CN103384523B - 硝呋太尔在治疗由梭菌属物种所引起的感染中的用途 - Google Patents

硝呋太尔在治疗由梭菌属物种所引起的感染中的用途 Download PDF

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CN103384523B
CN103384523B CN201280009547.7A CN201280009547A CN103384523B CN 103384523 B CN103384523 B CN 103384523B CN 201280009547 A CN201280009547 A CN 201280009547A CN 103384523 B CN103384523 B CN 103384523B
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安娜·布尔盖罗尼
F·马兰德
朱利亚娜·约伯
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Abstract

本发明涉及硝呋太尔或其生理上可接受的盐治疗因梭菌属种所引起的感染的用途。本发明还涉及硝呋太尔治疗艰难梭菌感染（CDI）且尤其是艰难梭菌相关性腹泻（CDAD）的用途。

Description

硝呋太尔在治疗由梭菌属物种所引起的感染中的用途
本发明涉及硝呋太尔（nifuratel）或其生理上可接受的盐治疗因梭菌（Clostridium）属物种所引起的感染的用途。本发明进一步涉及硝呋太尔治疗艰难梭菌（Clostridium difficile）感染（CDI）且尤其是艰难梭菌相关性腹泻（CDAD）的用途。
发明背景
艰难梭菌乃革兰氏阳性芽孢生成性厌氧杆菌，是医院里及长期护理设施中抗生素相关性腹泻最常见的起因。艰难梭菌感染（CDI）可能发生在病人接受广谱抗生素（克林达霉素被视为最主要起因）治疗时，广谱抗生素变更正常肠道菌群的生态平衡，允许艰难梭菌增殖及产生毒素。CDI的症状可从轻度腹泻变化至致命性假膜性大肠炎、猛爆性大肠炎、中毒性巨结肠及死亡。此等症状主要由于艰难梭菌产生的毒素A及毒素B的细胞毒性效应而引起。当临床迹象及症状二者出现时及当使用酶联结免疫吸附检定在粪便中检测到毒素A及毒素B时，可作出CDAD的诊断（Parkes G.C.等人，Lancet Infect Dis2009，9：237-44；Cohen S.H.等人，Infect control HospEpidemiol2010，31（5）：431-455）。
欧洲的艰难梭菌感染程度所知有限。2003年以来美国和加拿大的艰难梭菌感染发生率报告增高，比较这些国家先前报告重度及复发病例的比例更高。
此等感染的发生率增高及毒力的提高可由广泛使用属于氟喹啉酮类抗生素获得部分解释，该类抗生素造成属于PCR核糖体分型027的氟喹啉酮抗药性菌株的选择性及散播。核糖型027系在2005年在英国首次报告，随后此种核糖体分型的流行病在许多其它欧洲医院报告（Bauer MP等人，Lancet2011，377：63-73）。
业界对艰难梭菌感染的治疗主要限于口服甲硝唑或万古霉素共施用7日至14日。两种疗法对艰难梭菌皆高度有效且就总体反应功效而言两者相当，但万古霉素具有较短的症状平均持续时间。使用甲硝唑或万古霉素治疗后常见症状复发。许多卫生当局今日推荐使用甲硝唑作为第一线治疗剂，原因在于甲硝唑比万古霉素显然更便宜，且为了减低万古霉素抗药性肠球菌（VRE）的选择性压力（Cohen S.H.等人Infect control Hosp Epidemiol2010，31：431-455；Freeman J等人JAC2005，56：717-725）。
后果的严重造成目前治疗选项寻求能够充分治疗CDI及CDAD。数种分子目前正在发展用于艰难梭菌感染的治疗上，但尚在研究发展的极为早期（Johnson A.P.Expert Opin Ther Patents2010，20：1389-1399）。因此，就功效及复发的预防而言仍有尚待满足的医学需求。
硝呋太尔乃硝基呋喃衍生物，可有效地用于治疗因原虫（阴道毛滴虫（Trichomonas vaginalis））及细菌诸如阴道葛臬菌（Gardnerella vaginalis）（Mendling W.等人Arzneim Forsch Drug Res2002，52（1）：8-13）或阴道阿托波菌（Atopobium vaginae）（WO2010/121980）所引起的阴道感染。
今日出人意表地发现硝呋太尔除了对阴道病原体具有活性外，也对不同种艰难梭菌物种具有活性。
发明概述
本发明的目的是以硝呋太尔或其生理上可接受的盐用于治疗因细菌梭菌属物种，诸如艰难梭菌（Clostridium difficile）、丁酸梭菌（Clostridiumbutyricum）及拜氏梭菌（Clostridium beijerinckii）所引起的感染所表示。更明确地说，以硝呋太尔或其生理上可接受的盐用于治疗艰难梭菌感染（CDI）及更特别为艰难梭菌相关性腹泻（CDAD）所表示。
硝呋太尔或其生理上可接受的盐的固体、半固体或液体制剂以口服的片剂、薄膜包衣片剂、胶囊、糖衣丸或糖浆的形式，具有为每单次剂量10至1000毫克，优选地为每单次剂量50至800毫克，最优选地为每单次剂量100至600毫克的硝呋太尔的含量，适合用于治疗由梭菌属所引发的感染；这样的制剂可依据常规技术施用给受感染的病人；依据优选的实施方案，有规律地，优选每日三次将这样的制剂施用给受感染的病人。
药物组合物可依据常规技术制备，可含有药学上可接收的赋形剂、佐剂和/或载体，且还可组合地含有具有互补的活性或在任何情形下有用的活性的一种或多种有效成分。
可与本发明的硝呋太尔组合使用的活性剂包括但非限于抗生素、抗腹泻剂及益生菌；此等活性成分可连同硝呋太尔一起施用（即它们可以例如含在硝呋太尔的同一组合物内）或可与硝呋太尔分开施用或在时间上接近地施用。
抗生素的实例包括甲硝唑、万古霉素、枯草杆菌素、利福昔明、胺基糖苷类诸如新霉素、庆大霉素、阿米卡星、卡那霉素及其盐类。
抗腹泻剂的实例包括：碱式水杨酸铋、硅酸铝、高岭土、活性炭、洛哌丁胺、凹凸棒土、锌。益生菌的实例包括乳杆菌（Lactobacillus）、克劳氏芽孢杆菌（Bacillus clausii）及布拉氏酵母菌（Saccharomyces bouillardii）的属种。
依据本发明制备的组合物实例包括：适合用于口服施用的片剂、薄膜包衣片剂、胶囊、糖衣丸或糖浆。
本发明的药物组合物及用途现在将藉下列实施例更完整描述。但须注意此等实施例仅为说明性而非限制性。
实施例1
进行体外研究来调查研究3株艰难梭菌菌株（1株参考菌株ATCC17858及2株临床分离株）、1株丁酸梭菌参考菌株（ATCC17791）及2株拜氏梭菌参考菌株（ATCC8260及ATCC17795）对硝呋太尔的易感性，且与甲硝唑及万古霉素作比较。依据CLSI M11-A7，通过肉汤稀释法，在补充有氯高铁血红素（Hemin）（5微克/毫升）、维生素K1（1微克/毫升）、裂解马血（5%）及氧化酶（1:25v/v）的布氏肉汤内测定MIC（最低抑菌浓度）。硝呋太尔、万古霉素、甲硝唑（事先溶解于二甲亚砜）添加至培养基。全部化合物的测试浓度范围皆为0.125-128微克/毫升。
硝呋太尔对艰难梭菌试验菌株的体外活性（MIC范围：≤0.125-0.25微克/毫升）可相媲美于或优于甲硝唑（MIC范围：0.06-0.25微克/毫升）和万古霉素（MIC范围：0.25-0.5微克/毫升）。
使用丁酸梭菌及拜氏梭菌试验也观察到相当良好的活性。
表1：针对不同的梭菌属菌株的MIC的比较。
实施例2
口服片剂使用如下定性定量配方制造：
过程包括在连续搅拌下，用水及聚乙二醇于45℃下加热来制备（避光）黏结剂溶液；然后于葛拉特（Glatt）流体床篮内掺混硝呋太尔与淀粉直到物质为均质而进行造粒，随后喷洒黏结剂溶液，然后在60℃的输入空气温度下干燥；接着添加滑石和硬脂酸镁。在具有合适冲头的旋转压片机内压成片。
所得的片剂具有黄色的光滑表面。
实施例3
制备具有如下组成wt./wt.%的糖浆：
制备
该配方制备（避光）如下：
1）使用去离子水及羧甲基纤维素（水中3.75%）制备凝胶。静置让凝胶吸收（swallow）过夜。
2）分开制备水、蔗糖（50%）及氯化钠（0.5%）溶液。
3）于水中制备硝呋太尔（0.4%）与聚山梨醇酯80（1%）的混合物。然后搅拌混合物直到变均质。
4）于具有搅拌器的密闭容器内添加去离子水、山梨糖醇及甘油、溶液2）及蔗糖。混合物维持于连续搅拌下。然后添加对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、及二氧化硅。于100℃于搅拌下加热30分钟。于80℃冷却，添加柠檬酸。然后于40℃冷却，于连续搅拌下添加凝胶1）及制剂3）。
所得糖浆乃均质悬浮液剂。
实施例4
口服耐胃酸片剂，芯如实施例2所述制备，使用具如下定性定量组成的喷雾悬浮液进行薄膜包衣：
程序：缓慢添加甲基丙烯酸共聚物至2/3水中及搅拌直到粉末完全被润湿。循序地添加1N NaOH溶液及柠檬酸三乙酯至聚合物悬浮液中，各次添加后搅拌约60分钟。于另外的容器内，于剩余1/3水中均化滑石及二氧化钛历时约10分钟，及将所得悬浮液倾倒入聚合物分散液内同时搅拌。将所得喷雾悬浮液维持搅动。
将如按实施例2所述制备的片剂移至有适当设备的盘上。温度设定于40℃及开始在中等转速下喷雾先前所得悬浮液。包衣过程结束时，开始干燥搅拌并于25-30℃冷却。
实施例5
口服耐胃酸片剂，芯如实施例2所述制备，使用具如下定性定量组成的喷雾悬浮液进行薄膜包衣：
程序：添加乙酸邻苯二甲酸纤维素至1/3水中及搅拌直到获得均质分散液。添加邻苯二甲酸二乙酯及混合约30分钟。于另外的容器内，溶解Peg-6000于剩余2/3水中及将所得溶液添加至邻苯二甲酸纤维素分散液内。混合约10分钟。温度设定为70-80℃，如实施例4所述施加包衣至片剂。
实施例6
口服耐胃酸胶囊，填充以如实施例2所述制造的颗粒但未经压片过程，经以如实施例4或实施例5所述的喷雾悬浮液进行薄膜包衣。
实施例7
口服耐胃酸糖衣丸，其芯如实施例2所述制造，经以如实施例4或实施例5所述的喷雾悬浮液进行薄膜包衣，及最后，使用适当包衣盘以如下组成进行包糖衣：

Claims (15)

1.硝呋太尔或其生理上可接受的盐在制备用于治疗因一种或多种梭菌(Clostridium)属的物种所引起的感染的药物中的用途，其中所述物种选自于艰难梭菌(Clostridium difficile)、丁酸梭菌(Clostridium butyricum)及拜氏梭菌(Clostridium beijerinckii)。
2.如权利要求1所述的用途，其特征在于所述物种为艰难梭菌。
3.如前述权利要求中任一项所述的用途，其特征在于所述感染选自于肠毒素感染。
4.如权利要求3所述的用途，其特征在于所述肠毒素感染为艰难梭菌相关性腹泻。
5.如权利要求1-2和4中任一项所述的用途，其特征在于所述硝呋太尔以固体、半固体或液体药物制剂的形式被施用。
6.如权利要求5所述的用途，其特征在于所述药物制剂选自于：适合口服施用的片剂、胶囊、糖衣丸或糖浆。
7.如权利要求6所述的用途，其特征在于所述片剂是薄膜包衣片剂。
8.如权利要求5所述的用途，其特征在于所述制剂具有每单次剂量10毫克至1000毫克的硝呋太尔或其盐的含量。
9.如权利要求5所述的用途，其特征在于所述制剂具有每单次剂量50毫克至800毫克的硝呋太尔或其盐的含量。
10.如权利要求5所述的用途，其特征在于所述制剂具有每单次剂量100毫克至600毫克的硝呋太尔或其盐的含量。
11.如权利要求1-2、4和6-10中任一项所述的用途，其特征在于所述硝呋太尔与选自于抗生素、益生菌、抗腹泻剂中的至少一种有效成分共同地或时间上接近地被施用。
12.如权利要求11所述的用途，其特征在于所述至少一种抗生素选自于：甲硝唑、万古霉素、枯草杆菌素、利福昔明、氨基糖苷类及其盐类。
13.如权利要求12所述的用途，其特征在于所述氨基糖苷类是新霉素、庆大霉素、阿米卡星或卡那霉素。
14.如权利要求11所述的用途，其特征在于所述至少一种抗腹泻剂选自于：碱式水杨酸铋、硅酸铝、高岭土、活性炭、洛哌丁胺、凹凸棒土及锌。
15.如权利要求11所述的用途，其特征在于所述至少一种益生菌选自于乳杆菌(Lactobacillus)、克劳氏芽孢杆菌(Bacillus clausii)及布拉氏酵母菌属(Saccharomyces bouillardii)的物种。
CN201280009547.7A 2011-02-22 2012-01-19 硝呋太尔在治疗由梭菌属物种所引起的感染中的用途 Expired - Fee Related CN103384523B (zh)

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