CN106572969A - 用于治疗银屑病的药物组合物 - Google Patents

用于治疗银屑病的药物组合物 Download PDF

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CN106572969A
CN106572969A CN201580036407.2A CN201580036407A CN106572969A CN 106572969 A CN106572969 A CN 106572969A CN 201580036407 A CN201580036407 A CN 201580036407A CN 106572969 A CN106572969 A CN 106572969A
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D·比亚焦尼
C·德安格里斯
L·斯卡帕蒂奇
A·卡尔卡泰拉
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Abstract

用于在银屑病的治疗中局部施用的药物组合物，其包含作为活性成分的治疗有效量的4,6‑二甲基‑N‑(3,4,5‑三甲氧基苯基)嘧啶‑2‑胺(I)和2,4‑O‑(2‑呋喃基亚甲基)‑1,3,5,6‑四‑O‑甲基‑D‑葡萄糖醇，以及与其组合的适合的赋形剂和/或稀释剂。

Description

用于治疗银屑病的药物组合物
发明领域
本发明涉及用于在银屑病的治疗中局部施用的药物组合物，其包含作为活性成分的治疗有效量的4,6-二甲基-N-(3,4,5-三甲氧基苯基)嘧啶-2-胺(I)和2,4-O-(2-呋喃基亚甲基)-1,3,5,6-四-O-甲基-D-葡萄糖醇(II)和与其组合的适合的赋形剂和/或稀释剂。
技术状态
银屑病是慢性炎性皮肤病症，能侵袭身体的任何部分，但通常影响头皮、肘、膝、后背的腰部，生殖器、手掌和足底。
银屑病的病因目前未知，尽管确定涉及遗传、免疫和环境因素、包括各种类型的感染和代谢功能障碍。无论如何这是一个可以出现在任何年龄的病症，且其在高加索人中的发病率高于具有黑人血统的人。
针对该病症已经提出了多种治疗。例如，A.Krebs和H.Shaltegger证明柯桠素的治疗效果，柯桠素为从柯桠树(Andira Araroba)提取的基于植物的制剂，主要由1,8-二羟基-3-甲基-9-蒽酮和地蒽酚(1,8-二羟基-9-蒽酮)组成，已经长期用于治疗银屑病，主要由于其抑制细胞生长的作用(A.Krebs,H.Shaltegger,Experientia,1965,21,128)。
随后引入了许多新的治疗。然而，它们中的许多特征为低效和显著的副作用。基于水杨酸的保湿霜，由于它们的角质层分离作用，大概是最有效的。其他可能的治疗为局部或全身皮质类固醇、基于焦油(高刺激性的)的治疗和使用波长312-313nm的灯的光化学疗法，所述光化学疗法能容易地引起疹和灼伤。补骨脂素的同时施用导致了PUVA；然而，该治疗导致多种副作用、诸如恶心、头疼、灼热和瘙痒。
最近发现的其他治疗包括使用化学治疗剂或免疫抑制剂、诸如环胞素A、甲氨蝶呤和一些类视色素、诸如阿维A酯。然而，它们的应用限于对其他局部治疗无应答的最严重类型的银屑病，因为这些药物引起多种严重的副作用、尤其是它们的高肝毒性。
然而，最新一代的治疗使用一般由人源的或嵌合单克隆抗体组成的生物药品，其在各种水平和以不同的作用机制选择性地干预触发和支持银屑病的免疫进程。这些药物具有良好的活性和低器官毒性，但非常不宜用于有肿瘤临床史的患者，且在肥胖个体中无效。一些生物药品由于它们的高毒性和低效已经退市、诸如依法珠单抗，其引起进行性多灶性白质脑病。
意大利专利1161221公开了4,6-二甲基-N-(3,4,5-三甲氧基苯基)嘧啶-2-胺在治疗银屑病中的治疗用途。根据进行的研究，所述化合物对哺乳动物细胞具有显著的抗有丝分裂作用，同时显示低毒性，在小鼠中LD50(口服)为4110mg/kg，且在小鼠中LD50(腹膜内)为780mg/kg。
尽管所述活性成分比目前使用的药物更有效，因为其调节受银屑病侵袭的细胞的有丝分裂并适度减少炎症，但其仍然不能提供治疗银屑病问题的最佳解决方法。
发明描述
最近已经发现式I的4,6-二甲基-N-(3,4,5-三甲氧基苯基)嘧啶-2-胺或其或可药用盐
与式II的2,4-O-(2-呋喃基亚甲基)-1,3,5,6-四-O-甲基-D-葡萄糖醇的组合
在银屑病的治疗中更有效。
因此本发明的主题是用于治疗银屑病的局部药物组合物，其包含作为活性成分的治疗有效量的4,6-二甲基-N-(3,4,5-三甲氧基苯基)嘧啶-2-胺(I)和2,4-O-(2-呋喃基亚甲基)-1,3,5,6-四-O-甲基-D-葡萄糖醇(II)以及与其组合的适合的赋形剂和/或稀释剂。所述药物组合产生协同效应，改善了已知的治疗的功效、显著延长了复发的时间，且不引起副作用。
发明详述
本发明的组合物包含范围为1至10％、优选2至5％的浓度的化合物I，以整个组合物的重量计。化合物I可以以本身或以可药用盐形式存在。适用于配制的盐的实例包括盐酸盐、与羟基苯甲酸类、诸如水杨酸(2-羟基苯甲酸)和龙胆酸(2,5-二羟基苯甲酸)形成的盐和与磺酸类诸如甲磺酸、对甲苯磺酸和丁烷二磺酸形成的盐。与龙胆酸和与磺酸形成的盐是新的，其构成了本发明另外主题。此外I与羟基苯甲酸类的成盐带来了角质层分离作用(keratolitic effect)，其可以通过使用不同的酸来调节。
本发明的制剂中的式II的化合物以1至10％、优选2至5％的范围的浓度存在，以整个组合物的重量计。
使用常规技术和赋形剂，将式I和II的化合物配制在适用于局部施用的组合物中，诸如软膏剂、乳膏剂、混悬剂、乳剂、脂肪软膏剂(fatty ointments)、凝胶剂、粉末、洗剂等。特别指出的是，使用用于化妆品制剂的常规赋形剂(特别是凡士林、液体石蜡和羊毛脂)所配制的乳膏剂或软膏剂。
本发明的组合物可以每日一次施用达8-10天的时期，不一定连续施用。
实施例1-含化合物(I)和(II)的药物组合物的制备
将2g 4,6-二甲基-N-(3,4,5-三甲氧基苯基)嘧啶-2-胺(I)和2g 2,4-O-(2-呋喃基亚甲基)-1,3,5,6-四-O-甲基-D-葡萄糖醇(II)加入100g凡士林中。
将该混合物用机械搅拌器匀化。
实施例2
根据与之前实施例中所述的方法类似的方法，制备含以下成分的药物组合物:
化合物(I)2,89g
化合物(II)3,16g
液体石蜡20g
无水羊毛脂30g
凡士林44g
实施例3
将实施例2中所述的组合物同时施用于10位罹患银屑病的患者，用在特定的银屑病病损处，而以与实施例2中所述的组合物相同的量，将相似的但仅包含作为活性成分的成盐形式的化合物(I)的组合物施用于相同患者的另一处病损处。
每天每日一次地将这两种治疗组合物施用于所述患者。
总体上，在所有的患者中发现了：与使用仅包含化合物(I)的组合物(用作参比对照)治疗的身体部位相比，在使用实施例2中所述的组合物治疗的身体部位搔痒、发红和皮肤脱落消失地更迅速。这些作用(相对于每一种药物的单独施用而言，增加的临床功效和临床应答的发作减少)可以归因为具有不同活性的I和II的联合，其中促炎细胞因子类抑制剂所展现的消炎、角质层分离和抗氧化作用显示出协同效应。
此外，在使用实施例2中所述的组合物治疗1个月后，在至少6个月的时间没有复发。

Claims (9)

1.局部药物组合物，其包含作为活性成分的4,6-二甲基-N-(3,4,5-三甲氧基苯基)嘧啶-2-胺(I)或其或可药用盐和2,4-O-(2-呋喃基亚甲基)-1,3,5,6-四-O-甲基-D-葡萄糖醇(II)，以及与其组合的适合的赋形剂和/或稀释剂。
2.根据权利要求1的组合物，其包含1至10％的范围的浓度的化合物(I)或其盐。
3.根据权利要求1的组合物，其包含1至10％的范围的浓度的化合物(II)。
4.乳膏剂或软膏剂形式的根据权利要求1至3中的一项或多项的组合物。
5.根据权利要求4组合物，其中赋形剂为凡士林、液体石蜡或羊毛脂。
6.混悬剂或乳剂形式的根据权利要求1至3中的一项或多项的组合物。
7.根据上述权利要求中的一项或多项的组合物，其中式(I)的化合物为盐酸盐、水杨酸盐或与羟基苯甲酸类或磺酸形成的盐或任何其他可药用盐的形式。
8.根据权利要求1-7的组合物，其用于治疗银屑病。
9.4,6-二甲基-N-(3,4,5-三甲氧基苯基)嘧啶-2-胺的盐，其选自与龙胆酸(2,5-二羟基苯甲酸)或任何其他羟基苯甲酸形成的盐。
CN201580036407.2A 2014-07-04 2015-07-03 用于治疗银屑病的药物组合物 Pending CN106572969A (zh)

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EP0345362A1 (en) * 1987-05-28 1989-12-13 Laboratori Fitocosmesi E Farmaceutici Srl Use of 2,4-monofurfurylidene-sorbitol and its tetraalkyl derivatives in cosmetics and dermatology
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Application publication date: 20170419