24 | Henry; James P. | Reduction of hair growth |
ZA9711121B (en) * | 1996-12-13 | 1998-06-23 | Handelman Joseph H | Reduction of hair growth. |
US6037326A (en) * | 1996-12-31 | 2000-03-14 | Styczynski; Peter | Reduction of hair growth |
EP0991372B1 (en) * | 1997-05-15 | 2004-08-04 | Palomar Medical Technologies, Inc. | Apparatus for dermatology treatment |
EP0995745B1 (en) * | 1997-06-27 | 2005-10-19 | Kaneka Corporation | Heat shock factor activity inhibitors |
US6273885B1 (en) * | 1997-08-16 | 2001-08-14 | Cooltouch Corporation | Handheld photoepilation device and method |
US5939458A (en) * | 1997-09-22 | 1999-08-17 | Henry; James P. | Reduction of hair growth |
IL122840A (en) * | 1997-12-31 | 2002-04-21 | Radiancy Inc | Hair removal device and methods |
US5958946A (en) * | 1998-01-20 | 1999-09-28 | Styczynski; Peter | Modulation of hair growth |
US6060471A (en) * | 1998-01-21 | 2000-05-09 | Styczynski; Peter | Reduction of hair growth |
US6284234B1 (en) * | 1998-08-04 | 2001-09-04 | Johnson & Johnson Consumer Companies, Inc. | Topical delivery systems for active agents |
US6020006A (en) * | 1998-10-27 | 2000-02-01 | The Gillette Company | Reduction of hair growth |
US6121269A (en) * | 1999-02-22 | 2000-09-19 | Henry; James P. | Reduction of hair growth |
US7041094B2 (en) * | 1999-03-15 | 2006-05-09 | Cutera, Inc. | Tissue treatment device and method |
US6383176B1 (en) * | 1999-03-15 | 2002-05-07 | Altus Medical, Inc. | Hair removal device and method |
FR2796278B1 (fr) * | 1999-07-16 | 2002-05-03 | Oreal | Utilisation d'au moins un hydroxystilbene comme agent anti-glycation |
AU7995300A (en) * | 1999-10-05 | 2001-05-10 | Bethesda Pharmaceuticals, Inc. | Dithiolane derivatives |
US6608108B2 (en) * | 1999-10-15 | 2003-08-19 | Johns Hopkins University | Method for treatment of tumors using nordihydroguaiaretic acid derivatives |
US6235737B1 (en) * | 2000-01-25 | 2001-05-22 | Peter Styczynski | Reduction of hair growth |
US6299865B1 (en) * | 2000-05-02 | 2001-10-09 | Peter Styczynski | Reduction of hair growth |
ITNA20000037A1 (it) * | 2000-06-02 | 2001-12-02 | Dev Biotechnological Proces Se | Filtro solare multifunzione innovativo. |
ITNA20000036A1 (it) * | 2000-06-02 | 2001-12-02 | Dev Biotechnological Proces Se | Nuovi approcci terapeutici per il trattamento della forfora. |
FR2812193B1 (fr) * | 2000-07-28 | 2003-10-24 | Oreal | Utilisation d'antagoniste des recepteurs des prostaglandines ep-2 et/ou ep-4 pour attenuer, diminuer ou stopper la pousse des cheveux et des poils dans des preparations cosmetiques |
FR2812190B1 (fr) * | 2000-07-28 | 2003-01-31 | Oreal | Utilisation d'agonistes non prostanoiques des recepteurs des prostaglandines ep-2 et/ou ep-4 comme agent cosmetique permettant d'attenuer, de diminuer ou d'arreter la chute des cheveux et des poils |
FR2812192B1 (fr) * | 2000-07-28 | 2003-01-31 | Oreal | Utilisation d'antagonistes de recepteur des prostaglandines ep-3 comme agent cosmetique permettant d'attenuer, de diminuer ou d'arreter la chute des cheveux et des poils |
FR2812191B1 (fr) * | 2000-07-28 | 2003-10-17 | Oreal | Utilisation d'agonistes du recepteur des prostaglandines e2 (ep-3) pour attenuer, diminuer ou stopper la pousse des cheveux et des poils dans des preparations cosmetiques |
US6630511B2 (en) * | 2000-08-01 | 2003-10-07 | Rolland F. Hebert | Water-soluble salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) |
US6699900B2 (en) * | 2001-04-07 | 2004-03-02 | Jan E. Zielinski | Hydrophilic and lipophilic silibinin pro-forms |
US6743822B2 (en) * | 2001-08-10 | 2004-06-01 | The Gillette Company | Reduction of hair growth |
US20040072831A1 (en) * | 2001-10-12 | 2004-04-15 | Choongwae Pharma Corporation | Reverse-turn mimetics and method relating thereto |
US7044959B2 (en) * | 2002-03-12 | 2006-05-16 | Palomar Medical Technologies, Inc. | Method and apparatus for hair growth management |
-
2005
- 2005-12-21 EP EP05855095A patent/EP1841401A1/en active Pending
- 2005-12-21 KR KR1020077013897A patent/KR20070086431A/ko not_active Application Discontinuation
- 2005-12-21 CN CNA2005800445288A patent/CN101087583A/zh active Pending
- 2005-12-21 JP JP2007547049A patent/JP2008523159A/ja active Pending
- 2005-12-21 CA CA002589762A patent/CA2589762A1/en not_active Abandoned
- 2005-12-21 BR BRPI0519217-0A patent/BRPI0519217A2/pt not_active Application Discontinuation
- 2005-12-21 MX MX2007007624A patent/MX2007007624A/es not_active Application Discontinuation
- 2005-12-21 AU AU2005319166A patent/AU2005319166A1/en not_active Abandoned
- 2005-12-21 US US11/313,501 patent/US20060135461A1/en not_active Abandoned
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102793639A (zh) * | 2011-12-16 | 2012-11-28 | 百奥迈科生物技术有限公司 | 一种植物提取物介导的药物透皮导入系统及其透皮方法 |
WO2014029143A1 (zh) * | 2012-08-23 | 2014-02-27 | 百奥迈科生物技术有限公司 | 一种植物提取物介导的药物透皮导入系统及其透皮方法 |
CN107308451A (zh) * | 2017-06-08 | 2017-11-03 | 深圳培元生物科技有限公司 | 一种毛发生长抑制剂及其用途 |
Also Published As
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US20060135461A1 (en) | 2006-06-22 |
EP1841401A1 (en) | 2007-10-10 |
BRPI0519217A2 (pt) | 2009-01-06 |
CA2589762A1 (en) | 2006-06-29 |
JP2008523159A (ja) | 2008-07-03 |
KR20070086431A (ko) | 2007-08-27 |
AU2005319166A1 (en) | 2006-06-29 |
MX2007007624A (es) | 2007-08-03 |
WO2006069192A1 (en) | 2006-06-29 |
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