CN1351499A - 药物组合物 - Google Patents
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Abstract
本发明涉及用于皮肤的药物组合物,所述组合物包括含有至少一种维生素D或维生素D类似物的第一种药理学活性组分A和含有至少一种皮质甾类的第二种药理学活性组分B。
Description
发明领域
本发明涉及用于皮肤的药物组合物,所述组合物含有至少一种维生素D或维生素D类似物和至少一种皮质甾类。具体地说,本发明涉及含有两种或多种药理学活性化合物的药物组合物,所述化合物由于各自最佳稳定pH值而具有低的相容性,所述药理学活性化合物优选为至少一种维生素D类似物和至少一种皮质甾类。
发明背景
在采用皮肤给药治疗的疾病如牛皮癣中,常需要采用包括两种或多种不同药理学活性化合物的联合治疗。因此,在治疗例如牛皮癣时,采用包括类固醇化合物如皮质甾类化合物与维生素D类似物例如钙泊三醇的联合治疗是比较常见的,其中每种活性化合物均配制于独立的制剂中。
迄今为止,尚无有关包括维生素D类似物和局部用类固醇联用的描述。而且,上述两种类型化合物的最佳稳定性pH值明显不同,因此很难制备同时含有类固醇化合物和维生素D类似物的局部用药物制剂。US5565462涉及含有某些黄嘌呤化合物的局部用药物组合物,其中所述组合物还含有某些活性化合物,例如类固醇和维生素D及其衍生物。然而,并未公开同时含有类固醇和维生素D或维生素D类似物或衍生物的局部用组合物,也未披露这种组合物的制备方法。
下述实施例描述了本领域技术人员在制备同时含有维生素D或维生素D类似物或衍生物和局部用类固醇的局部联用组合物所要面临的困难:与维生素D类似物的其他实例一样,维生素D类似物钙泊三醇的最大稳定pH值为8以上,但是皮质甾类例如倍他米松(9-氟-11,17,21-三羟基-1,6-甲基孕甾-1,4-双烯-3,20-二酮)的最大稳定pH值却为4-6。由于在制备局部用制剂例如霜剂和/或软膏时,常采用包括具有某种酸或碱性或反应能力的碱性辅助材料和添加剂,因此迄今不可能将这两种化合物在同一制剂中联用同时保持两种活性化合物的稳定性。
因此,在使用这两种组分的治疗中,医师不得不让患者分开使用含有不同组分的霜/软膏,每种制剂中所含的化合物均处于其最稳定pH值状态。这有可能导致患者对制剂的不相容性,因为患者在早晨使用一种霜/软膏后,晚上又必须得使用另一种霜/软膏。不用说,在这种情况下患者顺从性和合适的给药量就成了一个问题。RicharDs,H.L.等在J Am AcaD Dermatol,1999年,12月,41(4):581-3页中报道了牛皮癣患者对药物治疗顺从性的研究。据报道,患者对慢性病症如牛皮癣的治疗医嘱不顺从,是对医护工作者的一个严重挑战:39%被调查者称其不顺从推荐的治疗方案。不顺从组通常是较年轻的人,他们对所患牛皮癣严重性的自我判断较重,他们在发作时比那些顺从的人年轻。不顺从组自称牛皮癣对其日常生活的影响更大。
本发明的一个目的是提供皮肤用药物组合物,其中所述组合物可减轻采用两组分或多组分方案治疗牛皮癣和其他炎性皮肤病包括指甲疾病所带来的不便。应用所述组合物,可使大批牛皮癣患者的生活质量明显改善,尤其是那些对所患牛皮癣严重性的自我判断较重的不顺从组,他们通常是较年轻的人,他们在发作时比那些顺从的人年轻。
发明概述
为了解决上述提及的问题,本发明提供皮肤用药物组合物,所述组合物包括含有至少一种维生素D或维生素D类似物的第一种药理学活性组分A和含有至少一种皮质甾类的第二种药理学活性组分B。发明详述
第一种药理学活性组分A优选选自断钙醇(seocalcitol);钙泊三醇;骨化三醇;tacalcitol,maxacalcitol;paricalcitol;falecalcitriol;1α,24S-二羟基-维生素D2;和1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯,及其混合物。
维生素D类似物更优选选自钙泊三醇,骨化三醇,tacalcitol,maxacalcitol,和1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯及其混合物。按照本发明,合成维生素D类似物比天然维生素D’s或维生素D衍生物更为优选,因为对于皮肤病如牛皮癣的治疗而言,后者治疗作用的选择性较低。
组成第一种药理学活性组分A的维生素D化合物的其他非限定性实例包括:
alphacalcidol;
1α-羟基-维生素D2;
1α-羟基-维生素D5;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基-1-庚基)-9,10-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6-羟基-6-甲基-1-庚基)-9,10-断孕甾-5(2),7(E)10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6-羟基-6-甲基庚-1(E)-烯-1-基-9,10)-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6-乙基-6-羟基-1-辛基)-9,10)-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(7-羟基-7-甲基-1-辛基)-9,10)-断孕甾-5(2),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(7-羟基-7-甲基辛-1(E)-烯-1-基-9,10)-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6’-甲基-1’-庚基)-9,10-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-(5’-羟基-5’-甲基-1’-己氧基)-9,10-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4’-羟基-4’乙基-1’-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6’-羟基-1’-己氧基-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(5’-羟基-5’-乙基-1’-庚氧基)-9,10-断-孕甾-5(Z),7(E),10,19-三烯;
1(S),3(R)-二羟基-20(R)-(5’-羟基-5’-甲基-1’-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(5’-甲基-1’-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4’-羟基-4’-(1″-丙基)-1’-庚氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4’-羟基-4’-甲基-1’-戊氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3’-羟基-3’-甲基-1’-丁氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-(4-羟基-4-甲基-1-戊基)-9,10-断孕甾-(5Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-(5-乙基-5-羟基-1-庚-基)-9,10-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-(5-乙基-5-羟基-庚-1(E)-烯-1-基),9,10-断孕甾烷5(2),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-(5’-羟基-5’-甲基-己-1’(E),3’(E)-二烯-1’-基)-9,10-断孕甾-5(2),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-(5’-乙基-5’羟基-庚-1’(E),3’(E)-二烯-1’-基)-9,10-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-(6’-羟基-己-1’(E),3’(E)-二烯-1’-基)-9,10-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-(5’-环丙基-5’-羟基-戊-1’(E),3’(E)-二烯-1’-基)-9,10-断-孕甾-5(Z)-7(E),10,19-三烯(5’(R)和5’(S)异构体);
1(S),3(R)-二羟基-20-(6’-羟基-6’-甲基-庚-1’(E),3″(E)-二烯-1’-基)-9,10-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-(2-羟基-2-戊基)-苯基甲氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-(3-羟基-3-丙基)-苯基甲氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-羟基-4-甲基-1-戊氧基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-羟基-4-甲基-1-戊-2-炔氧基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-羟基-4-三氟甲基-5,5,5-三氟-1-戊-2-炔氧基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-[3-(2-羟基-2-丙基)-苯氧甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-羟基-3-乙基-1-戊基硫甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-羟基-3-乙基-1-戊基磺基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-((1-羟基-1-甲基)乙基)戊基硫甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3,3-二氟-4-羟基-4-甲基-1-戊氧基甲基)-9,10-断-孕甾-5(Z)-7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6’-乙基-6’-羟基-辛-1’-炔-1’-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(7’-乙基-7’-羟基-壬-1’-炔-1’-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(1,5-二羟基-5-乙基-2-庚炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基-1-甲氧基-2-庚炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(1-乙氧基-5-乙基-5-羟基-2-庚炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(1-甲氧基-4-羟基-4-乙基-2-己炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(1-乙氧基-4-羟基-4-乙基-2-己炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20-(4-乙基-4-羟基-1-己炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)17(20)(Z)-四烯;
1(S),3(R)-二羟基-20-(5-乙基-5-羟基-1-庚炔-1-基)-9,10-断-孕甾-5(Z),7(E)10(19),17(20)(Z)-四烯;
1(S),3(R)-二羟基-20-(6-乙基-6-羟基-1-辛炔-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),17(20)(Z)-四烯;
1(S),3(R)-二羟基-20(R)-(5-乙基-4,4-二氟-5-羟基-庚氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4,4-二氯-5-羟基-5-甲基-己氧基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4,4-二氟-5-羟基-5-甲基-己氧基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-氟-4-甲基-戊基-氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-乙基-4-氟-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(5-氟-5-甲基-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R),20(S)-三羟基-20-(4-乙基-4-羟基-1-己基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-甲氧基-20-(4-乙基-4-羟基-1-己基)-9,10-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-乙氧基-20-(4-乙基-4-羟基-1-己基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-[3-(2-羟基-2-甲基-1-丙氧基)-丙-1E-烯-1-基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-乙基-4-羟基-1-己基硫)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-[5-甲基-5-羟基-1-已基硫基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-[3-(1-甲基-1-羟乙基)苄基硫]-9,10-断-孕甾-5(Z),7E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-甲基-3-羟基-1-丁基硫)-9,10-断-孕甾-5(Z)7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基-庚-1(E)-烯-3-炔-1-基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
24-氧代-1(S),3(R),25-三羟基-20(S)-9,10-断-胆甾-5(Z),7(E),10,19-三烯;
1(S),3(R)-二羟基-20(R)-(3-氧代-4-羟基-4-乙基-1-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(5-甲基-5-羟基-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(4-乙基-4-羟基-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(4-乙基-4-羟基-己-2-炔基氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(4-羟基-4-甲基戊氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(4-羟基-4-甲基戊)-2-炔-1-基氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(3,1-羟基-1-甲基乙基)苯基甲氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(1-甲氧基-4-羟基-4-甲基-1-戊基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(1-乙氧基-4-羟基-4-甲基-1-戊基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;异构体A;
1(S),3(R),25-三羟基-(20(S)-9,10-断-胆甾-5(Z),7(E),10(19),23(E)-四烯;
1(S),3(R)-二羟基-(20(S)-(6’-羟基-6’-甲基-4’(E)-庚烯-1’基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R),22(S),25-四羟基-20(R),9,10-断-胆甾-5(Z),7(E),10(19),23(E)四烯;
22(S)-乙氧基-1(S)-3(R),25-三羟基-10(R)-,9,10-断-胆甾-5(Z),7(E),10(1,23(E)四烯;
1(S),3(R)-二羟基-20(S)-(3-(1-羟基-1-甲基乙基)苯氧甲基)-9,10-断孕甾-5(Z),7(E),10(19),16-四烯或相应的20(R)异构体;
1(S),3(R)-二羟基-20(S)-(3-(1-羟基-1-甲基乙基)苯基硫甲基-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或相应的20(R)异构体;
1(S),3(R)-二羟基-20(S)-(4-羟基-4-甲基戊-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟庚-1-基)-9,10-断孕甾-5(Z),7(E),10(19),16-四烯或相应的20(S)异构体;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟庚-1(E),3(E)-二烯-1-基)-9,10-断孕甾-5(Z),7(E),10(19),16-四烯或相应的20(S)异构体;
1(S),3(R)-二羟基-20(R)-(3-环丙基-3-羟丙-1(E)-烯-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯(24(S)异构体)或相应的24(R)异构体;和
1(S),3(R)-二羟基-20(1,5-二羟基-5-乙基-2-庚炔-1-基)-9,10-断-孕甾烷5(Z),7(E),10(19),17(20)Z-四烯,均为22-异构体。
第二种药理学活性组分B优选采用I、II或III组局部用类固醇,更优选为具有中等至较弱作用的类固醇(I和II组)。组分B优选自倍他米松(9-氟-11,17,21-三羟基-16-甲基孕甾-1,4-双烯-3,20-二酮)及其酯,例如21-醋酸酯、17-金刚烷酸酯、17-苯甲酸酯、17-戊酸酯和17,21-二丙酸酯;阿氯米松(Alclomethasone)及其酯例如二丙酸酯;氯倍他索及其酯例如丙酸酯;氯倍他松及其酯例如17-丁酸酯;去羟米松;二氟米松及其酯,二氟拉松及其酯例如二醋酸酯;氟轻松醋酸酯;二氟美松及其酯例如新戊酸酯;Fluocinolon及其酯例如丙酮化物;氟地松及其酯例如丙酸酯;氟强的松及其酯例如醋酸酯;哈西奈德;氢化可的松及其酯例如-17-丁酸酯;莫米他松及其酯例如糠酸酯;和去炎松及其醚和酯例如丙酮化物;及其混合物。皮质甾类的更优选实例为倍他米松及其酯例如17-戊酸或酯17,21-二丙酸酯,氯倍他索及其酯例如丙酸酯,去炎松或醚和/或酯例如丙酮化物或丙酮化物-21-N-苯甲酰基-2-甲基-对-丙氨酸酯(alaninate)或丙酮化物21-(3,3-二甲基丁酸酯),或氢化可的松及其酯例如17-丁酸酯。
另外,本发明涉及用于皮肤药物组合物,其中含有至少一种维生素D或维生素D类似物和至少一种皮质甾类,与单独使用任一药理学组分的治疗相比,它在治疗人或其它哺乳动物的牛皮癣或其它炎性皮肤病中显示了较高的效力。所述效力优选是基于对牛皮癣和相关皮肤病PASI评分的百分比变化值而测定的,所述疾病例如皮脂-牛皮癣和皮脂溢皮炎。
PASI(牛皮癣区域和严重程度指标)评分用以评定患者牛皮癣的范围和严重程度。下述公式用于计算PASI评分:
臂部 0.2(R+T+S)E=X
躯干 0.3(R+T+S)E=Y
腿部 0.4(R+T+S)E=Z其中R=红色评分,T=厚度评分,S=有鳞评分,和E=范围评分,其中评按0-4级评定:
0=无关(no involvement),1=小于10%,2=10-29%,3=30-49%,和4=50-69%。合计X+Y+Z得到PASI总评分,范围为0-64.8。
附图简述
图1为4周临床试验内的PASI评分百分比变化值表,其中对本发明含有钙泊三醇水合物(52.2μg/g)和倍他米松二丙酸酯(0.643mg/g)的制剂、同样载体中仅含有钙泊三醇水合物(52.20ug/g)的制剂和同样载体中仅含有倍他米松二丙酸酯(0.643mg/g)的制剂的效力作了比较。图1表明本发明制剂的效力明显高于两种仅含单组分的制剂。PAS评分变化值表明:采用本发明制剂治疗的患者组成功地治疗牛皮癣,而这是迄今为止用含有钙泊三醇或倍他米松的市售制剂治疗、或者用此类市售制剂(对照)交替治疗所不能达到的,这也正是本发明同时含有这两种活性组分的优点所在。(EOT=治疗结束)。
图2为采用如图1的临床试验时,在患病和治疗结束时PASI评分的百分变化表。
图3为采用如图1的临床试验时,在患病和治疗结束时,研究者以百分显效率评估总效所得结果的柱形图。显效定义为患者有显著的改善或光洁。
图4为采用如图1的临床试验时,在患病和治疗结束时,研究者以百分显效率评估总效所得结果表,参见图3。
局部用制剂
在本发明的一个优选实施方案中提供了局部用药物组合物,它为软膏、霜剂、洗液优选为洗头液、搽剂或其他可涂布的液体或半液体制剂形式,优选为非水性或水包油或油包水乳剂。在本发明的一个优选实施方案中,本发明组合物为单相组合物即含有单一溶剂系统的组合物,例如软膏。
在本发明另一优选实施方案中提供了用于皮肤的非水性药物组合物,所述组合物包括:
含有至少一种维生素D或维生素D类似物的第一种药理学活性组分A;
含有至少一种皮质甾类的第二种药理学活性组分B;
其中第一种药理学活性组分A与第二种药理学活性组分B的最稳定pH值至少相差1;和
至少一种选自以下的溶剂组分C:
(i)通式为R3(OCH2C(R1)H)xOR2(I)的化合物,其中x为2-60,每一x单元中的R1独立地为H或CH3,R2直链或支链的C1-20烷基或苯甲酰基,和R3是H或苯基羰基氧基;
(ii)C4-C8二羧酸的双-(直链或支链)-C4-10烷基酯;
(iii)直链或支链C12-18-烃基苯甲酸酯;
(iv)直链或支链C10-8-链烷或-链烯酸的直链或支链C2-4-烷基酯;
(v)含有C8~14-链烷酸的丙二醇二酯;和
(vi)支链的伯C18-24链烷醇,和其中组分A和B如上定义。
业已发现,此类含有溶剂组分C的联用组合物中,虽然各活性组分具有不同的pH值/稳定性特征,但是它们可以共存且无降解。活性化合物间相互对稳定pH值的影响被最小化或被排除。
药理学活性化合物之间最佳稳定pH值的最大差值优选至少1.5,更优选至少2,具体地说是至少2.5,更具体地说是至少3,尤其是至少4,例如至少5。
在上述通式(I)中,系数x(表示圆括号内单元的个数)优选为4-50,更优选为4-40,具体地说是4-30,尤其是5-25,更具体地说是10-20,例如约15。进一步优选R1为CH3。
所述组分C优选自具有通式H(OCH2C(R1)H)xOR2(II)的化合物及其混合物,其中R1、x和R2如上定义。
上述定义的(i)-(vi)型溶剂组分C的非限定性实例如下所述,其中包括其商品名:Arlamol E(聚氧乙烯(15)硬脂醚);Arlamol DoA(己二酸的二异辛酯);Arlasolve 200(聚氧乙烯-20-异十六烷基醚);Eutanol G(2-辛基十二烷醇);Finsolv(异硬脂酰苯甲酸酯);Finsolv P(聚氧丙烯-15-硬脂醚苯甲酸酯);直链或支链C10-18-链烷或-链烯酸的异丙基酯,例如异丙基豆蔻酸酯,异丙基棕榈酸酯,异丙基异硬脂酸酯,异丙基亚油酸酯和异丙基一油酸酯;Miglyol840(辛酸和癸酸的丙二醇二酯);DPPG(丙二醇二壬酸酯);Procetyl AWS(CH3(CH2)14CH2(OCH(CH3)CH2)5-(OCH2)20OH)。
可采用制剂学领域技术人员已知的方法制备本发明组合物。因此,非水性组合物的制备可通过掺入已知的软膏或洗液基质赋形剂中,例如白色软石蜡(即凡士林)、或PlastibaseTM(由聚乙烯(平均MW约为21,000)和石蜡液体制得的基质)、或ESMA-PTM(一种微晶蜡)。作为一个实例,典型地采用熔化白色软石蜡,加入含有维生素D类似物(浓度典型地为0.0005-2.5%w/w)的所需量的溶剂组分C例如Arlamol E溶液,然后加入分散在石蜡油中的皮质甾类组分B分散体,其粒径典型地为0.1-20μm,然后冷却混合物即可制得本发明组合物。最终本发明组合物中各种组分的含量典型地为:0.005-0.1% w/w的皮质甾类组分B,0.0001-0.025% w/w的维生素D类似物组分A,和1-20% w/w的溶剂组分C,其余部分主要为基质赋形剂例如上述白色软石蜡和/或石蜡油。所述组合物还可含有其它常规添加剂例如抗氧剂(如α-生育酚)。
与先有技术中采用单一化合物或联合用药的疗法相比,本发明组合物在治疗皮肤病如牛皮癣、皮脂-牛皮癣及有关疾病方面具有以下优点:●临床研究表明,与使用单一化合物治疗的患者相比,使用本发明含有钙泊三醇和倍他米松的组合物治疗的牛皮癣患者,可更快地开始恢复并可更有效地治愈斑块。●含有维生素D类似物和局部用类固醇的组合物,除了可使患者受益于活性物质的直接治疗作用以外,它可提供附加的协同作用。已知在牛皮癣患者皮肤上同时给予类固醇如倍他米松,可减轻维生素D类似物例如钙泊三醇的皮肤刺激性副作用,这种效果只有采用两组分或多组分的治疗方案才能达到,然而维生素D类似物和类固醇却因为不配伍而不能在同一制剂中同时给药。目前,采用维生素D类似物和局部用类固醇联合治疗牛皮癣时,必须分别施用,典型地是一个在早晨而另一个在傍晚施用,这样就不可能获得两种活性化合物的协同作用(参见Ortonne,J.P.,Nouv.Dermatol.,1994年,13(10):746-751页),或者这种两组分治疗方案不能到达一定的协同作用,例如减轻皮肤刺激性,使相当多的牛皮癣患者因对治疗方案的不顺从性而无法受益(参见Kragballe,K.等,Br J Dermatol,1998,12月,139(4):649-54页,和Ruzicka,T.et Lorenz,B. Br J Dermatol,1998年,138(2):254-58页)。●在皮肤病如牛皮癣的治疗中,使用本发明组合物可减少类固醇的副作用如皮肤萎缩和回缩,因此可在短期内达到满意的疗效。此外,还可推测,采用目前不用于牛皮癣治疗的作用更温和的I组类固醇如氢化可的松,可有效地减轻或甚至消除钙泊三醇治疗后的皮肤刺激性。●因此,由于减轻了活性化合物的副作用,使得患者对治疗的耐受性大大提高。●治疗医嘱将会简化,单一制剂疗法可提高患者的顺从性,这样就有可能对大量的牛皮癣患者施以有效的治疗。●治疗医嘱将会简化,单一制剂疗法可提高患者的安全性。
本发明还涉及优选的药物制剂,它尤其适用于治疗并发有真菌感染的牛皮癣性疾病,其中还可含有选自如咪康唑,克霉唑,特比萘芬,环吡司、联苯苄唑,制霉菌素,酮康唑,益康唑和阿莫罗芬的抗真菌剂。
优选地,本发明组合物不含有选自黄嘌呤衍生物己酮可可碱,丙戊茶碱和torbafylline,或者其他黄嘌呤或黄嘌呤衍生物的治疗有效化合物。
本发明还涉及治疗牛皮癣和有关皮肤疾病的方法,包括将有效量的本发明组合物经局部给予对此有需要的患者。所述方法优选包括每日一或两次经局部给予医用有效量的所述组合物。
本发明组合物优选含有0.001-0.5mg/g或ml或者更优选0.001-0.25mg/g或ml的所述组分A和0.05-0.1mg/g或ml的所述组分B。
通过下面的非限定性实施例对本发明作进一步阐述。实施例1含有钙泊三醇和倍他米松二丙酸酯软膏
将919,3g白色软石蜡于80℃熔化,然后冷却至70℃并维持此温度。然后,将52.2mg钙泊三醇水合物(50mg钙泊三醇)溶于50gArlamol E(聚氧丙烯-15-硬脂醚)中形成一溶液(溶液1)。然后将溶液1搅拌下缓慢加到熔化的石蜡中。
倍他米松(0,5g,为0.643g二丙酸酯形式)以颗粒形式(99%<15μm)分散于30g石蜡液体中形成分散体1。于搅拌下,将分散体1和20mgα-生育酚加到含有钙泊三醇的石蜡混合物中,然后将混合物冷却至低于30℃以下,得到含有下述组分的本发明组合物:
1g软膏含有:
倍他米松(为二丙酸酯形式0.643mg)…………………0.5mg
钙泊三醇(为水合物形式52.2μg)……………………50μg
石蜡,液体……………………………………30mg
聚氧丙烯-15-S-硬脂醇醚……………………50mg
α-生育酚……………………………………20μg
白色软石蜡……………………………………制成1g实施例2稳定性试验
在40℃贮存1个月和25℃、40℃下贮存3个月后,分别考察两种活性组分的化学稳定性。钙泊三醇的定量采用HPLC。
将制剂中的钙泊三醇提取到甲醇和0.01M磷酸氢二铵(70∶30)的混合物中,然后采用以下HPLC条件定量:柱:填有5um LiChrospherRP-18的约125mmφ0.4mm(内径)的不锈钢柱;流动相:乙腈-甲醇-0.01M含水磷酸铵pH6(20∶50∶30);流速:约2ml/min;检测:可变波长UV-检测器,于265nm检测。采用上述反相HLPC法分离钙泊三醇和相关物质;柱:Superspher RP-18,4μm;流速:1.2ml/min。倍他米松二丙酸酯用HLPC定量。将制剂中的倍他米松二丙酸酯提取到乙腈∶水(50∶55)的混合物中,然后采用以下HPLC条件定量:柱:填有5μm LiChrospher RP-18的约125mmφ0.4mm(内径)的不锈钢柱;流动相∶乙腈∶水(50∶55)。流速:2ml/min。检测:可变波长UV-检测器,于240nm检测。采用上述反相HLPC法测定除了倍他米松的相关物质。倍他米松∶流动相∶乙腈/甲醇/0.05M缓冲剂pH值7(25∶5∶70)。其他条件同上。结果如表1所示。表1
钙泊三醇 与钙泊三醇有 倍他米松二丙 与倍他米松有
μg/g 关的物质% 酸酯mg/g 关的物质%
开始 50.0 1.6 0.63 1.2
25℃
3个月 50.5 1.4 0.64 0.2
40℃
1个月 48.0 2.1 0.64 0.6
3个月 49.7 1.8 0.64 0.2
如表1所示,钙泊三醇和倍他米松酯在试验条件下均非常稳定。
比较了类似软膏中钙泊三醇的稳定性,所述软膏中含溶剂丙二醇和乳化剂羊毛脂。对照软膏组合物中的钙泊三醇和倍他米松二丙酸酯同上,还含有10% w/w丙二醇、10% w/w无水羊毛脂和80% w/w白色软石蜡。对照软膏分别于5℃和40℃下贮存2.5个月。用上述方法仅测定到与钙泊三醇有关的物质。结果见表2。表2
与钙泊三醇有关物质%
5℃ 20
40℃ 96
从上述结果可知,在试验条件下,对照组合物中的钙泊三醇几乎完全降解,而本发明组合物中的钙泊三醇基本上没有降解。实施例3含有两相溶剂系统的医用皮肤洗液:
1g中含有:
倍他米松(为二丙酸酯0,643mg) 0.5mg
钙泊三醇(为水合物52.2μg) 50μg
磷酸二钠二水合物 2.5mg
二偶氮利定脲 3mg
聚氧丙烯-15-硬脂醚(ArlamolE) 50mg
异十六烷(Isohexadecan)(ArlamolHD) 200mg
聚氧乙烯-15-硬脂醚(Brij 72) 30mg
水,经纯化 制成1g
制备1kg洗液的方法:
2.5g磷酸二钠和3g二偶氮利定脲溶于约714g水中。将溶液加热到60-70℃得到水相。将30g聚氧乙烯-2-硬脂醚和200g异十六烷于60-70℃下熔化,然后加入含52.2mg钙泊三醇水合物的50g聚氧丙烯-15-硬脂醚溶液,得到油相。均化时混合两相,将643mg倍他米松二丙酸酯分散到混合相中,和搅拌下冷却洗液至室温。该制剂在25℃下至少稳定14天。
Claims (30)
1.一种用于皮肤的药物组合物,所述组合物包括含有至少一种维生素D或维生素D类似物的第一药理学活性组分A和含有至少一种皮质甾类的第二药理学活性组分B。
2.如前述权利要求的组合物,进一步包括至少一种可药用载体、溶剂或稀释剂。
3.如权利要求1或2的组合物,其中所述维生素D类似物选自断钙醇;钙泊三醇;骨化三醇;tacalcitol,maxacalcitol;paricalcitol;falecalcitriol;1α,24S-二羟基-维生素D2;和1(S),3(R)二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯,及其混合物。
4.如前述权利要求的组合物,其中所述维生素D类似物选自钙泊三醇,骨化三醇,tacalcitol,maxacalcitol,和1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯,及其混合物。
5.如前述任一权利要求的组合物,其中维生素D类似物可有效地抗人和其他哺乳动物牛皮癣和相关皮肤病。
6.如前述权利要求的组合物,其中所述维生素D类似物为钙泊三醇或其水合物。
7.如前述任一权利要求的组合物,其中所述皮质甾类选自倍他米松,氯倍他索,氯倍他松,去羟米松,二氟米松,二氟拉松,氟轻松,二氟美松,Fluocinolon,氟地松,氟甲叉龙,哈西奈德,氢化可的松,莫米他松,曲安西龙,及其可药用酯和丙酮化物及其混合物。
8.如前述权利要求的组合物,其中所述酯或丙酮化物选自17-戊酸酯,17-丙酸酯,17,21-二丙酸酯,丙酮化物,丙酮化物-21-N-苯甲酰基-2-甲基-对-丙氨酸酯,丙酮化物-21-(3,3-二甲基丁酸酯)和17-丁酸酯。
9.如权利要求1-6的组合物,其中所述皮质甾类选自具有中等至较弱作用的皮质甾类。
10.如前述权利要求的组合物,其中所述皮质甾类是氢化可的松或其17-丁酸酯。
11.如前述任一权利要求的组合物,为单相组合物形式。
12.如前述权利要求的组合物,为软膏。
13.如前述权利要求的组合物,基本上如实施例1的描述。
14.如权利要求1-10之一的组合物,为洗液。
15.如前述权利要求的组合物,基本上如实施例3的描述。
16.如前述任一权利要求的组合物,在治疗人和其他哺乳动物牛皮癣和相关皮肤病方面,比仅含有组分A或B的组合物有更高的效力。
17.如前述权利要求的组合物,其中所述效力是基于PASI评分的百分变化值。
18.如权利要求1或2的组合物,其特征在于第一组分A的最佳稳定pH值与第二组分B的最佳pH值的差值至少为1;和至少一种选自以下的溶剂组分C:
(i)通式为R3(OCH2C(R1)H)xOR2(I)的化合物,其中x为2-60,每一x单元中的R1独立地为H或CH3,R2直链或支链的C1-20烷基或苯甲酰基,和R3是H或苯基羰基氧基;
(ii)C4-C8二羧酸的双-(直链或支链)-C4-10烷基酯;
(iii)直链或支链C12-18-烃基苯甲酸酯;
(iv)直链或支链C10-18-链烷或-链烯酸的直链或支链C2-4-烷基酯;
(v)含有C8-4-链烷酸的丙二醇二酯;和
(vi)支链的伯C18-24链烷醇,和其中组分A和B如上定义。
19.如前述权利要求的组合物,其中所述组分C为选自通式H(OCH2C(R1)H)xOR2(II)的化合物及其混合物,其中R1、x和R2如权利要求18定义。
20.如前述权利要求的组合物,其中R1为CH3。
21.如权利要求19的组合物,其中所述组分C为聚氧丙烯-15-硬脂醚。
22.如权利要求18-21之一的药物组合物,其中所述第二组分B选自倍他米松,氯倍他索,氯倍他松,去羟米松,二氟米松,二氟拉松,氟轻松,二氟美松,Fluocinolon,氟地松,氟甲叉龙,哈西奈德,氢化可的松,莫米他松,曲安西龙,及其可药用酯和丙酮化物,及其混合物。
23.如权利要求18-22之一的药物组合物,其中所述酯选自17-戊酸酯,17-丙酸酯,17,21-二丙酸酯,丙酮化物,丙酮化物-21-N-苯甲酰基-2-甲基-β-丙氨酸酯,丙酮化物21-(3,3-二甲基丁酸酯),和17-丁酸酯。
24.如权利要求18-23之一的组合物,其中第一组分A选自钙泊三醇,骨化三醇,tacalcitol,maxacalcitol,和1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯,及其混合物。
25.如前述任一权利要求的组合物,含有0.001-0.25mg/g或ml组分A和0.05-0.1mg/g或ml组分B。
26.如前述任一权利要求的药物制剂,进一步含有优选自咪康唑,克霉唑,特比萘芬,环吡司、联苯苄唑,制霉菌素,酮康唑,益康唑和阿莫罗芬的抗真菌剂。
27.如前述任一权利要求的药物制剂,其中不含有选自己酮可可碱,丙戊茶碱和torbafylline的黄嘌呤衍生物,或者任何其他黄嘌呤或黄嘌呤衍生物。
28.如前述任一权利要求的组合物用于人和其他哺乳动物牛皮癣和相关皮肤病的局部治疗。
29.治疗牛皮癣和相关皮肤病的方法,包括将有效量的如 1-27之一的组合物经局部给予对此有需要的患者。
30.如前述权利要求的方法,包括每日一次或两次局部给予医用足够量的所述组合物。
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