CN101563082A - 治疗免疫介导性皮肤病的组合物和方法 - Google Patents
治疗免疫介导性皮肤病的组合物和方法 Download PDFInfo
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Abstract
本发明公开了(1)液体或半液体的药物组合物和(2)对免疫介导性疾病，如银屑病患者进行治疗的方法。
Description
背景技术
银屑病是一种慢性皮肤病，表现为由银色鳞状表层所覆盖的尖锐红斑，具有周期性反复发作的特点，引起银屑病的原发病活动发生在皮肤表层。
即使是轻微的银屑病也能引起发痒、灼烧、刺痛和流血。在更严重的病例中，这些症状表现尤其明显。银屑病的严重程度，从一两个鳞片状红肿的斑点银屑病到大面积的脓疱性银屑病，在罕见的病例中，还会威胁生命。
治疗选择
一般而言，治疗银屑病有下列三种可供选择的传统治疗方法，其效力从最小到最大为：
局部药疗法：可选药物包括洗剂、软膏、乳膏和洗洁剂。这些药物可用于治疗轻微到中等程度的银屑病。然而，目前可用的局部用的药物很少能完全根除银屑病。局部用的药物的范例包括阿克美他松丙酯(Alclometasone Dipropionate)软膏和乳膏(GlaxoSmithKline生产)、鳞皮病(Psoriatec)软膏(Sirius生产)和丙氯酸倍他索(Temovate)软膏和凝胶(GlaxoSmithKline生产)。
光线疗法：可选的光线疗法包括：利用宽或窄谱紫外线B(UVB)或补骨脂素和紫外线A(PUVA)进行的光波辐射疗法。这种疗法可以有效治疗中等到严重程度的银屑病。
系统性口服药物疗法：该疗法采用了各种能影响全身系统而不仅是皮肤的口服药。这些药剂有巨大副作用，通常专用于严重的银屑病，特别是当身体超过10％的皮肤患病时。这类药例如有环孢菌素和氨甲蝶呤。
角化细胞中炎症介质或其受体的异常表达与慢性发炎皮肤疾病，如银屑病、特应性皮炎和变应性接触性皮炎的发病机理有关。过去几年的研究使科学家们更加确信：银屑病是由免疫系统中活动过度或有缺陷的细胞引起的。免疫系统分泌的细胞因子被认为是银屑病的几种症状发生的原因。
调节细胞因子的分泌或抑制其活性已成为寻找银屑病治疗方法的最有希望的答案之一。
TNF-α，主因
TNF-α(肿瘤坏死因子-α)是一种重要的细胞因子。与其他细胞因子相似，TNF-α分泌过量可导致炎症。研究发现，银屑病患者皮肤表层中的TNF-α过量。
正常情况下，当没有抗原需要抵抗时，人体会产生可溶性的TNF-α受体，它能在TNF-α依附到免疫细胞上之前使其失活。银屑病患者的这种自然过程已在某种程度上被破坏，因为免疫系统会持续分泌大量TNF-α，就如同抗原在继续出现，而身体产生的可溶性TNF-α受体的量不足。
生物制剂
生物制剂疗法是一种相对新型的疗法，其中心在于免疫调节药疗法。生物制剂由来源于活体，如病毒、动物和人类的蛋白质分子组成。
2004年4月，FDA(国家食品药品监管局)批准了一种新型生物制剂，就是利用
(依坦西普，etanercept)的新用途来治疗中等到严重程度的斑块型银屑病。与TNF-α受体功能相似，依坦西普特异地针对TNF-α抗原；依坦西普捕获多余的TNF-α并使其失活，中断引发免疫介导性疾病过程的链。
另一种生物制剂是(因福利美，infliximab)，是治疗银屑病关节炎的“未许可药物”。因福利美同样针对和阻断TNF-α。然而，此药物不可单独使用，但有时可与免疫抑制剂氨甲蝶呤配合使用。
简言之，依坦西普和因福利美是治疗银屑病的有效药物，这也说明TNF-α疗法是有效的。然而，依坦西普和因福利美还存在几个明显的问题：
●须注射使用，因而有许多不便。
●药物本身的性质(蛋白质分子)确定其制作成本昂贵。
●因过度阻断TNF-α的活动而可能引起严重的反作用，如肺结核。
所以，局部性服用小分子TNF-α调节剂可以显著超过目前最`先进药物(依坦西普和因福利美)的药效。然而，据我们所知，现在还没有包含小分子TNF-α调节剂的液体组合物作为局部用的药物来治疗银屑病和其他免疫介导性皮肤病。
发明内容
众所周知，有些异噁唑衍生物是TNF-α调节剂。一个具体的例子就是化合物(I)，N-5-甲基异噁唑-4-羧酸-(4-三氟甲基)苯酰胺(5-methylisoxazole-4-carboxylic acid-(4-trifluoromethyl)-anilide)
利用化合物(I)治疗银屑病的研究已有报道(K.Reich et al.，英国皮肤病学杂志，2002年，146期，335-336页)，但都未经局部的应用。化合物(I)的固体组合物已取得治疗自身免疫性疾病的专利(美国专利，专利号7,071,222)，包括风湿性关节炎、系统性红斑狼疮、多发性硬化和银屑病。然而，至今还没有化合物(I)的液体或半液体组合物及其局部给药治疗银屑病的报道。
近期，我们开发了一个新的体外模型(美国专利申请，顺序号11/343,835)，该体外模型是将EpiDermTM应用于筛选治疗银屑病的药物。通过这种模型，我们可以证明有几种异噁唑衍生物可以有效减少市售的皮肤组织模型，EpiDermTM所释放的TNF-α，该模型包含正常的，源自人类的表皮层角化细胞，这些细胞用于被培养成多层的、高度分化的人类表皮模型。我们的发现显示：这些异噁唑衍生物能够渗透进入EpiDermTM组织，减少TNF-α，因此是有效的局部药。我们的发现是独一无二的，因为目前尚无报导明确指出TNF-α是主要由EpiDermTM组织诱导的。此外，也没有报导关于使用异唑衍生物涂在EpiDermTM上来减少EpiDermTM组织释放的TNF-α。
具体实施方式
实施例 用异噁唑衍生物减少体外EpiDermTM组织所释放的TNF-α
试验材料：
试验材料的原液如下：
1.UTL-5d原液：按1.7毫克/毫升将UTL-5d溶于50∶50 EtOH∶PEG 600v/v的赋形剂中
2.UTR-1原液：按3.5毫克/毫升将UTR-1溶于50∶50 EtOH∶PEG 600v/v的赋形剂中
3.赋形剂原液：50∶50的EtOH∶PEG 600
预处理：
将人表皮角化细胞接种到6孔板中，在37±2℃、5±1％CO2条件下用制造商推荐的不加血清的
培养基进行培育。细胞一旦汇合，即除去培养基，然后用含有1％v/v上述两种原液(赋形剂原液和UTR-1原液)的
培养基将该细胞处理过夜。UTR-1的最终浓度为35μg/ml。每项处理都需要制备6孔板中的两个孔。投放好试验材料后，在37±2℃，5±1％CO2条件下对细胞培育24小时。
处理及微矩阵分析
在培育期结束时，通过抽吸装置去除培养基，代以磷酸盐缓冲液，并用30mJ/cm2的UVB辐射来照射细胞。照射后，用新鲜的培养基在37±2℃，5±1％CO2条件下，对细胞进行整夜培育。培育之后，集中细胞培养基，用市售ELISA试剂盒来测量TNF-α的释放。
用PBS(磷酸盐缓冲液)将细胞清洗一遍，然后加入胰蛋白酶/EDTA(乙二胺四乙酸)溶液来释放细胞，然后加入胰蛋白酶中和液。按其处理的方式，将细胞集中在各个15ml的离心管里，并在4±2℃下，以1000转/分钟的速度进行离心分离而形成细胞团。
除去上清液后，向每个离心管加入500μl硫氰酸胍溶解液，然后用移液管反复吸、放溶液，直到细胞团分散而使细胞溶解。随后用RNAqueous提取试剂盒(Ambion)提取总RNA。纯化RNA后，提取mRNA并转化为反义RNA(aRNA)。然后用荧光探针标记aRNA。这种情况下，用Cy3(绿色荧光信号)来标记未处理样本的sRNA，用Cy5(红色荧光)标记处理过的样本的aRNA。一旦标记了aRNA并且除去了样本中一些未掺入的染料后，将标记的aRNA与杂交溶液混合并加到微矩阵上。然后在60-65℃，使微矩阵杂交过夜。杂交后，洗去微矩阵未结合的aRNA探针，然后用微矩阵扫描器进行扫描。评定基因表达变化的标准可能有多种。一般情况下，能表明基因表达发生了±30％的变化的情况为：(1)基因标记物的荧光强度应比背景强度大，和(2)Cy5/Cy3(处理/未处理)荧光强度比率应该大于1.3或小于0.66。
结果：
如下表所示，结果说明两种异噁唑衍生物都能够渗透进EpiDermTM组织并且降低TNF-α的上升水平。
基因微矩阵分析结果表明大量的基因表达被抑制(相对于背景)。目的基因包括JAK3、MAP3K2以及和癌症相关的基因。下面的表说明了对JAK3和MAP3K2基因的抑制：
下表表明了对结肠癌和TNF-α相关基因的抑制：
本发明公开了一种液体或半液体的药用组合物，此组合物包含以下所示的(1)UTL-5d、(2)UTR-1、(3)含有结构式(I)的化合物或(4)含有结构式(II)的化合物中的一种或多种：
上述的液体或半液体组合物包括溶液、乳剂、悬浮液、凝胶、乳膏、洗剂或皮肤贴。
上述的液体或半液体组合物包含药学上可接受的赋形剂。前述赋形剂包括水、乙醇、异丙醇、羊毛醇，丙三醇、矿物油、氢化油、表面活性剂、丙二醇、聚乙二醇、甲氧基聚乙二醇、1，2-环氧丙烷、聚环氧乙烷、甲基纤维素、羟丙基甲基纤维素、山梨醇、二氧化硅、去沫剂、防腐剂、芳香剂和着色剂。
本发明还公开了一种治疗免疫介导性皮肤病患者的方法，包括对患者局部使用有药效数量的液体或半液体的药用组合物，其中所说的皮肤病包括银屑病、湿疹、痤疮、皮炎和皮肤癌。
皮肤癌包括基底细胞癌。基底细胞癌是最常见的皮肤癌，与上升的TNF-α水平密切相关。
尽管上述说明包括很多特殊性，但不应将其解释成是对发明范围的限制，而只是提供了本发明目前的一些较佳实施例的说明。因此，本发明的范围应由后附的权力要求书及其合法的等效文件来确定，而不应由列举的实施例确定。
Claims (5)
1.一种液体或半液体的药物组合物，该组合物包括下述(1)UTL-5d、(2)UTR-1、(3)含有结构式(I)的化合物或(4)含有结构式(II)的化合物中的一种或多种：
2.权利要求1所述的药物组合物，其中所述的液体或半液体的组合物包括溶液、乳剂、悬浮液、凝胶、乳膏、洗剂或皮肤贴。
3.一种治疗免疫介导性皮肤病患者的方法，该方法包括对患者局部使用治疗有效量的权利要求1所述之组合物。
4.权利要求3所述的方法，其中所述的皮肤病包括银屑病、湿疹、痤疮、皮炎和皮肤癌。
5.权利要求4所述的方法，其中所述的皮肤癌包括基底细胞癌。
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