CN1213302A - 含有n－5－甲基异噁唑－4－羧酸－(4－三氟甲基)－酰苯胺和n－(4－三氟甲基苯基)－2－氰基－3－羟基巴豆酸酰胺的组合制剂 - Google Patents
含有n－5－甲基异噁唑－4－羧酸－(4－三氟甲基)－酰苯胺和n－(4－三氟甲基苯基)－2－氰基－3－羟基巴豆酸酰胺的组合制剂 Download PDFInfo
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Abstract
含有N－5－甲基异噁唑－4－羟酸－(4－三氟甲基)－酰苯胺和N－(4－三氟甲基苯基)－2－氰基－3－羟基巴豆酸酰胺的固态制剂,适合于治疗免疫性疾病。
Description
由公开号为0 013 376的欧洲专利申请书，已知，N-5-甲基异噁唑-4-羧酸-(4-三氟甲基)-酰苯胺(化合物1)具有抗风湿、消炎、退热和镇痛的作用，用以治疗多发性硬化。含有活性物质N-5-甲基异噁唑-4-羧酸-(4-三氟甲基)-酰苯胺的药物以25mg至150mg的剂量口服应用。
公开号为0 217 206的欧洲专利申请书中说明了，N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺(化合物2)具有免疫调节特性，适合于治疗慢性移植物抗宿主疾病和自身免疫性疾病，尤其是系统性红斑狼疮。可以应用含有10至200mg，但优选50至100mg剂量的化合物1或2的药物制剂，当为安瓿形式的注射剂(静脉内注射)时，优选以化合物2或其一种盐为基础，剂量为1至30mg，优选5至10mg，以及当为直肠用药时，剂量为50至300mg，优选100至200mg。但是分别单独口服应用5mg/kg或10mg/kg的化合物1或2并没有明显的作用。
现已发现，含有化合物1和2的组合制剂令人惊异地具有有利的免疫抑制作用。将少量的化合物2添加至主要活性成份化合物1中，可以明显增强组合制剂的作用。在此作用范围的基础上，可以扩展该组合制剂的应用范围，应用单独成份的免疫抑制治疗至今一直属于该范畴。此外减少剂量而不降低作用可以提高应用的安全性。同时还有一个出发点，即通过减少剂量，又保持同等作用效果，在值得一提的范围内可以降低治疗费用。
因此本发明涉及一种固态制剂，它含有成份1)N-5-甲基异噁唑-4-羧酸-(4-三氟甲基)-酰苯胺、成份2)N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺和/或N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺的一种生理耐受盐和/或N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺的一种立体异构体形式、和3)一种制药学载体，
本固态制剂的特征为，成份1)的含量为2至20mg，成份2)的含量为成份1)的0.3％至50％。
可以按照已知的方法制备化合物N-5-甲基异噁唑-4-羧酸-(4-三氟甲基)-酰苯胺和N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺(EP 0 529500)。在按照本发明的制剂中，具有以下结构式的N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺
以其本身的形式和/或N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺的生理耐受盐和/或N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺的立体异构体被应用。
N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺的合适的生理耐受盐例如有碱盐、碱土盐或铵盐，包括生理耐受有机铵碱的生理耐受盐。
按照本发明的固态制剂例如适合于治疗-. 急性免疫性病变，如败血症、变态反应、移植物抗宿主反应和宿主抗
移植物反应-. 自身免疫性疾病，尤其是类风湿性关节炎、系统性红斑狼疮、多发硬
化-. 银屑病、局限性皮炎、哮喘、荨麻疹、鼻炎、葡萄膜炎-. Ⅱ型糖尿病-. 肝纤维化、囊状纤维化、结肠炎-. 癌症如肺癌、白血病、卵巢癌、肉瘤、Kaposi＇s肉瘤、脑脊膜瘤、
结肠癌、淋巴结癌、脑瘤、乳腺癌、胰腺癌、前列腺癌或皮癌。
本发明固态制剂也可以包括组合制剂包或组合制剂，其组成成份分别制备，因此可以同时、分隔地或分时间阶段地在同一人类机体或动物机体上应用。按照本发明，成份1和2还可以同存却又分隔开的药剂形式存在，尤其是当药物制剂在空间大小上难以应用时。这尤其适于口服形式，因为老年病人常常倾向于较大片剂或胶囊。强制的是，分隔开的并同存在的药剂形式用以同时共同服用。也可以同存于各种剂型例如片剂和胶囊中。
此外本发明还涉及化合物1和2的组合制剂的应用，用以制备具有免疫抑制作用加倍增强的一种药物。
本发明此外还涉及制备本发明制剂的方法，其特征为，将化合物1和2以及一种制药学载体加工成一种药物制剂。
本发明固态制剂可以作为剂量单位以如胶囊(包括微粒胶囊)、片剂(包括糖衣丸剂和丸剂)或栓剂的形式存在，当应用胶囊时胶囊材料便具有载体的功用，而内容物例如作为粉剂、凝胶、乳剂、分散体或溶剂存在。但特别有利而简单的是，用化合物1和2制备口服(经口)剂型，它含有准确剂量的活性物质和每一种所希望的制药学载体。也可以应用相应的剂型(栓剂)用以直肠治疗。同样地可以以软膏、乳霜的形式经皮用药或以含有按照本发明制剂的溶剂的形式口服用药。
软膏、糊剂、乳霜和粉末散剂除含有活性物质以外，还可以含有例如动物性和植物性脂肪、蜡、石蜡、淀粉、西黄耆胶、纤维素衍生物、聚乙二醇、硅氧烷、膨润土、滑石粉、氧化锌、乳糖、硅酸、氢氧化铝、硅酸钙和聚酰胺粉或这些物质的混合物。
可以按照通常的方法如压制方法、浸入方法或流化床方法或包糖衣法(Kesseldragierung)制备糖衣丸，制备片剂、丸剂或颗粒体，它们含有载体物质和其它的常用佐剂如明胶、琼脂糖、淀粉(例如土豆淀粉、玉米淀粉或大麦淀粉)、纤维素如乙基纤维素、二氧化硅、各种糖如乳糖、碳酸镁和/或磷酸钙。糖衣溶液通常由糖和/或淀粉糖浆构成，并且按现有技术，大多还含有明胶、阿拉伯胶、聚乙烯吡咯烷酮、合成纤维素酯、表面活性物质、软化剂、染色剂和类似添加剂。为了制备发明制剂，可以应用每一种常见的流动调节剂、润滑剂或滑动剂如硬脂酸镁和分离剂。
制剂优选膜衣-/核-片剂或多层片剂的剂型，其中化合物2在膜衣中或在核内或在某一层中。化合物1和2也可以以缓释剂型存在，或者吸附在缓释材料上或者结合在缓释材料(例如基于纤维素树脂或聚苯乙烯树脂的缓释材料，如羟基乙基纤维素)之中。还可以通过将相关层面或间格小腔用通常的、胃液不溶解的薄层涂布，以延缓活性物质的释放。
所应用的剂量自然与各种因素有关，如待治疗的生物体(也即人或动物)、年龄、重量、一般健康状况、症状的严重程度、待治疗的疾病、可能的并发症、(如果存在)用其它药物并行治疗的方式、或者治疗的频率。剂量一般每日多次用药，优选每日1至3次。所应用的单个活性物质的剂量在此以相应单个活性物质的推荐剂量为准，一般在组合制剂中为推荐日剂量的10％至100％，优选为20％至80％，特别是在50％。用本发明组合制剂进行的合适治疗处理例如为，由以下物质构成制剂，并以1个、2个或3个单独剂量用药1)N-5-甲基异噁唑-4-羧酸-(4-三氟甲基)-酰苯胺，其剂量为2至20mg、2至19.9mg、4.5至19.5mg、4.85至19mg、5至18mg、5至15mg、5至10mg、5至9.9mg、5至9.7mg或5至9.0mg，和2)N-(4-三氟甲基苯基)-2-氰基-3-羟基巴豆酸酰胺，其剂量为0.3％至50％、优选0.5％至20％、特别是0.8％至15％，特别优选1％至10％、特别优选1％至5％；它们分别基于N-5-甲基异噁唑-4-羧酸-(4-三氟甲基)-酰苯胺的含量计。3)一种制药学可以耐受的载体。化合物1和2的百分数值(％)分别是重量百分比。活性成份的剂量自然与单独剂量的数目以及有待于治疗的疾病种类有关。单独剂量也可以由多个的、同时用药的剂量单位构成。
实施例1药理学试验佐药引起的关节炎、按照Perper的改进(试验生物医学学会会志(Proc.Soc.exp.Biol.Med.)137期,506页(1971年))
用体重160至210g的Lewis种雄性大鼠(Moellegard，丹麦)作为试验动物。用含有分支杆菌属酪酸悬浮液于重石蜡油中的完全的Freund氏佐药给动物每日皮下注射至尾巴根部(Difco；6mg/kg于石蜡油中；Merck)。将化合物1和2悬浮于羧甲基纤维素(1％于水中)中并且口服用药。第1至第12个试验日每日一次应用化合物；然后在第18天测定爪子容积和关节炎指数。
通过测量二个后爪的爪子容积来测定疾病的严重程度。采用水排挤方法用容积测量仪2060(Rhema-试验技术，Hofheim，德国)进行测量。然后在注射后第18天测定关节炎指数。
测定关节炎指数：1．耳朵 每只耳朵出现红斑和结节形成为0.5点2．鼻 结缔组织肿胀为1点3．尾巴 出现结节为1点4．前爪 每只爪子至少出现一个关节炎症为0.5点5．后爪 轻度炎症(肿胀)为1点中度炎症为2点强度炎症反应为3点
对照组动物只是给用溶剂(1％羧甲基纤维素于水中)。每种剂量和每个对照组分别用6只动物。相对于未经治疗的对照组，爪子溶剂增加的减少和关节炎指数的减低作为作用评判标准。
结果见表1。化合物1和2的总剂量在各个试验中分别恒定。表1
| 化合物1(mg/kg大鼠) | 化合物2(mg/kg大鼠) | 爪子体积的减少(％) | 关节炎指数的减少(％) |
| 109.99.79.054.854.5 | 00.10.31.000.150.5 | 7493949510％增加1046 | 5866716612％增加535 |
随着化合物2剂量的增加，不管是在5mg/kg还是在10mg/kg大鼠活体重量，本发明制剂的作用明显增强。因此，添加小剂量化合物2可使本发明制剂作用明显增强。
Claims (11)
1．固态制剂，它们含有成份1)N-5-甲基异噁唑-4-羧酸-(4-三氟甲基)-酰苯胺、成份2)式Ⅰ化合物和/或式Ⅰ化合物的一种立体异构体形式和/或式Ⅰ化合物的一种生理耐受盐、和3)一种制药学载体，其特征为，成份1)的含量为2至20mg，成份2)的含量为成份1)含量的0.3％至50％。
2．按照权利要求1的制剂，其特征为，成份2)的含量为成份1)含量的0.5％至20％。
3．按照权利要求1或2的制剂，其特征为，成份2)的含量为成份1)含量的0.8％至15％。
4．按照权利要求1至3之一项或多项的制剂，其特征为，成份2)的含量为成份1)含量的1％至10％。
5．按照权利要求1至4之一项或多项的制剂，其特征为，成份2)的含量为成份1)含量的1％至5％。
6．按照权利要求1至5之一项或多项的制剂，其特征为，它含有成份1和2，其用药形式为直肠或口服用药。
7．按照权利要求1至6之一项或多项的制剂，其特征为，成份1和2为同类的但分隔开的药剂形式，用以同时用药。
8．按照权利要求1至7之一项或多项的制剂，其特征为，成份1和2为分隔开的且不同的药剂形式，用以同时用药。
9．按照权利要求1至8之一项或多项的制剂的应用，用以治疗免疫性疾病。
10．按照权利要求1至8之一项或多项的制剂的应用，用以治疗急性免疫性疾病败血症、变态反应、移植物抗宿主反应和宿主抗移植物反应，或自身免疫性疾病，尤其是类风湿性关节炎、系统性红斑狼疮，或多发硬化，或银屑病、局限性皮炎、哮喘、荨麻疹、鼻炎、葡萄膜炎、Ⅱ型糖尿病、肝纤维化、囊状纤维化、结肠炎，或癌症如肺癌、白血病、卵巢癌、肉瘤、Kaposi＇s肉瘤、脑脊膜瘤、结肠癌、淋巴结癌、脑瘤、乳腺癌、胰腺癌、前列腺癌或皮癌。
11．按照权利要求1至8之一项或多项的制剂的制备方法，其特征为，将N-5-甲基异噁唑-4-羧酸-(4-三氟甲基)-酰苯胺、式Ⅰ化合物和/或式Ⅰ化合物的一种生理耐受盐和/或式Ⅰ化合物的一种立体异构体形式和制药学载体加工处理成药剂形式。
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| DE10112924A1 (de) * | 2001-03-13 | 2002-10-02 | Erich Eigenbrodt | 1-Butansäurederivate, pharmazeutische Zusammensetzungen enthaltend solche Derivate und Verwendungen solcher Derivate |
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