CN108472292A - 药物组合物、固定剂量的甲氟喹的用途和用于治疗结核病的方法 - Google Patents

药物组合物、固定剂量的甲氟喹的用途和用于治疗结核病的方法 Download PDF

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CN108472292A
CN108472292A CN201680076963.7A CN201680076963A CN108472292A CN 108472292 A CN108472292 A CN 108472292A CN 201680076963 A CN201680076963 A CN 201680076963A CN 108472292 A CN108472292 A CN 108472292A
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mefloquine
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tuberculosis
ofloxacin
rifampin
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CN108472292B (zh
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M·V·N·德索萨
R·S·B·贡萨尔维斯
M·C·达斯瓦·洛伦索
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Abstract

本发明涉及甲氟喹抗结核分枝杆菌的用途。本发明进一步考虑甲氟喹与用于结核病的首选和次选治疗的药物的组合，实现了结核病(TB)和多药耐药结核病(MDR‑TB)的较短的治疗期。

Description

药物组合物、固定剂量的甲氟喹的用途和用于治疗结核病的 方法
技术领域
本发明在其最广泛的概念中涉及甲氟喹(mefloquine，MFL)抗结核分枝杆菌(Mycobacterium tuberculosis)的用途。
背景技术
结核病(TB)是由结核分枝杆菌引起的古老的感染性疾病并且在世界各地依然是由感染性疾病导致的死亡的主要原因。结核分枝杆菌由Robert Koch于1882年发现和鉴定，并且为了纪念他，其也称为Koch氏杆菌(BK)。
TB的治疗基于固定组合剂量的四种药物：利福平(rifampicin，RIF)、异烟肼(isoniazid，INH)、吡嗪酰胺(pyrazinamide，PYR)和乙胺丁醇(ethambutol，ETB)。设计固定剂量方案不仅是为了预防由活动性TB(active TB)引起的症状，也为了预防在单一疗法的情况下经常观察到的耐药菌的发展。然而，治疗的周期长(六个月)，并且副作用在个体中的出现非常常见。因此，尽管事实上目前的治疗已经降低了由TB引起的死亡人数，但是已经观察到了高水平的失效(lapsing)和中断(interruption)。该事实已经直接导致了结核分枝杆菌的耐药菌株的出现。
目前，世界卫生组织(WHO)将TB的耐药分为两个层次：多药耐药结核病(MDR-TB)和广泛耐药结核病(XDR-TB)。MDR-TB是由至少对INH和RIF耐药的细菌引起的。在XDR-TB的情况下，细菌对INH和RIF以及一种氟喹诺酮和用于次选治疗的可注射药物(阿米卡星(amikacin)、卡那霉素(kanamycin)和卷曲霉素(capreomycin))耐药。这些形式的TB对标准的六个月治疗不响应，有必要使用毒性更大且效果更差的药物。结果，除了延长(约两年)以外，治疗也变得更加昂贵。
随着HIV的出现，结核病化学疗法已经经历了很大的变化。多药耐药菌株、尤其是对利福平和异烟肼耐药的那些的出现已经造成了很多公共卫生问题。结果，已经有必要采用新的药物，其已经导致抗结核病药物分为两组：
(1)效力较高且毒性较小的主要药物(一线或首选)；和，
(2)效力较低且毒性较大的次要药物(二线或次选)。
描述为“一线”的药物包括异烟肼(INH)、利福平(RIF)、乙胺丁醇(ETB)和吡嗪酰胺(PYR)；并且二线药物包括链霉素(streptomycin，SM)、乙硫异烟胺(ethionamide，Et)、氨基水杨酸(Aa)、环丝氨酸(cycloserine，Cs)、阿米卡星(Am)、卡那霉素(Cn)、卷曲霉素(Cp)和利奈唑胺(linezolid，L)。
Mao等人，[ChemMedChem.2007Nov；2(11):1624-30.Design,synthesis,andpharmacological evaluation of mefloquine-based ligands as novelantituberculosis agents.Mao J,Wang Y,Wan B,Kozikowski AP,Franzblau SG.]提到开发了甲氟喹类似物并且关于针对抗结核分枝杆菌H37Rv的抗TB活性对它们进行评价。
Lowell S.Young等人[Antimicrob.Agents Chemother.November 2009 vol.53no.11 4577-4579,Reconsidering Some Approved Antimicrobial Agents forTuberculosis,Published ahead of print 8September 2009,doi:10.1128/AAC.00887-09]报道，对耐氯喹(cloroquine)的菌株具有活性的甲氟喹具有对由非结核分枝杆菌引起的最常见的感染鸟型分支杆菌复合体(Mycobacterium Avium Complex，MAC)的杀菌活性。单人病例报告描述了通过将利奈唑胺和甲氟喹添加至其它抗Mac药剂中而对表现为对MAC疾病耐受的患者的成功的治疗，但是第一种化合物在长期治疗中具有局限性。该文章推测甲氟喹对结核分枝杆菌(M.tuberculosis)也有效果并且可以为异烟肼和利福平的替代品。
Raoni等人，[Bioorganic&Medicinal Chemistry中，第20卷，第1期，2012年1月1日，243-248页。Mefloquine-oxazolidine derivatives,derived from mefloquine andarenecarbaldehydes:In vitro activity including against the multidrug-resistant tuberculosis strain T113]提出其中新的甲氟喹-噁唑烷衍生物相对于一线药物显示改善的抗结核病活性的研究。
值得注意的是Mao等人和Raoni等人的研究是对尚未经历一系列试验如动物模型和毒理学试验的甲氟喹分子(新物质)进行的修饰的报告。仅完成了体外试验并且体外试验没有使用其它药物进行试验，也就是说它们是新药开发中的基础研究。
Lowell S.Young等人的研究提供了在这种使用利奈唑胺的情况下甲氟喹与其他药物组合的潜力的一个良好的实例。然而，作者仅使用了尚未批准作为抗TB药物的利奈唑胺。
在这种背景下，认为具有降低的副作用、也有助于缩短不同形式的TB的治疗时间的新的、更有效且毒性更小的组合的开发在公共卫生领域为全球优先事项。
发明内容
本发明提出了相对于文献中报道的其它研究完全不同且非显而易见的概念，其为用于结核病的治疗的不同药物与甲氟喹的组合，证明当与其它抗TB药物组合时，该药物显示重要的协同作用(synergism)，显示了在耐药结核病的治疗中在新的组合(药物)的开发中的重大的潜力。
本发明在其最广泛的概念中涉及甲氟喹抗结核分枝杆菌从而抵抗结核病的用途。
本发明还涉及抗结核分枝杆菌的甲氟喹与抗结核病药剂组合用于更有效地治疗结核病的用途。
本发明提供用于结核病的治疗的组合物。
附图说明
图1示出药物甲氟喹的化学结构。
图2A-2L示出与甲氟喹组合使用的一些药物的化学结构。
具体实施方式
在寻找新的疗法从而抵抗结核病(TB)时，本发明人确定了甲氟喹(MFL)潜在地可用于TB的治疗。
本发明人在选择甲氟喹用于治疗结核病的固定剂量的组合制剂时考虑的重要方面为：(i)其相对长的半衰期；(ii)其被HIV患者很好地耐受；(iii)其不显示与抗逆转录病毒药物如蛋白酶抑制剂的药物相互作用；(iv)其显示良好的胃肠道吸收；和(v)其主要集中在肺部，其为受结核分枝杆菌影响最大的器官。
MFL目前用于疟疾预防(世界疟疾报告)。然而，MFL也对不同种类的革兰氏阳性菌有活性(Kunin CM等人)。然而，Fu LM等人报道结核分枝杆菌相对于其它细菌的系统发育地位(phylogenetic position)是有争议的。结核分枝杆菌的细胞壁具有革兰氏阳性菌和革兰氏阴性菌二者的特征。在基于保守基因含量(conserved gene content)构建的基因组树(genome tree)中，与革兰氏阳性菌相比，结核分枝杆菌与革兰氏阴性菌更密切地相关。
如上所述，虽然现有技术是有争议的，但是本发明人继续研究从而理解甲氟喹、特别是当与其它药物组合时在结核病的治疗中的效果。
本发明人的研究揭示了甲氟喹与用于结核病的治疗的一线和二线药物的组合的协同效应。
因此，本发明涉及甲氟喹抗结核分枝杆菌的用途。
本发明还包括甲氟喹与用于结核病的首选和次选治疗的药物的组合，实现了结核病(TB)和多药耐药结核病(MDR-TB)的治疗中的治疗期的潜在的缩短。
本发明的另一目的在于提供包含甲氟喹的有效的组合，从而治疗包括对用于结核病的治疗的药物多重耐药的多种结核分枝杆菌的结核病。
本发明提供用于在哺乳动物中治疗结核病的药物组合物，其包括对有需要的所述哺乳动物给予有效量的甲氟喹与在结核病的治疗中有效的药剂的组合。
通过将一种或多种在结核病的治疗中有效的药剂与甲氟喹混合来制备根据本发明使用的药物制剂。
用于本发明的药物组合物的甲氟喹和药物(可用于结核病的治疗的药剂)二者的使用比例的范围为0.01-10。
与甲氟喹组合的药物的数量为至多3种药物。
现在将参考不应该解释为限制本发明的范围的以下实施例来描述本发明。
材料和方法
1.1结核分枝杆菌
使用结核分枝杆菌的以下菌株：
–标准菌株结核分枝杆菌H37Rv(ATCC 27294)；
–耐药菌株结核分枝杆菌T3609，对氧氟沙星(ofloxacin，OFX)和链霉素耐药；和，
–多重耐药菌株T113，对异烟肼(INH)、利福平(RIF)、乙胺丁醇(ETB)和氧氟沙星(OFX)耐药。
所有菌株属于Oswaldo Cruz基金会Evandro Chagas临床研究所生物技术与生物检测实验室(Bacteriologia e Bioensaio do Instituto de Pesquisa Clínica EvandroChagas-IPEC)的收集品(collection)。
1.2使用的物质
在进行的试验中，对这里先前提及的结核分枝杆菌的菌株(项目1.1)使用最低抑菌浓度(minimum inhibitory concentration，MIC)的甲氟喹。甲氟喹与以下组合进行试验：
-首选药物：异烟肼(INH)、吡嗪酰胺(PYR)、利福平(RIF)和乙胺丁醇(ETB)。
-结核病的治疗中的次选药物。
-利奈唑胺(LYN)。
-喹诺酮类：加替沙星(gatifloxacin，GAT)、莫西沙星(moxifloxacin，MCX)、司帕沙星(sparfloxacin，SPR)、氧氟沙星(CFX)、环丙沙星(ciprofloxacin，CPX)和左氧氟沙星(levofloxacin，LVX)。
1.3使用的物质的比例和数量
甲氟喹和使用的药物二者的使用比例的范围为0.01-10。与甲氟喹组合的药物的数量为至多3种。
1.3使用的物质的比例和数量
甲氟喹和使用的药物二者的使用比例的范围为0.01-10p/p。与甲氟喹组合的药物的数量为至多3种。
1.4最低抑菌浓度(MIC)的测定
针对结核分枝杆菌在培养基7H9中测定抗结核病活性并且使用阿尔玛蓝(AlamarBlue，MABA)比色法测定MIC值。
1.5物质之间的协同作用的测定
试验的药物之间的协同相互作用通过部分抑菌浓度(Fractional InhibitoryConcentration，FIC)指数来测定，其为被科学界广泛地接受和使用的方法(美国微生物学会指南(Guidelines of American Society for Microbiology))。FIC的计算使用下式来进行：
FIC的计算
(在组合中测得的物质A的MIC)/单独测得的物质A的MIC+(在组合中测得的物质B的MIC)/单独测得的物质B的MIC)
相互作用如下进行评价：
FIC≤0.5→协同相互作用
0.5<FIC≤4.0→加和相互作用
FIC>4.0→拮抗相互作用
实施例1
实施例1显示药物甲氟喹与结核病的治疗中的首选药物的最佳组合的结果(表1A和1B)。
表1A-菌株H37RV-标准菌株
组合 MIC组合 FIC 比例
甲氟喹 12.5μg/mL - -
甲氟喹+吡嗪酰胺 6.25μg/mL 0.3 0.5-1.0
甲氟喹+异烟肼 0.20μg/mL 0.5 1.0-1.0
表1B-菌株T3609-对氧氟沙星和链霉素耐药
组合 MIC组合 FIC 比例
甲氟喹 25μg/mL - -
甲氟喹+异烟肼 0.03μg/mL 0.03 1.0-1.0
实施例2
实施例2显示突出MFL与不同的次选药物喹诺酮类和利奈唑胺(LYN)之间的最佳组合的结果(表2A和2B)。
表2A-菌株T3609-对氧氟沙星和链霉素耐药
组合 MIC组合 FIC 比例
甲氟喹+加替沙星 0.62μg/mL 0.5 1.0-0.5
甲氟喹+莫西沙星 1.25μg/mL 0.5 1.0-0.5
甲氟喹+司帕沙星 1.25μg/mL 0.5 1.0-0.5
表2B-菌株T113-对异烟肼、利福平、乙胺丁醇和氧氟沙星耐药
组合 MIC组合 FIC 比例
甲氟喹 25μg/mL - -
甲氟喹+氧氟沙星 1.25μg/mL 0.5 1.0-0.5
甲氟喹+环丙沙星 0.62μg/mL 0.5 1.0-0.5
甲氟喹+左氧氟沙星 0.62μg/mL 0.5 1.0-0.5
实施例3
MFL的MIC、单独测得的各药物的MIC(MIC 1)和在组合中测得的各药物的MIC(MIC2)表示在表3和4中。
表3.MFL与不同喹诺酮类的组合
MIC 1：单独测得的物质的MIC/MIC 2：在组合中测得的物质的MIC。GAT-加替沙星，MOX-莫西沙星，SPR-司帕沙星，OFX-氧氟沙星，CPX-环丙沙星，LVX-左氧氟沙星
表4.MFL和LYN与用于TB的首选治疗的不同药物的组合
MIC 1：单独测得的物质的MIC/MIC 2：在组合中测得的物质的MIC。INH-异烟肼，PYR-吡嗪酰胺，ETB-乙胺丁醇，LYN-利奈唑胺，N.D.-未测定
当与首选药物组合时，观察到三种协同相互作用：MFL+PYR和MFL+INH(针对菌株H37Rv)、以及MFL与INH之间的强的协同相互作用(FIC＝0.03)(针对菌株T3609)。INH和PYR在TB的治疗中起根本作用。然而，这些药物在结核分枝杆菌的发展的不同阶段起作用。INH对生长中的细菌具有杀菌效果(bactericide effect)，而PYR具有灭菌效果(sterilizingeffect)并且作用于潜伏的微生物。
鉴于这里显示的结果，可以观察到的是甲氟喹对所有菌株显示相同的MIC-不存在交互抗性(cross-resistance)。除此以外，在组合中未观察到甲氟喹的拮抗反应。
本发明的药物组合物可以为通常用于给予药物用于治疗目的的任何形式。因此，组合物可以为片剂、胶囊剂、糖浆剂、液体混悬剂、酏剂(elixirs)、精细分散的颗粒(finelydivided particles)和相似的物质的形式。本发明的药物组合物可以包括调味剂、着色剂和甜味剂或其混合物。
本发明的药物组合物还可以包括选自由微晶纤维素、乳糖、交聚维酮、玉米淀粉、氨基藻酸钙、泊洛沙姆(聚氧乙烯-聚氧丙烯共聚物)、滑石、硬脂酸镁、月桂基硫酸钠、硬脂酸钙、羧甲基纤维素钠、碳酸镁、巴西棕榈蜡、松香、白蜂蜡、石蜡、糖衣、阿拉伯树胶、明胶、高岭土、二氧化钛(E171)、胶态二氧化硅、聚乙烯吡咯烷酮K30、蔗糖、日落黄(E110)组成的组中的赋形剂。
因此，本发明人证明了甲氟喹与用于结核病和多药耐药结核病的治疗的一线和二线药物的组合的协同效应。
本发明不限于这里示出的具体化，而是根据与在此描述的原理和新的方面一致的宽泛的范围。
应当理解的是在此描述的实施例和具体化仅仅用于说明性目的并且基于此的各种修改或变更对于本领域技术人员将会发生且应当包括在权利要求范围内。
参考文献
(1)World Malaria Report 2011,available at www.who.int/malaria.
(2)Kunin,C.M.；Ellis,W.Y.Antimicrob Agents Chemother.2000,44(4)；848-852.
(3)Tuberculosis(Edinb)2002；82(2-3)；85-90.Is Mycobacteriumtuberculosis a closer relative to Gram-positive or Gram-negative bacterialpathogens？Fu LM；Fu-Liu CS.
(4)Guidelines of American Society for Microbiology.Disponível emwww.aac.asm).

Claims (6)

1.一种药物组合物，其特征在于包含：
(a)0.01p/p的甲氟喹；和，
(b)0.01p/p的选自由异烟肼、吡嗪酰胺、利福平、乙胺丁醇、链霉素、乙硫异烟胺、氨基水杨酸、环丝氨酸、阿米卡星、卡那霉素、卷曲霉素、利奈唑胺、加替沙星、莫西沙星、司帕沙星、氧氟沙星、环丙沙星和左氧氟沙星组成的组中的至少1种且至多3种在结核病的治疗中有用的药物；和，
(c)任选的赋形剂。
2.根据权利要求1所述的药物组合物，其特征在于，所述在结核病的治疗中有用的药物优选选自由异烟肼、利福平、乙胺丁醇、莫西沙星和加替沙星组成的组中的至少1种且至多3种药物。
3.根据权利要求1所述的药物组合物，其特征在于，赋形剂选自由微晶纤维素、乳糖、交聚维酮、玉米淀粉、氨基藻酸钙、泊洛沙姆(聚氧乙烯-聚氧丙烯共聚物)、滑石、硬脂酸镁、月桂基硫酸钠、硬脂酸钙、羧甲基纤维素钠、碳酸镁、巴西棕榈蜡、松香、白蜂蜡、石蜡、糖衣、阿拉伯树胶、明胶、高岭土、二氧化钛(E171)、胶态二氧化硅、聚乙烯吡咯烷酮K30、蔗糖、日落黄(E110)组成的组。
4.固定剂量的甲氟喹与至少1种且至多3种抗结核病药物组合在制备用于结核病的治疗的药物中的用途，其中所述抗结核病药物选自由异烟肼、吡嗪酰胺、利福平、乙胺丁醇、链霉素、乙硫异烟胺、氨基水杨酸、环丝氨酸、阿米卡星、卡那霉素、卷曲霉素、利奈唑胺、加替沙星、莫西沙星、司帕沙星、氧氟沙星、环丙沙星和左氧氟沙星组成的组。
5.根据权利要求4所述的甲氟喹的用途，其中所述抗结核病药物优选选自来自由异烟肼、利福平、乙胺丁醇、莫西沙星和加替沙星组成的组中的至少1种且至多3种药物。
6.一种用于在哺乳动物中治疗结核病的方法，其包括对有需要的所述哺乳动物给予有效量的甲氟喹与至少1种且至多3种抗结核病药物的组合，其中所述抗结核病药物选自由异烟肼、吡嗪酰胺、利福平、乙胺丁醇、链霉素、乙硫异烟胺、氨基水杨酸、环丝氨酸、阿米卡星、卡那霉素、卷曲霉素、利奈唑胺、加替沙星、莫西沙星、司帕沙星、氧氟沙星、环丙沙星和左氧氟沙星组成的组。
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