CN1283507A - 处理皮肤色素沉着的方法 - Google Patents
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Abstract
本发明涉及改变皮肤色素沉着的方法及组合物,更确定地说,本发明涉及一种化合物其可影响黑色素生成且可利用PAR-2途径作为去色素剂或作为使皮肤变黑的药剂使用。
Description
本案系美国专利申请序号09/110,409(Attorney Docket No.JBP 430)的部份继续申请案,其并于本文供参考。
本发明系关于使皮肤产生色素沉着及/或造成皮肤除色之方法及组合物,更确定地说,本发明系关于一种化合物其可影响黑色素生成且可作为去色素剂或作为使皮肤变黑的药剂使用。
多年以来人类一值都关心皮肤的颜色,尤其是去除色素沉着过度的能力,例如发现在老人斑、雀斑、或一般性的老化皮肤,是要求均匀肤色之个人有兴趣之处,在地球上的某些地区,普遍希望身体能白化,也有色素沉着不足及色素沉着过度疾病需要治疗,同样地,能产生黄褐色外观而不会因为太阳辐射造成无法医治的光照伤害对许多人很重要,曾经提出许多方法以完成去除色素,以及完成使皮肤变黑,例如曲酸、氢醌、视黄醛及曾经用于去除色素的其他化学物质,曾经利用二羟基丙酮等化合物在不暴露于阳光的情况下使皮肤变成黄褐色的能力。
许多这些先前的解决方法不曾发现可以接受,在使用这些先前组合物的皮肤区域之间,经常有明显的分界线,因此需要精确地使用全部这些化合物以便达到所要的结果,许多这些化合物被发现对皮肤相当刺激因此不希望使用。
对黑色素生成化学及酶原理的了解,在文献中有许多记载,黑色素细胞从胚胎神经管突触转移至皮肤内,造成分泌粒、色素颗粒而产生黑色素,黑色素生成发生在色素颗粒内,且黑色素随后经由黑色素细胞树状突分布至角质形成细胞,黑色素生成的关键酶是酪氨酸酶,其引发级联反应将酪氨酸转化成生物聚合物黑色素,两种已知的与酪氨酸酶相关的蛋白质(TRP’s)是TRP-1及TRP-2,这些蛋白质与酪氨酸酶共有约40%之同源性且在黑色素生成中具有催化活性以及调节作用,TRP-1在黑色素细胞中是最多的糖蛋白。
虽然事实上黑色素生成之化学及酶学原理有完善的记录,其在细胞水平的调节只有部份了解,酪氨酸酶及TRP’s与溶酶体相关的膜蛋白质(LAMP)基因族共有结构及生物性质,因此其靶至色素颗粒膜可引发其活化,这些蛋白质在胞浆尾之磷酸化作用/去磷酸化作用可牵涉调节黑色素生成,蛋白质激酶C(PKC)族之β异构物形式经证明可经由酪氨酸酶活化作用调节人类的黑色素生成,酪氨酸酶、TRP-1及TRP-2之基因释出经协调,全部三种酶在人类的表皮释出,在黑色素细胞与角质形成细胞共同培养时,这些转录物分别在45∶45∶10之比率下释出,在单独培养黑色素细胞时,只存在TRP-1转录物,表示角质形成细胞衍生的讯号牵涉协调释出这些基因,角质形成细胞-黑色素细胞相互作用之调节及色素颗粒转移至角质形成细胞之机制尚未了解。
蛋白酶活化的受体-2(PAR-2)是一种七个跨膜G-蛋白质偶联的受体,其系相关但明显不同于凝血酶受体(TR,也称为PAR-1,及PAR-3)之序列,两种受体经由在细胞外区域分解的精氨酸-丝氨酸蛋白水解性活化,然后新产生的N-末端活化这些受体如栓系配位体,两种受体可经由胰蛋白酶活化,但是只有TRs经由凝血酶活化,只有PAR-2经由巨噬细胞类胰蛋白酶活化,两种受体也可经由相当于其新N-末端与受体分解无关的肽活化,小白鼠PAR-2活化肽之SLIGRL可等势性地活化人类受体,虽然TR之功能经详细记载,PAR-2之生物学尚未完全证明,PAR-2活化作用在抑制角质形成细胞生长及分化之角色最近经揭示(Derian等,“新的一族蛋白酶激活受体对人角质形成细胞生长和分化的差向调节”,Cell Growth&Differentiation,Vol.8,pp.743-749,July 1997)。
根据本发明,我们发现一种影响哺乳动物皮肤色素沉着变化的方法,包括将可影响PAR-2途径的化合物给哺乳动物皮肤局部用药,本发明组合物可含一或多种作为胰蛋白酶、类胰蛋白酶、丝氨酸蛋白酶或PAR-2刺激剂之化合物用于增加色素沉着,或者是,其可含一或多种作为丝氨酸蛋白酶抑制剂、胰蛋白酶抑制剂、凝血酶抑制剂、类胰蛋白酶抑制剂、PAR-2途径抑制剂或PAR-2拮抗剂之化合物用于减低色素沉着或″去除色素″。
在本文中使用时,″哺乳动物″根据Webster’s Medical Desk Dictionary 407(1986)之定义,系指包括″哺乳动物″纲之较高等脊椎动物之任何成员,且包括但不限于人类。在本文中使用时,″受体″将包括细胞内及细胞外的受体且系指可接受及转导讯号之分子,名词PAR-2系指蛋白酶活化的受体-2或相关的蛋白酶活化受体,蛋白酶活化的受体-2(以下称为″PAR-2″)是一种丝氨酸-蛋白酶活化受体,其可在多种组织中释出,包括角质形成细胞及纤维组织母细胞,凝血酶受体(也称为PAR-1,以下称为″TR″)是一种丝氨酸-蛋白酶活化受体,其可在多种组织中释出,包括角质形成细胞,PAR-2及TR在皮肤中的生物学作用尚未完全了解,但是我们发现角质形成细胞及黑色素细胞经由PAR-2途径之相互作用影响黑色素生成,我们发现凝血酶抑制剂及/或类胰蛋白酶抑制剂及/或胰蛋白酶抑制剂及PAR-2拮抗剂可作为去色素剂使用而不会刺激皮肤,PAR-2刺激剂及丝氨酸蛋白酶例如胰蛋白酶及类胰蛋白酶可作为皮肤黑化剂使用,而且PAR-2可作为靶用于皮肤白化及黑化剂。
我们还发现Bowman-Birk型抑制剂之BBI也可作为活性去色素剂使用,在美国专利申请序号09/110,409中建议作为去色素剂使用的得自大豆的萃取物及混合物含STI及BBI,我们现在发现单独BBI可影响皮肤除色,在本申请案中陈述的全部调制物及组合物中,可使用与STI相同浓度范围的BBI。
图1显示含非洲人-美洲人供体黑色素细胞的表皮同等物,经由从同等物上方观察显示没有色素沉着,证明用BBI处理可降低色素沉积在这些同等物中。
图2显示含非洲人-美洲人供体黑色素细胞的表皮同等物,经由这些同等物组织学切片的Fontana-Mason色素沉着法,证明用BBI处理可降低色素沉积在这些同等物中。
图3显示含非洲人-美洲人供体黑色素细胞的表皮同等物,经由这些同等物组织学切片的Fontana-Mason色素沉着法,证明在剂量相关方式下用增加浓度之BBI处理可降低色素沉积在这些同等物中。
图4是BBI处理后,定量抑制色素沉积之百分比图。
图5显示猪皮用BBI及STI处理后之F&M染色组织切片,用BBI及STI处理后,猪皮内的黑色素沉积明显地降低。
图6是例如图5显示的皮肤切片之电脑影像分析图,此图将用BBI或STI处理后猪皮的抑制色素沉积百分比定量化。
我们发现在哺乳动物皮肤中,胰蛋白酶、类胰蛋白酶及PAR-2刺激剂可用于增加色素沉着且胰蛋白酶抑制剂及/或类胰蛋白酶抑制剂及/或凝血酶抑制剂及PAR-2拮抗剂可作为减低色素沉着,我们认为揭示在并于本文供参考之美国专利5,523,308号并作为凝血酶及/或胰蛋白酶及/或类胰蛋白酶抑制剂的部份化合物,将可在本发明方法中使用,部份这些化合物也揭示在Costanzo等,“探测S1’亚部位的潜在凝血酶:基于杂环激活的羰基的三肽过渡状态类似物”J.Med.Chem.,1996,Vol 39,pp.3039-3043且具有下列结构式:其中:
A选自C1-8烷基、羧基C1-8烷基、C1-4烷酯基C1-4烷基、苯基C1-4烷基、经取代之苯基C1-4烷基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、甲酰基、C1-4烷酯基、C1-2烷基羰基、苯基C1-4烷酯基、C3-7环烷基羰基、苯基羰基、经取代之苯基羰基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、 C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、C1-4烷基磺酰基、C1-4烷氧基磺酰基、全氟C1-4烷基磺酰基、苯基磺酰基、经取代之苯基磺酰基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、10-樟脑基磺酰基、苯基C1-4烷基磺酰基、经取代之苯基C1-4烷基磺酰基、C1-4烷基亚磺酰基、全氟C1-4烷基亚磺酰基、苯基亚磺酰基、经取代之苯基亚磺酰基(其中苯基之取代基独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、苯基C1-4烷基亚磺酰基、经取代之苯基C1-4烷基亚磺酰基、1-萘基磺酰基、2-萘基磺酰基或经取代之萘基磺酰基(其中萘基之取代基独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、1-萘基亚磺酰基、2-萘基亚磺酰基或经取代之萘基亚磺酰基(其中萘基之取代基独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基);
D或L氨基酸在其羧基末端偶合至式Ⅰ所示之氮且系选自丙氨酸、天冬酰胺、2-铃兰氨酸、甘氨酸、N-C18烷基甘氨酸、脯氨酸、1-氨基-1-环C3-8烷基羧酸、噻唑烷-4-羧酸、5,5-二甲基噻唑烷-4-羧酸、唑烷-4-羧酸、六氢吡啶羧酸、缬氨酸、甲硫氨酸、半胱氨酸、丝氨酸、苏氨酸、正亮氨酸、亮氨酸、第三亮氨酸、异亮氨酸、苯基丙氨酸、1-萘基丙氨酸、2-萘基丙氨酸、2-噻吩基丙氨酸、3-噻吩基丙氨酸、[1,2,3,4]-四氢异喹啉-1-羧酸及[1,2,3,4]-四氢异喹啉-2-羧酸,其中该氨基酸之氨基末端连接至如下基团之一:C1-4烷基、四唑-5-基C1-2烷基、羧基C1-4烷基、C1-4烷酯基C1-4烷基、苯基C1-4烷基、经取代之苯基C1-4烷基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、1,1-二甲基C1-4烷基、3-苯基-2-羟基丙酰基、2,2-二苯基-1-羟基乙基羰基、[1,2,3,4]-四氢异喹啉-1-羰基、[1,2,3,4]-四氢异喹啉-3-羰基、1-甲基氨基-1-环己羰基、1-羟基-1-环己羰基、1-羟基-1-苯基乙酰基、1-环己基-1-羟基乙酰基、3-苯基-2-羟基丙酰基、3,3-二苯基-2-羟基丙酰基、3-环己基-2-羟基丙酰基、甲酰基、C1-4烷酯基、C1-12烷基羰基、全氟C1-4烷基、C1-4烷基羰基、苯基C1-4烷酯基、经取代之苯基C1-4烷基羰基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、1,1-二苯基C1-4烷基羰基、经取代之1,1-二苯基C1-4烷基羰基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1- 4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、全氟C1-4烷基磺酰基、C1-4烷基磺酰基、C1-4烷氧基磺酰基、苯基磺酰基、经取代之苯基磺酰基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、10-樟脑基磺酰基、苯基C1-4烷基磺酰基、经取代之苯基C1-4烷基磺酰基、全氟C1-4烷基亚磺酰基、C1-4烷基亚磺酰基、苯基亚磺酰基、经取代之苯基亚磺酰基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、1-萘基磺酰基、2-萘基磺酰基、经取代之萘基磺酰基(其中萘基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、1-萘基亚磺酰基、2-萘基亚磺酰基及经取代之萘基亚磺酰基(其中萘基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基);
或是含两个氨基酸之多肽,其中第一个氨基酸是D或L氨基酸,经由其羧基末端键结至式Ⅰ所示之氮且系选自包括甘氨酸、N-C18烷基甘氨酸、丙氨酸、2-铃兰氨酸、脯氨酸、噻唑烷-4-羧酸、5,5-二甲基噻唑烷-4-羧酸、唑烷-4-羧酸、1-氨基-1-环C3-8烷基羧酸、3-羟基脯氨酸、4-羟基脯氨酸、3-(C1-4烷氧基)脯氨酸、4-(C1-4烷氧基)脯氨酸、3,4-去氢脯氨酸、2,2-二甲基-4-噻唑烷羧酸、2,2-二甲基-4-唑烷羧酸、六氢吡啶羧酸、缬氨酸、甲硫氨酸、半胱氨酸、天冬酰胺、丝氨酸、苏氨酸、亮氨酸、第三亮氨酸、异亮氨酸、苯基丙氨酸、1-萘基丙氨酸、2-萘基丙氨酸、2-噻吩基丙氨酸、3-噻吩基丙氨酸、[1,2,3,4]-四氢异喹啉-2-羧酸、天冬氨酸-4-C1-4烷酯及谷氨酸-5-C1-4烷酯,
且第二个D或L氨基酸是连接至该第一个氨基酸之氨基末端且系选自包括苯基丙氨酸、4-苯甲酰基苯基丙氨酸、4-羧基苯基丙氨酸、4-(羧基C1-2烷基)苯基丙氨酸、经取代之苯基丙氨酸(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、3-苯并噻吩基丙氨酸、4-联苯基丙氨酸、高苯基丙氨酸、八氢吲哚-2-羧酸、2-吡啶基丙氨酸、3-吡啶基丙氨酸、4-噻唑基丙氨酸、2-噻吩基丙氨酸、3-(3-苯并噻吩基)丙氨酸、3-噻吩基丙氨酸、色氨酸、酪氨酸、天冬酰胺、3-三C1-4烷基矽烷基丙氨酸、环己基甘氨酸、二苯基甘氨酸、苯基甘氨酸、甲硫氨酸亚砜、甲硫氨酸砜、2,2-二环己基丙氨酸、2-(1-萘基丙氨酸)、2-(2-萘基丙氨酸)、苯基经取代之苯基丙氨酸(其中取代基是选自C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、天冬氨酸、天冬氨酸-4-C1-4烷基、谷氨酸、谷氨酸-5-C1-4烷酯、环C3-8烷基丙氨酸、经取代之环C3-8烷基丙氨酸(其中环取代基是羧基、C1-4烷基羧基、C1-4烷酯基或氨基羰基)、2,2-二苯基丙氨基及全部α-C1-5烷基之其全部氨基酸衍生物,其中该第二个氨基酸之氨基末端是未经取代或经选自包括甲酰基、C1-12烷基、四唑-5-基C1-2烷基、羧基C1-8烷基、C1-4烷酯基C1-4烷基、苯基C1-4烷基、经取代之苯基C1-4烷基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、1,1-二苯基C1-4烷基、C1-6烷酯基、苯基C1-6烷酯基、C1-2烷基羰基、全氟C1-4烷基C0-4烷基羰基、苯基C1-4烷基羰基、经取代之苯基C1-4烷基羰基(其中苯基之取代基是独立地选自一或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、1,1-二苯基C1-4烷基、全氟C1-4烷基、C1-4烷酯基、10-樟脑基磺酰基、苯基C1-4烷基磺酰基、经取代之苯基C1-4烷基磺酰基、C1-4烷基亚磺酰基、全氟C1-4烷基亚磺酰基、苯基亚磺酰基、经取代之苯基亚磺酰基(其中苯基之取代基是独立地选自-或多个C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、苯基C1-4烷基亚磺酰基、经取代之苯基C1-4烷基亚磺酰基、1-萘基磺酰基、2-萘基磺酰基、经取代之萘基磺酰基(其中萘基之取代基是选自C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基)、1-萘基亚磺酰基、2-萘基亚磺酰基及经取代之萘基亚磺酰基(其中萘基之取代基是选自C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基或C1-4烷酯基);R1是选自包括氢及烷基;
R2是选自包括氨基C2-5烷基、胍基C2-5烷基、C1-4烷基胍基C2-5烷基、二C1-4烷基胍基C2-5烷基、脒基C2-5烷基、C1-4烷基脒基C2-5烷基、二C1-4烷基脒基C2-5烷基、C1-3烷氧基C2-5烷基、苯基、经取代之苯基(其中取代基是独立地选自一或多个氨基、脒基、胍基、C1-4烷基氨基、C1-4二烷基氨基、卤素、全氟C1-4烷基、C1-4烷基、C1-3烷氧基或硝基)、苄基、苯基经取代之苄基(其中取代基是独立地选自一或多个氨基、脒基、胍基、C1-4烷基氨基、C1-4二烷基氨基、卤素、全氟C1-4烷基、C1-4烷基、C1-3烷氧基或硝基)、羟基C2-5烷基、C1-5烷基氨基C2-5烷基、C1-5二烷基氨基C2-5烷基、4-氨基环己基C0-2烷基及C1-5烷基;
p是0或1;
E是杂环基且系选自包括唑啉-2-基、唑-2-基、噻唑-2-基、噻唑-5-基、噻唑-4-基、噻唑啉-2-基、咪唑-2-基、4-氧代-2-喹 啉-2-基、2-吡啶基、3-吡啶基、苯并[b]噻吩-2-基、三唑-4-基、三唑-6-基、吡唑-2-基、4,5,6,7-四氢苯并噻唑-2-基、萘并[2,1-d]噻唑-2-基、萘并[1,2-d]噻唑-2-基、喹啉-2-基、异喹啉-1-基、异喹啉-3-基、苯并[b]呋喃-2-基、吡嗪-2-基、喹唑啉-2-基、异噻唑-5-基、异噻唑-3-基、嘌呤-8-基及经取代之杂环基其中取代基是选自包括C1-4烷基、全氟C1-4烷基、C1-4烷氧基、羟基、卤素、酰氨基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、羧基、C1-4烷酯基、羟基或苯基C1-4烷基氨基羰基;
或其药学上可接受之盐类。
更确定地说,我们认为部份上式化合物含d-苯基丙氨酸-脯氨酸-精氨酸组成要素可以影响抑制PAR-2途径且造成去除色素,作为凝血酶及胰蛋白酶抑制剂且可有效使哺乳动物皮肤去除色素之一种特别较佳的化合物是(S)-N-甲基-D-苯基丙氨酸基-N-[4-[(氨基亚氨基甲基)氨基]-1-(2-苯并噻唑基羰基)丁基]-L-脯氨酸酰胺(化学文摘名称)(以下称为″化合物I″),我们建议同系物或功能类似于化合物I且陈述在美国专利5,523,308号之其他化合物可在本发明方法及组合物中具有活性。
抑制胰蛋白酶的其他化合物,例如丝氨酸蛋白酶抑制剂,且尤其是大豆胰蛋白酶抑制剂(STI)也可在本发明方法中使用,大豆、青豆及黑豆萃取物、以及从这些豆类制成的天然产物例如但不限于豆奶、豆浆、日本豆浆等,也可经由此机制减少色素沉着。
丝氨酸蛋白酶抑制剂的其他来源可从属于下列植物族之物种萃取:茄科(例如马铃薯、番茄、粘果酸浆等);禾本科(例如稻米、荞麦、高粱、小麦、大麦、燕麦等);葫芦科(例如黄瓜、南瓜、葫芦、丝瓜等);及较宜是豆科(例如豆类、豌豆、滨豆、花生等)。
虽然不局限在下列理论,我们的理论是该化合物可经由直接或间接与角质形成细胞PAR-2或与其活化蛋白酶作用,因而直接或间接影响黑色素生成而影响皮肤色素沉着,本发明化合物可能在增加色素沉着之情形下引发或在减低色素沉着之情形下减少讯号经由黑色素细胞至输送色素颗粒,或经由皮肤角质形成细胞接受色素颗粒。
最近我们证实不同种类得自荚果类蛋白质的Bowman-Birk抑制剂(″BBI″)也可作为着色剂。
虽然STI是一种具有主要胰蛋白酶抑制活性的21KD蛋白质,从大豆衍生的BBI是一种较小的8KD蛋白质,其可抑制胰凝乳蛋白酶及胰蛋白酶,不同于STI,BBI不含Kunitz型部份,此建议与丝氨酸蛋白酶有不同的相互作用,已知BBI在多种活体内及试管内模型中具有防癌症能力,在部份癌症动物模型中,发现BBI具有强烈的抗炎效应,BBI对热变性的抵抗性高于STI,对于BBI的回顾文献,可参见Kennedy AR,化学防护剂:蛋白酶抑制剂,Pharmacol Ther 78:3,167-209,Jun,1998。
在本发明组合物及方法中具有活性的化合物可通过本领域技术人员已知的任何方法局部输送,如果局部活性医药或化妆剂之输送参数需要,本发明的局部活性组合物较宜再含医药或化妆上可需要之载体,其可作为输送系统以促进局部活性剂穿透至皮肤内。
供局部输送部份本发明组合物特别是蛋白质例如胰蛋白酶及STI的一种可接受的载体可含脂质体,该脂质体更宜是非离子型且含a)二月桂酸甘油酯(含量较宜是介于约5%及约70%重量);b)具有见于胆固醇的类固醇骨架的化合物(含量较宜是介于约5%及约45%重量);及c)一或多种含从约12至约18个碳原子的脂肪酸醚类(总含量较宜是介于约5%及约70%重量),其中脂质体各成份化合物之比率较宜是约37.5∶12.5∶33.3∶16.7,最宜是由二月桂酸甘油酯/胆固醇/聚氧乙烯-10-硬脂酰基醚/聚氧乙烯-9-月桂基醚组成的脂质体(GDL脂质体),以组合物的总体积为基准,脂质体的较佳存在量是从约10毫克/毫升至约100毫克/毫升,更宜从约20毫克/毫升至约500毫克/毫升,约37.5∶12.5∶33.3∶16.7之比率为最佳,合适的脂质体较宜按实例1所述方法进行制备,虽然本领域中惯用的其他方法也可接受。
制备上述组合物可经由在合适的容器内掺合所需成份,并在环境情形下在非离子脂质体制备领域所熟知的任何惯用高剪力混合装置中将其混合,例如揭示在Niemiec等:“非离子脂质体组合物对肽类药物给毛囊皮脂腺单元局部给药的影响:用Hamster耳模型进行体内研究”,12 Pharm.Res.1184-88(1995)(″Niemiec″),其全文并于本文供参考,我们发现在本发明组合物中存在这些脂质体可促进部份本发明组合物的色素沉着能力。
其他较佳的调制物可含例如豆浆或直接得自荚果类或其他合适植物的其他液体调制物,例如此种调制物可含大量比率的豆浆、维持豆浆的物理稳定性的乳化剂、及视需要选用的螯合剂、防腐剂、润滑剂、湿润剂及/或稠化剂或胶凝剂。
本领域技术人员已知的油/水乳化剂、水/油乳化剂、溶剂基质之调制物及水凝胶也可作为载体使用供输送本发明的组合物。
需要调制的活性化合物来源一般决定于化合物的特定形式,小的有机分子及肽基片断可化学合成,并以合适用于医药/化妆用途的纯品形式供应,天然萃取物可用本领域已知的技术纯化,本领域技术人员也可采用重组体来源的化合物。
在另一个具体实施例中,局部用活性医药或化妆组合物可视需要结合其他成份例如增湿剂、化妆辅剂、抗氧化剂、漂白剂、胰蛋白酶抑制剂及其他已知的去色素剂、表面活性剂、发泡剂、调适剂、湿润剂、香料、粘合剂、缓冲剂、防腐剂、防晒剂等,本发明组合物也可含活性量的视黄醛(例如结合至任何视黄醛受体的化合物),包括例如全反视黄醛、视黄醇、全反视黄醛及/或视黄醇之酯类等。
局部用活性医药或化妆组合物必须施加有效量,以影响哺乳动物皮肤色素沉着之变化,在本文中使用的″有效量″系指足够覆盖需要改变色素沉着的皮肤表面区域之量,当需要色素沉着变化时,较宜将组合物充分施加至皮肤表面,以平方公分皮肤表面为基准,存在从约2微升/平方公分至约200微升/平方公分的局部用活性剂,当使用凝血酶及胰蛋白酶抑制剂例如化合物I或其同系物时,不论是合成或得自天然调制物中,此活性化合物必须存在的量是从约0.0001%至约15%重量/体积组合物,更宜其存在量是从约0.0005%至约5%重量/体积组合物,最宜其存在量是从组合物的约0.001至约1%,当然这些范围是建议用于前述成份,较低的范围值是用于具有高治疗指数且不需要明显较大量浓度或剂量就可有效进行本发明方法之PAR-2途径刺激剂/拮抗剂及/或抑制剂,此种化合物可以合成或天然衍生。
直接从植物或植物来源制成的液体衍生物及天然萃取物可以从约1至约99%浓度(重量/体积)下用于本发明组合物,天然萃取物及天然来源的蛋白酶抑制剂例如STI可有不同的从约0.01%至约20%的较佳范围,更宜为组合物的约1%至约10%,当然,本发明活性剂的混合物可以掺混且同时用在同一调制物中,或依序使用不同的调制物。
我们意外地发现当局部用的活性剂例如PAR-2刺激剂及/或抑制剂及胰蛋白酶及/或凝血酶及/或类胰蛋白酶及/或其抑制剂局部用于动物皮肤时,可以达到色素沉着的明显变化,去色素剂(以及本发明的其他色素沉着影响剂)较宜在相当高浓度及剂量(具有高治疗指数的化合物例如化合物I及相关的化合物是从约0.005%至约1%;植物的液体衍生物及萃取物是从约20%至约99%;天然萃取物及天然来源的蛋白酶抑制剂例如STI或其混合物部份是从约1%至约20%)下每天一或二次施加于哺乳动物皮肤直到皮肤色素沉着明显变化,此需要进行从约四至约十周或更久,随后一但达到色素沉着变化后,较低浓度及剂量(具有高治疗指数的化合物例如化合物I及相关的化合物是从约0.00001%至约0.005%;植物液体衍生物及萃取物是从约10%至约90%;天然萃取物及天然来源的蛋白酶抑制剂例如STI或其混合物部份是从约0.01%至约5%)的活形成份可在较不常用的时间表例如每天一次至约每周两次下使用,本发明活性剂之效应为可逆性,因此为了维持这些效应,必须进行持续使用或用药。
在此举例说明的本发明可在缺乏本文具体公开的任何成份、组份或步骤下进行,以下陈述数个实施例以进一步说明本发明的本质及其实施方法,但是不能作为本发明方法及组合物的范围限制。
实施例1:BBI影响色素沉着
为了研究BBI在色素沉着上的可能作用,使用含黑色素细胞的试管内表皮同等物系统,在此研究中使用的表皮同等物系统可购自MatTek Co.of Ashland,MA的MelanoDerm mel-300系统,此系统含人类正常的黑色素细胞,以及得自非洲人-美洲人包皮的正常人的表皮角质形成细胞,这些细胞经培养而形成多层高度分化模式的人类表皮,在下列实例中,同等物用BBI(0.1%)处理三天并在开始处理后第四天收取样品,收取的同等物先与没有色素沉着的样品比较颜色,然后使用本领域已知的Fontana-Mason(F&M)色素沉着法进行组织检视,F&M色素沉着法是一种银色素沉着技术,其清楚且乾净地标示具有高硝酸银还原活性的黑色素,也捕捉色素沉着切片的影像进行影像分析,至少每个实验有三个同等物,每个同等物进行三个切片,在Gateway 2000 P5-100电脑上使用Empire Images database 1.1(Media Cybernetics,Silver Springs,MD)捕捉影像,使用Image Pro Plus 3.0版分析影像,测量的参数是黑色素细胞内银沉积物表面积及各画素之密度发光度,″色素沉着因子″定义为银沉积物表面积除以总表皮面积,以1(100%)的值定为未经处理之对照组,且处理群的值对其相关的对照组标准化。
如图1所示,未经处理的mel-300同等物在没有任何色素沉着下可看出较黑暗,BBI处理的同等物之颜色比这些对照组淡,证明BBI在视觉上有减少色素沉着之能力,图2显示这些同等物在F&M色素沉着后的组织切片,在此图中,黑色区域代表在黑色素细胞及角质形成细胞内的黑色素沉积物,如图2所示,BBI处理导致减少黑色素沉积在处理后的同等物的黑色素细胞及角质形成细胞内,影像分析显现经BBI处理的同等物相对于对照组只有50.6%的黑色素沉积物。
实施例2:BBI去除色素沉着的效应是剂量-反应性的
如图1所示将含黑色素细胞的表皮同等物用从0.001%至0.1%之增加浓度的BBI处理,相同于实例1叙述的实验步骤后,发现BBI的去除色素效应是与剂量相关的,图3显示经处理的同等物的F&M色素沉着切片,证明剂量-反应及去除色素沉着效应可低至0.001%BBI,图4所示之电脑化影像分析将此效应定量化,进一步证明其剂量-反应性本质。
实施例3:活体内证明BBI的去除色素沉着效应
使用含20毫克/毫升脂质体的BBI或STI的1%PBS溶液处理深色皮肤的Yucatan猪,非离子性脂质体制剂例如揭示在Niemiec等,“非离子脂质体组合物对肽类药物给毛囊皮脂腺单元局部给药的影响:用Hamster耳膜型进行体内研究”,12 Pharm.Res.1184-88(1995)(″Niemiec″),其全文并于本文供参考,这是本领域中熟知的,在JBP-430中有揭示,我们发现在本发明组合物中存在这些脂质体时,可促进某些本发明组合物的去除色素沉着能力,GDL脂质体的制备在上述Niemiec等的文章中有描述,例外的是有下列变化:非离子性脂质体调制物含二月桂酸甘油酯(Emulsynt GDL,ISP Van Dyk)/胆固醇(Croda)/聚氧乙烯-10-硬脂酰基醚(Brij76,ICI)/聚氧乙烯-9-月桂基醚的比率是37.5∶12.5∶33.3∶16.7,在制备脂质体时使用Hepes缓冲剂0.05M,pH7.4(Gibco-BRLof Gaithersburg,MD)作为水相。
将BBI、STI及脂质体载体制剂各施加至猪肋腹的两个部位上,每天两次,一星期五天共进行八周,经处理八周后,使用BBI或STI导致视觉上的浅色化效应,从未经处理及处理部位的F&M色素沉着皮肤切片组织分析证实此观察,图5显示经处理的猪的F&M色素沉着皮肤切片,证明用BBI或STI处理的部位大幅减少颜色沉积,图6显示电脑化影像分析将此效应定量化,进一步证明BBI的去除色素沉着效应。
Claims (10)
1.一种可有效改变哺乳动物皮肤色素沉着的方法,其包括将色素沉着变化有效量的Bowman-Birk抑制剂或含Bowman-Birk抑制剂之天然萃取物对哺乳动物用药。
2.一种去除哺乳动物皮肤色素沉着的方法,其包括将色素沉着淡化有效量的Bowman-Birk抑制剂或含Bowman-Birk抑制剂的天然萃取物对哺乳动物用药。
3.如权利要求2所述的方法,其中该Bowman-Birk抑制剂得自一或多种豆科、茄科、禾本科及葫芦科植物。
4.如权利要求3所述的方法,其中该化合物得自荚果类。
5.如权利要求4所述的方法,其中该化合物得自未经变性的大豆萃取物。
6.如权利要求5所述的方法,其中该化合物得自未经变性的大豆萃取物之部份。
7.一种可有效改变哺乳动物皮肤色素沉着的组合物,其中含色素沉着变化有效量的Bowman-Birk抑制剂或含Bowman-Birk抑制剂之天然萃取物。
8.一种去除哺乳动物皮肤色素沉着的组合物,其中含色素沉着淡化有效量的Bowman-Birk抑制剂或含Bowman-Birk抑制剂之天然萃取物。
9.如权利要求8所述的组合物,其中该Bowman-Birk抑制剂得自一或多种豆科、茄科、禾本科及葫芦科植物。
10.如权利要求9所述的组合物,其中该化合物得自未经变性的大豆萃取物。
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-
1999
- 1999-07-27 US US09/361,429 patent/US6750229B2/en not_active Expired - Lifetime
-
2000
- 2000-07-25 AU AU48819/00A patent/AU779448B2/en not_active Ceased
- 2000-07-26 EP EP00306352A patent/EP1077063B1/en not_active Expired - Lifetime
- 2000-07-26 AT AT00306352T patent/ATE371475T1/de not_active IP Right Cessation
- 2000-07-26 DE DE60036169T patent/DE60036169T2/de not_active Expired - Lifetime
- 2000-07-26 ES ES00306352T patent/ES2292406T3/es not_active Expired - Lifetime
- 2000-07-26 CA CA002314569A patent/CA2314569A1/en not_active Abandoned
- 2000-07-26 KR KR1020000042946A patent/KR100778086B1/ko not_active IP Right Cessation
- 2000-07-27 JP JP2000227770A patent/JP4808304B2/ja not_active Expired - Fee Related
- 2000-07-27 MX MXPA00007388A patent/MXPA00007388A/es active IP Right Grant
- 2000-07-27 BR BR0003184-4A patent/BR0003184A/pt not_active Application Discontinuation
- 2000-07-27 CN CNB001222872A patent/CN1163261C/zh not_active Expired - Fee Related
- 2000-10-05 TW TW089114978A patent/TWI292715B/zh not_active IP Right Cessation
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2001
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106999372A (zh) * | 2014-09-29 | 2017-08-01 | Elc 管理有限责任公司 | 用于刺激角质形成细胞的分化以美白色素沉着过度的皮肤的活性物 |
Also Published As
Publication number | Publication date |
---|---|
JP2001081011A (ja) | 2001-03-27 |
JP4808304B2 (ja) | 2011-11-02 |
CN1163261C (zh) | 2004-08-25 |
DE60036169D1 (de) | 2007-10-11 |
HK1032543A1 (en) | 2001-07-27 |
BR0003184A (pt) | 2001-12-18 |
US20020065300A1 (en) | 2002-05-30 |
MXPA00007388A (es) | 2004-03-09 |
AU779448B2 (en) | 2005-01-27 |
KR100778086B1 (ko) | 2007-11-26 |
KR20010049880A (ko) | 2001-06-15 |
EP1077063A2 (en) | 2001-02-21 |
US6750229B2 (en) | 2004-06-15 |
TWI292715B (en) | 2008-01-21 |
ES2292406T3 (es) | 2008-03-16 |
CA2314569A1 (en) | 2001-01-27 |
EP1077063A3 (en) | 2003-02-12 |
AU4881900A (en) | 2001-02-15 |
ATE371475T1 (de) | 2007-09-15 |
EP1077063B1 (en) | 2007-08-29 |
DE60036169T2 (de) | 2008-05-21 |
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