CN1642538B - 阿达帕林治疗皮肤病的用途 - Google Patents

阿达帕林治疗皮肤病的用途 Download PDF

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CN1642538B
CN1642538B CN038058391A CN03805839A CN1642538B CN 1642538 B CN1642538 B CN 1642538B CN 038058391 A CN038058391 A CN 038058391A CN 03805839 A CN03805839 A CN 03805839A CN 1642538 B CN1642538 B CN 1642538B
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M·格雷伯
J·切尔尼莱夫斯基
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Abstract

本发明涉及6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸(阿达帕林)或其盐在制备治疗伴有炎症或增生的皮肤病的药物组合物中的用途，所述药物组合物包含占组合物总重量0.3重量％的阿达帕林。

Description

阿达帕林治疗皮肤病的用途
本发明涉及6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸在药物组合物，特别是皮肤病学组合物中，用于治疗伴有炎症或增生的皮肤病的用途，所述6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸的化学结构如下所示：
Figure G038058391D00011
6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸(以下称作阿达帕林)是由萘甲酸衍生而来的类维生素A物质，具有抗炎功能。该分子已被用于局部治疗寻常痤疮和对类维生素A物质敏感的皮肤病。
在EP 0 199 636中申请人对阿达帕林已有描述，并且在EP 0 358574中提供了合成该组分的方法。
该申请人销售以0.1％重量浓度配制的阿达帕林，为醇洗液、水凝胶和乳膏形式。这些组合物用于治疗痤疮。
最后，阿达帕林被描述为对光损伤皮肤具有有益功能(“阿达帕林0.1和0.3％的凝胶和赋形剂在光损伤皮肤上作用的详细评价”，M.Goldfarb等人，Clinical Dermatology，Vienna，Austria，2000年5月)。
申请人现已研究开发出一种新的药物组合物，含有0.3％重量浓度的阿达帕林，用于治疗伴有炎症或增生的皮肤病。具体地，申请人吃惊地发现，本发明的组合物，除显示比已知组合物更好的治疗功效外，还具有与已知含有较低浓度活性成分的组合物相当的良好耐受性。
在本发明范围内不能使用从平均年龄65岁个体获得的、在有关光损伤皮肤(表示“光致损伤”)试验中观察到的耐受性效果。具体的，关于在年轻个体上应用阿达帕林(特别是有关于青少年或青年成人人群的痤疮)，皮肤显示非常不同的病生理特征(出现许多损害，特别是炎性损害，改变皮肤的渗透性，滤泡通道的过度角化，免疫应答，皮肤细菌建群(痤疮丙酸杆菌)，伴有过度皮脂溢的皮脂增生。
因此，本发明的主题是6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸(阿达帕林)或其盐在制备治疗伴有炎症或增生的皮肤病的药物组合物中的用途，其特征在于该药物组合物中含有占组合物总重量0.3重量％的阿达帕林。
术语“阿达帕林盐”是指与药学上可接受的碱，特别是无机碱，如氢氧化钠、氢氧化钾和氨水，或有机碱，如赖氨酸、精氨酸或N-甲基葡糖胺形成的盐。
术语“阿达帕林盐”也指与脂肪胺，如二辛基胺和硬脂胺形成的盐。
本发明组合物可以经肠道、肠胃外、局部或眼部(occularly)给药。
本发明的药物组合物优选被局部给药。
对于肠道给药，本发明的药物组合物可以是片剂、明胶胶囊、糖锭剂、糖浆剂、混悬液、溶液、粉末、颗粒、乳剂，或者控释的微球或纳米球或者类脂或聚合物囊泡的混悬液。对于肠胃外给药，药物组合物可以采用输液或注射用溶液或混悬液的形式。
对于局部给药，本发明的药物组合物特别用于治疗皮肤和粘膜，可以是软膏、乳膏、乳剂、香膏剂、粉末、浸渍垫、溶液、凝胶、喷雾剂、洗液或混悬液形式。也可以是控释的微球或纳米球或者类脂或聚合物囊泡的混悬液、或聚合物贴片和水凝胶的形式。这种局部应用的组合物可以是无水形式、含水形式或乳液形式。
在本发明优选方案中，本发明的药物组合物是凝胶、乳膏或洗液。
特别地，该药物组合物可以是特别含有一种或多种选自卡波姆940(BF Goodrich，Carbopol 980)和丙二醇的成分的水凝胶，或特别含有一种或多种选自全氢角鲨烯、环甲基硅酮、PEG-20甲基葡萄糖倍半硬脂酸酯和甲基葡萄糖倍半硬脂酸酯的成分的乳膏，或基于聚乙二醇的醇洗液。
本发明的药物组合物还可以含有惰性添加剂或这些添加剂的组合，例如
-润湿剂；
-增香剂；
-防腐剂，如对羟基苯甲酸酯；
-稳定剂；
-湿度调节剂；
-pH调节剂；
-渗透压调节剂；
-乳化剂；
-UV-A和UV-B掩蔽剂；
-和抗氧化剂，如α-生育酚、丁基羟基苯甲醚或丁基羟基甲苯、超氧化物歧化酶、泛醌醇或某些金属螯合剂。
当然，本领域的技术人员将会注意以如下方式对任选添加到这些组合物中的化合物进行选择，即所设计的添加应不会利地影响或者基本上不会不利地影响本发明内在的有益性质。
用于制备本发明药物组合物的阿达帕林的使用意在用于治疗伴有炎症或增生的皮肤病，选自：
-寻常痤疮、黑头粉刺、多形痤疮、结囊性痤疮、聚合性痤疮、继发性痤疮，如日光性、药物相关或职业性痤疮，
-广布和/或重型牛皮癣、鱼鳞病和鱼鳞病样状况，
-达里埃氏病，
-光化性角化病，
-掌跖角皮病和毛化角化病，
-粘膜白斑病(leucoplasias)和粘膜白斑病样状况、扁平苔藓，
-任何良性或恶性的、重度和扩散性皮肤病学标本。
本发明的组合物特别适合治疗痤疮，如寻常痤疮，和特别是治疗中度至中重度的寻常痤疮。
为了说明本发明，现在给出含有0.3％阿达帕林的组合物的各种制剂，但不以任何方式限制本发明。同时给出显示本发明组合物的治疗模式和所治患者对其良好耐受性的结果。
实施例1-局部给药制剂
在本实施例中，举例说明各种含有0.3％阿达帕林的具体局部用制剂。
本实施例中的阿达帕林由Sylachim，Division Finorga公司提供(产品编号CF9611996)。
(a)乳膏
阿达帕林                             3mg
卡波姆934(BF Goodrich Carbopol 974)  4.5mg
乙二胺四乙酸二钠                     1mg
PEG 20甲基葡萄糖倍半硬脂酸酯         35mg
甲基葡萄糖倍半硬脂酸酯               35mg
甘油                                 30mg
对羟基苯甲酸甲酯                     2mg
环甲基硅酮                           130mg
全氢角鲨烯                           60mg
苯氧乙醇                             5mg
对羟基苯甲酸丙酯                     1mg
氢氧化钠：调至pH 6.5+/-0.3所需的量
纯净水                               足量至1g
(b)洗液
阿达帕林                             3mg
PEG 400                              1700mg
乙醇                                 足量至1g
(c)水凝胶
阿达帕林                             3mg
卡波姆940(BF Goodrich Carbapol 980)  11mg
乙二胺四乙酸二钠                     1mg
对羟基苯甲酸甲酯                     2mg
泊洛沙姆124                          2mg
丙二醇                               40mg
氢氧化钠：调至pH 5.0+/-0.3所需的量
纯净水                               足量至1g
实施例2-0.3％阿达帕林凝胶剂的效力和与0.1％阿达帕林凝胶剂的比较
试验在痤疮患者组成的群体中进行。在该群体中，分成三组：第一组接受每日局部给药0.3％阿达帕林凝胶剂，第二组接受每日局部给药在同样赋形剂中的0.1％阿达帕林凝胶剂，第三组是对照组，接受每天局部给药与前两种凝胶剂相对应但不含活性成分的凝胶剂。
根据损害性质，图1至3给出了所得到的损害数目消退结果。
从这些观察结果得出以下结论：
-0.3％阿达帕林凝胶剂比0.1％阿达帕林凝胶剂起效快；具体地，从治疗第四周，可以看出0.1％阿达帕林凝胶剂和0.3％阿达帕林凝胶剂效力的区别；
-治疗八周后，0.3％阿达帕林凝胶剂明显表现出更强的治疗效果。
实施例3-关于0.3％阿达帕林凝胶剂的耐受性
1、阿达帕林血浆浓度的测定
八个中度至中重度寻常痤疮患者，每天用2g 0.3％阿达帕林凝胶剂涂敷在1000cm2要治疗的皮肤(面部、胸部和背部)上进行治疗，治疗10天。
分别在第1、2、4、6、8和10天取血样。在第10天中并在最终的涂敷之后，在第1、2、6、8、10、12、16和24小时取样。
使用以下程序检测这些试样中的总阿达帕林(游离和结合的阿达帕林)的血浆浓度：
-用β-葡糖醛酸糖苷酶(glucurodinase)和芳基硫酸酯酶的混合物进行酶水解；
-液-液萃取；
-通过HPLC(高效液相色谱)；
-然后进行荧光检测。
该方法可以检测的最小浓度是0.15ng/ml，并且可以对最小浓度为0.25ng/ml的阿达帕林定量。
结论：
治疗10天后，检测到的阿达帕林的血浆浓度非常低，可以证实每天使用0.3％阿达帕林凝胶剂的安全性。
2a)临床观察局部施用0.3％阿达帕林凝胶剂所引起的副作用
可以进行两种类型的观察：
-第一，监视按本实施例3第1点的方案治疗的患者，可以注意到所有患者对0.3％阿达帕林凝胶剂的耐受性都很好。他们全部显示皮肤干燥和脱屑的症状，峰值出现在治疗的第七天，然后这些症状减轻直至治疗结束。
2b)此外，还参考进行上述实施例2中描述的试验。
与效力测定并行，试验员记录可能引起的副反应，首先是通过局部施用0.3％阿达帕林凝胶剂引起的副反应引起的副作用，其次是施用0.1％阿达帕林凝胶剂引起的副反应；最后，同样观察施用不含活性成分的凝胶剂的对照群体。
在下表中给出现察结果：
  不良局部效果   0.3％阿达帕林凝胶剂(N＝70)   0.1％阿达帕林凝胶剂(N＝70)   赋形剂凝胶剂(N＝74)
  皮肤和二级结构(指甲、毛发)   31(44.3％)   28(40.0％)   5(6.8％)
  干燥皮肤   16(22.9％)   13(18.6％)   2(2.7％)
  红斑   8(11.4％)   3(4.3％)   0(0.0％)
  皮肤不适   8(11.4％)   7(10.0％)   0(0.0％)
  脱屑   6(8.6％)   5(7.1％)   0(0.0％)
  皮炎   3(4.3％)   1(1.4％)   0(0.0％)
  瘙痒   3(4.3％)   1(1.4％)   1(1.4％)
  刺激性皮炎   2(2.9％)   7(10.0％)   0(0.0％)
  局部变态反应   1(1.4％)   0(0.0％)   0(0.0％)
  虱病   1(1.4％)   0(0.0％)   0(0.0％)
  接触性皮炎   1(1.4％)   0(0.0％)   0(0.0％)
  日射病   1(1.4％)   3(4.3％)   1(1.4％)
  灼烧感   1(1.4％)   0(0.0％)   0(0.0％)
  荨麻疹   1(1.4％)   0(0.0％)   0(0.0％)
  感染   1(1.4％)   0(0.0％)   0(0.0％)
  表皮脱落   0(0.0％)   0(0.0％)   1(1.4％)
  湿疹   0(0.0％)   0(0.0％)   1(1.4％)
  水肿   0(0.0％)   1(1.4％)   0(0.0％)
阅读上表后，发现对于含两种不同浓度活性成分的凝胶剂，不良副作用的出现在统计学上是相等的。不良副作用的强度为平均水平，结论为患者对这两种凝胶剂都有良好的耐受性。
以这些观察为基础，可以得出以下结论：寻常痤疮患者可以使用0.3％阿达帕林凝胶剂治疗，这样的阿达帕林暴露剂量据说在临床条件下是微小的或非常微小的。
因此，基于这些不同的研究推知，含有0.3％阿达帕林的药物组合物显示特别适合治疗伴有炎症或增生的皮肤病，特别是寻常痤疮的获益/风险比。

Claims (7)

1.6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸，即阿达帕林，或其盐在制备治疗伴有炎症或增生的皮肤病的药物组合物中的用途，所述药物组合物是凝胶剂或乳膏，所述皮肤病选自寻常痤疮，黑头粉刺，多形痤疮，结囊性痤疮，聚合性痤疮，继发性痤疮，广布和/或重型牛皮癣，鱼鳞病和鱼鳞病样状况，达里埃氏病，掌跖角皮病和毛化角化病，以及炎症后色素沉着，其特征在于所述药物组合物包含占组合物总重量0.3重量％的阿达帕林。
2.根据权利要求1的用途，其中所述的继发性痤疮是日光性、药物相关或职业性痤疮。
3.根据权利要求1或2的6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸或其盐的用途，用于制备治疗寻常痤疮的药物组合物。
4.根据权利要求1-3任一项的6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸或其盐的用途，用于制备治疗中度至中重度寻常痤疮的药物组合物。
5.根据权利要求1-4任一项的用途，其特征在于所述组合物被局部施用。
6.根据权利要求1-5任一项的用途，其特征在于所述组合物是具有如下配方的凝胶剂：
-阿达帕林                                 3mg
-卡波姆940(BF Goodrich Carbopol 980)      11mg
-乙二胺四乙酸二钠                         1mg
-对羟基苯甲酸甲酯                         2mg
-泊洛沙姆124                              2mg
-丙二醇                                   40mg
-氢氧化钠：调至pH 5.0+/-0.3所需的量
-纯净水                                   足量
至1g
7.一种药物组合物，其是凝胶剂或乳膏，其在生理上可接受的介质中含有6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸，即阿达帕林，或其盐，用于治疗伴有炎症或增生的皮肤病，特征在于所述药物组合物含有占组合物总重量0.3重量％的阿达帕林。
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