CN113473994A - 抗病毒剂的组合、基于其治疗的试剂盒和方法 - Google Patents
抗病毒剂的组合、基于其治疗的试剂盒和方法 Download PDFInfo
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- CN113473994A CN113473994A CN201980093074.5A CN201980093074A CN113473994A CN 113473994 A CN113473994 A CN 113473994A CN 201980093074 A CN201980093074 A CN 201980093074A CN 113473994 A CN113473994 A CN 113473994A
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Abstract
本发明组涉及医学和制药工业，具体涉及用于HIV感染治疗的组合，包含(i)5'‑氨基羰基膦酸酯‑3'‑叠氮基‑3'‑脱氧胸苷铵盐和(ii)选自恩曲他滨和拉米夫定的胞苷类似物，药剂(i)与药剂(ii)的重量比为从250:1至1:250；涉及包含所述组合和用于使用其的说明书的试剂盒；以及涉及治疗包括人的哺乳动物中的HIV感染的方法，所述方法通过向有此需要的哺乳动物施用治疗有效量的所公开的组合。本组发明拓宽了用于HIV感染治疗的组合的抗病毒药物的范围，以及此类治疗的更高有效性。
Description
技术领域
本发明涉及医学和制药工业领域，并且旨在用于治疗病毒感染。
更具体地，本发明涉及抗HIV的组合的抗病毒剂，即5'-氨基羰基膦酸酯-3'-叠氮基-3'-脱氧胸苷铵盐(5'-amino carbonyl phosphonate-3'-azido-3'-deoxythymidineammonium salt)(6HP)与恩曲他滨(FTC)或与拉米夫定(3TC)的组合。
发明背景
HIV感染是由人类免疫缺陷病毒(HIV)感染引起的一种长期存在的感染性疾病。HIV感染对免疫系统的损害会进展，导致称为获得性免疫缺陷综合征(AIDS)的病症，在这种情况下，患者会发展“机会性疾病(opportunistic diseases)”：由机会性病原体和某些癌症引起的严重感染。
感染者仍然是终生的传染源。未经治疗的HIV感染会持续3-10年，并以感染者的死亡告终。
HIV感染的多种临床表现和出现针对它的机会性疾病，以及该疾病的长期持续时间，使得开发用于治疗HIV感染者和AIDS患者的药物成为必要。现在我们知道的药物有以下几类：核苷、核苷酸、和非核苷病毒逆转录酶抑制剂；蛋白酶和整合酶抑制剂；和融合抑制剂。许多对HIV其他部位有活性的化合物正在开发中。
病毒逆转录酶的核苷抑制剂是最广泛使用的。这些包括：齐多夫定(AZT)、拉米夫定(3TS)、恩曲他滨(FTC)、去羟肌苷(DDI)、叠氮膦(phosphazide)、替诺福韦(tenofovir)(TDF)，和其他。
对于长期、几乎终身使用的药物的需要引起毒性表现和病毒的抗药性的发展。根据一些数据，6个感染周期后发展出对齐多夫定(AZT)的抗性，4个感染周期后发展出对拉米夫定(3TS)的抗性，以及10个感染周期后发展出对叠氮膦的抗性[Machardo J.等人Antiviral activity and resistance profile of phosphazide,a novel prodrug ofAZT/Nucleosides&Nucleotides,1999,V.18,pp.901-906]。使用抗病毒药物的组合允许通过影响病毒的不同部位来更有效地抑制HIV。因此，一些研究[专利RU 2139059 C1,publ.10.10.1999；专利RU2331420 C2，publ.20.08.2008；Perez-Olmeda M.等人，In vitroanalysis of synergism and antagonism of different nucleoside/nucleotideanalogue combinations on the inhibition of HIV 1replication/Journal ofMedical Virology,2009,V.81,pp.211-216]表明，拉米夫定(3TS)或其氟化类似物恩曲他滨(FTC)与齐多夫定或叠氮膦或阿巴卡韦或替诺福韦组合可增强第二种组分的作用(协同效应)或降低第二种组分的细胞毒作用，或兼具以上两种效应。然而，所使用的每种组合都有各自的弊端。
拉米夫定与阿巴卡韦的组合的弊端包括：
-对阿巴卡韦的迟发型超敏反应的发展[Pokrovsky V.V.等人，Protocols forthe dispensary supervision and treatment of HIV patients/Epidemiology andinfectious diseases,2014,No.6,43p]；
-缺乏协同效应[Perez-Olmeda M.等人，In vitro analysis of synergism andantagonism of different nucleoside/nucleotide analogue combinations on theinhibition of human immunodeficiency virus type 1replication/Journal ofMedical Virology,2009,V.81,pp.211-216]。
恩曲他滨与替诺福韦的组合的弊端包括：
-高肾毒性和破坏骨矿化[Pokrovsky V.V.等人，Protocols for the dispensarysupervision and treatment of HIV patients/Epidemiology and infectiousdiseases,2014,No.6,43p.]。
拉米夫定与齐多夫定组合的弊端包括[Pokrovsky V.V.等人，Protocols for thedispensary supervision and treatment of HIV patients/Epidemiology andinfectious diseases,2014,No.6,43p.]：
-毒性，主要表现为贫血、中性粒细胞减少和白细胞减少；
-诱变效应，表现为在体外代谢激活系统中诱导指示微生物的基因突变；
-治疗有效性不足。
拉米夫定与叠氮膦组合的弊端可以包括：
-每天施用药物两次，导致疗法坚持性(therapy adherence)不足，随之发生治疗有效性不足[Pokrovsky V.V.等人，Protocols for the dispensary supervision andtreatment of HIV patients/Epidemiology and infectious diseases,2014,No.6,43p.]；
-选择性指数不足[Khandazhinskaya A.L.等人，5'-AminocarbonylPhosphonates as New Zidovudine Depot Forms:Antiviral Properties,IntracellularTransformations,and Pharmacokinetic Parameters/Drug Metabolism andDisposition,2009,V.37,N.3,pp.494-501]。
本申请的作者发现，在与拉米夫定或与恩曲他滨的已知组合中，用5'-氨基羰基膦酸酯-3'-叠氮基-3'-脱氧胸苷的铵盐(6HP)替代齐多夫定或阿巴卡韦或替诺福韦导致大幅降低这些药物的典型毒性效应。
临床前试验的结果表明，与阿巴卡韦不同，5'-氨基-羰基膦酸酯-3'-叠氮基-3'-脱氧胸苷的铵盐(6HP)提供阴性迟发型超敏反应[Khandazhinskaya A.L.等人，5'-Phosphonates AZT:achievements and prospects in the treatment and preventionof HIV infection/Acta Naturae,2013,V.5,N.3,pp.57-65]。
对BALB系小鼠和Wistar大鼠的临床前急性毒性试验结果表明6HP的潜在毒性低[Khandazhinskaya A.L.等人，5'-Phosphonates AZT:achievements and prospects inthe treatment and prevention of HIV infection/Acta Naturae,2013,V.5,N.3,pp.57-65；Galegov G.A.Nikavir(phosphazide),an antiretroviral agent:anti-HIVactivity,toxicology,pharmacokinetics,and some perspectives of its clinicaluse/Antibiotics and Chemotherapy,2004,Vol.49,No.7,pp.3-8]。当腹膜内施用到小鼠时平均致死剂量(LD50)对于为6HP≥5g/kg，对于叠氮膦为≥2.3g/kg，并且当胃内施用到大鼠时平均致死剂量(LD50)对于6HP为超过40g/kg，对于叠氮膦为13g/kg。
6HP(与齐多夫定不同)没有表现出诱变效应，所述诱变效应表现为在体外代谢激活系统中能够诱导指示微生物的基因突变(Ames测试)[Khandazhinskaya A.L.等人，5'-Phosphonates AZT:achievements and prospects in the treatment and preventionof HIV infection/Acta Naturae,2013,V.5,N.3,pp.57-65]。
此外，6HP没有表现出替诺福韦的毒性特征(肾毒性和骨密度降低)[KravchenkoA.V.等人，Safety and tolerability of 6HP in adult HIV-infected patients whohave not previously received ART/HIV infection and immunosuppression,2015,Vol.7,No.4,p.64-73]。
6HP的抗病毒效应通过MT-4细胞中的HIV逆转录酶活性来评估。发现6HP选择性指数显著地高于叠氮胸苷和叠氮膦[Khandazhinskaya A.L.等人，5'-AminocarbonylPhosphonates as New Zidovudine Depot Forms:Antiviral Properties,IntracellularTransformations,and Pharmacokinetic Parameters/Drug Metabolism andDisposition,2009,V.37,N.3,pp.494-501]。
药物6HP在体内缓慢生成齐多夫定，因此6HP的作用时间增加，可实现每日单次施用模式[Sizova N.V.等人，High-performance liquid chromatography for theselection of optimal dosages and course of treatment with 6HP,a reversetranscriptase inhibitor/Medical Academic Journal,2015,Vol.15,No.4,p.76-81]。
因此，该组合的低毒性和每日单次施用提供了机会以增加患者对治疗的坚持性，并最终改善了用于治疗HIV感染的化疗的有效性。
最接近本发明的(原型)是叠氮膦与拉米夫定的组合[专利RU 2331420 C2，publ.20.08.2008]。
然而，如上所述，这种组合的弊端是每日两次摄入治疗方案(regimen)，治疗有效性低，且选择性指数不足。
发明的公开内容
本发明的目的是开发抗HIV感染的组合药剂，而没有原型中指出的弊端。
本发明所取得的技术结果扩大了用于治疗HIV感染的组合抗病毒药物的库(armamentarium)，并提高了这种治疗的有效性。
本申请指出，在与拉米夫定的已知组合中，用6HP替代叠氮膦导致治疗有效性的显著增加。由于6HP像叠氮膦一样，在哺乳动物体内生成齐多夫定[Skoblov Y.等人，Intracellular metabolism and pharmacokinetics of 5′-hydrogenphosphonate of3′-azido-2′,3′-dideoxythymidine,a prodrug of 3′-azido-2′,3′-dideoxythymidine/Antiviral Research,2004,V.63,N.2,pp.107-113；Khandazhinskaya A.L.等人，5'-Aminocarbonyl Phosphonates as New Zidovudine Depot Forms:AntiviralProperties,Intracellular Transformations,and Pharmacokinetic Parameters/DrugMetabolism and Disposition,2009,V.37,N.3,pp.494-501；Sizova N.V.等人，High-performance liquid chromatography for selection of optimal dosages and courseof treatment with 6HP,a reverse transcriptase inhibitor/Medical AcademicJournal,2015,Vol.15,No.4,pp.76-81]，将其与拉米夫定(而不是叠氮膦)组合使用应该不会产生所指出的优势(增加的治疗有效性)。在细胞实验中，6HP的有效性低于叠氮膦[Khandazhinskaya A.L.等人，5'-Phosphonates AZT:achievements and prospects inthe treatment and prevention of HIV infection/Acta Naturae,2013,V.5,N.3,pp.57-65]，但在临床研究中6HP的有效性高于叠氮膦。
因此，所获得的结果可以被归类为无法提前预测的出乎意料的结果。
该技术结果通过用于治疗HIV感染的组合来实现，所述组合含有(i)5'-氨基-羰基膦酸酯-3'-叠氮基-3'-脱氧胸苷的铵盐(6HP)和(ii)选自恩曲他滨(FTC)和拉米夫定(3TC)的胞苷类似物，药剂(i)与药剂(ii)的质量比为从250:1至1:250。
在本发明的一个优选实施方案中，(i)5'-氨基羰基膦酸酯-3'-叠氮基-3'-脱氧胸苷的铵盐与(ii)恩曲他滨或拉米夫定的质量比为从1:50至50:1，或甚至更优选从1:10到10:1。
所提出的抗病毒组合可以另外含有药学上可接受的载体并且优选旨在用于口服施用，例如可以是片剂或胶囊剂形式，包括用于放置在泡罩包装(blister pack)中的那些。
6HP和恩曲他滨的组合或6HP和拉米夫定的组合可旨在用于同时或分开施用，例如，顺序(sequential)施用。与原型一样，顺序施用不需要抑制剂之间的长间隔。它可以是几分钟到3小时。优选同时施用。治疗所需的6HP剂量，以及恩曲他滨和拉米夫定之间的选择可能会因施用方法、HIV感染进程的特征以及患者的年龄和病症而异，并且可由医生个体化地确定。所使用的剂量范围为每日每kg体重1至250mg，优选在2至100mg/kg/日之间，每种抑制剂最优选在5至50mg/kg/日之间。
该技术结果还通过HIV治疗试剂盒来实现，所述HIV治疗试剂盒包含建议的(i)5'-氨基羰基膦酸酯-3'-叠氮基-3'-脱氧胸苷的铵盐(6HP)和(ii)选自恩曲他滨(FTC)和拉米夫定(3TC)的胞苷类似物的组合，以及用于使用所述组合的说明书。
因此，该技术结果通过治疗包括人的哺乳动物中的HIV感染的方法来实现，所述方法通过向有此需要的哺乳动物施用治疗有效量的6HP与恩曲他滨或拉米夫定的组合。
如在本发明的范围内使用的术语“治疗”是指减轻患者中特定障碍的症状或改善与特定障碍相关的可确定参数，并且可以包括抑制无症状患者(诸如病毒感染已经变得潜伏的患者)中的症状复发。治疗可包括预防，其是指防止疾病或病症或防止患者经历此类疾病或病症的症状。
术语“治疗有效”是指在治疗AIDS和HIV感染方面医师(practioner)所理解的缓解患者的病症所需的药剂(i)和(ii)的量。优选地，治疗的目标是抑制病毒载量、恢复和维持免疫功能、改善生活质量并降低与HIV相关的发病率和死亡率。
6HP与恩曲他滨或拉米夫定可以以物质(substance)的形式用于治疗目的。然而，优选将指定的抑制剂与药学上可接受的载体一起施用。
作为药学上可接受的载体，可以使用与药物的其他成分相容且不引起不良效应的在成品剂型(finished dosage form)(片剂、胶囊剂、栓剂、输液剂等)的生产中使用的各种添加剂。
由于6HP、恩曲他滨和拉米夫定分子的特性以及它们对细胞内HIV效应的特定机制，用于口服、肠胃外和直肠施用的剂型最受关注。药物也可以通过药剂学中已知的任何方法来制造，其概念上包括许多步骤：将抑制剂与固体或液体载体混合和造粒；以离散的统一剂型的形式形成产品。
片剂、胶囊剂、口服溶液剂和药剂学中已知的其他标准剂型可用于口服施用。片剂和胶囊剂可能含有用于其制造技术和用于实现满足相关药典要求的必要定性和定量指标所必需的标准赋形剂。赋形剂的实例有乳糖、甘露醇、淀粉、改性淀粉、纤维素及其衍生物、明胶、硬脂酸或其盐、润湿剂、香料和着色剂。
口服液体制剂(preparation)可以被制成溶液剂的形式(水性或油性混悬剂、溶液剂、乳剂、糖浆剂等)或作为干燥产品，所述干燥产品在直接使用前必须用水或其他溶剂稀释。
用于肠胃外施用(例如用于输注)的制剂可以被制成标准小瓶、安瓿、填充注射器等形式。药物还必须在无菌情况下制造，并且可能含有各种防腐剂、缓冲剂、稳定剂和等渗剂。冻干形式应在使用前与不致热无菌溶剂混合。
制备的用于直肠施用的剂型可以被制成统一形式的栓剂。此外，固体形式通常使用合适的载体通过将抑制剂与固体或熔融载体混合，然后在冷却时从熔体模塑来制造。
除了上述之外，可以使用修饰的化合物制备药物组合物，导致抑制剂在体内的延长释放。
执行本发明的最佳型式(version)
通过但不限于以下实施例来说明本发明。
实施例1.片剂形式的组合的抗病毒剂
型式1：
| 6HP | 600mg |
| 恩曲他滨 | 200mg |
| 碳酸钙 | 200mg |
| 硬脂酸镁 | 6mg |
| Aerosil | 3mg |
型式2：
| 6HP | 600mg |
| 拉米夫定 | 300mg |
| 碳酸钙 | 200mg |
| 硬脂酸镁 | 6mg |
| Aerosil | 3mg |
实施例2.含有不同颜色的两排的10片剂的泡罩包装
型式1：
型式2：
实施例3.含有不同颜色的两排的10胶囊剂的泡罩包装
型式1：
型式2：
实施例4.用于注射的溶液剂形式的组合的抗病毒药物
型式1：
| 6HP | 20mg |
| 恩曲他滨 | 200mg |
| 苯甲醇 | 100mg |
| Glycofurol 75 | 1000mg |
| 注射级水 | 最多3ml |
型式2：
实施例5.栓剂形式的组合的抗病毒剂
型式1：
| 6HP | 500mg |
| 恩曲他滨 | 2mg |
| Witepsol | 1498mg |
型式2：
| 6HP | 500mg |
| 拉米夫定 | 2mg |
| Witepsol | 1498mg |
实施例6.含有6HP和拉米夫定的治疗方案的临床研究(II期)
进行了一项多中心、随机、部分盲、II期临床试验，以检查6HP相对叠氮膦在用拉米夫定和依非韦伦的标准疗法中对HIV感染的抗逆转录病毒首次用于实验的患者(
patient)的有效性和安全性。
HIV感染的患者(125名受试者)以1:1:1:1:1的比例随机分配至以下之一：600mg、800mg、1000mg或1200mg 6HP每日一次或叠氮膦(F-AZT)400mg每日两次(比较组)。在所有五组中的标准疗法都是相同的，包括每日两次150mg拉米夫定和每日一次600mg依非韦伦。
该研究疗法持续了24周。从研究开始后的第1、2、4、8、12、16和24周进行访视，以评估疗法的安全性和有效性参数。
在唯一发生与6HP或拉米夫定相关的不良事件需要退出研究的病例中：最大剂量6HP(1200mg)组中的患者血液中的血红蛋白水平下降至75g/L。患者退出研究并制定(prescribe)了适当的治疗。不过，此次事件对6HP整体有效性的评价没有显著影响。6HP在所有组中的累积有效性与比较组相当，且累积有效性对于所有患者分别为85％和84％，或对于完成治疗的患者分别为89.5％和87.5％。
6HP最低剂量组(每日600mg和800mg)的治疗有效性显著地高于比较组。
6HP最低剂量组(第1组和第2组)中的抗逆转录病毒疗法有效性的实验室标志物(HIV RNA水平)模式见表1。
表1
*包括所有患者/包括完成研究的患者
以上数据表明：
-对于所有完成研究的患者，在治疗24周后，观察到第1组95.7％、第2组95.8％和比较组87.5％的患者“病毒载量”显著降低至低于50拷贝数/mL。
-治疗前高HIV RNA载量(>100000拷贝数/mL)的患者数量为：第1组和比较组5例患者，第2组9例患者。治疗24周后，这些患者的病毒载量在对照组100％病例和第二组89％的病例中降至未检测出的水平(低于50拷贝数/mL)。
因此，到治疗的第24周，所有组患者中的“病毒载量”都有显著降低。总体而言，4个组的有效性并不逊于比较组。对于6HP低剂量组(600和800mg)的治疗有效性高于比较组。
治疗24周后，CD4+T-淋巴细胞的平均含量和中位数的最大值出现在第1组。第2-4组也表现出治疗24周后CD4+T-淋巴细胞数量的显著增加，但与对照组相比，这些细胞的增加不太显著(P<0.05-0.01)。
6HP最低剂量组(第1组和第2组)和比较组在治疗进程中CD4+T-淋巴细胞计数的模式及其数量与初始值比较的变化见表2。
表2
这些数据表明含有6HP和拉米夫定的治疗方案的免疫有效性。在所有组的患者中观察到治疗24周后CD4+T-淋巴细胞的中位数增加。在第1组患者(6HP 600mg/日)中观察到CD4+T-淋巴细胞计数中位数增加的最大结果(164个细胞/μL)。
实施例7.所研究组合的体外抗HIV活性。
在对人类免疫缺陷病毒MT-4高度敏感的细胞培养物中评估了所研究组合的抗HIV-1活性。来自俄罗斯卫生部伊万诺夫斯基病毒研究所(D.I.Ivanovsky ResearchInstitute of Virology,Ministry of Health of Russia)的病毒集合的HIV-1899A毒株被用作病毒来源。移植的人的类淋巴母细胞MT-4细胞来自俄罗斯卫生部伊万诺夫斯基病毒研究所的细胞培养物集合。细胞在含有10％牛胎血清(由脊髓灰质炎和病毒性脑炎研究所((Research Institute of Poliomyelitis and Viral Encephalitis)，RAMS生产)和100μg/mL庆大霉素的RPMI-1640培养基(由脊髓灰质炎和病毒性脑炎研究所，RAMS生产)中培养。
将测试培养基添加到细胞并以0.01TCID50/细胞的剂量用病毒感染。细胞培养物在37℃下在5％CO2和98％湿度的气氛中孵育3-6天。
如[Fedyuk N.V.等人，Detection and quantitative determination ofantigens of human immunodeficiency virus types 1and 2/Question of Virology,1992,No.3,p.135-138]中所描述，根据感染细胞的培养液中HIV p24抗原的积聚压力，通过免疫测定确定，利用分光光度法和光学显微镜用四唑鎓染料染色细胞(MTT方法)来记录结果。
获得的实验数据在表3-6中给出。
表3
表4
表5
表6
因此，作为研究核苷抑制剂6HP、恩曲他滨(FTC)、拉米夫定(3TS)以及6HP与FTC的组合和6HP与3TC的组合对MT-4细胞培养物中的HIV-1毒株的抗HIV活性的结果，确定了6HP和恩曲他滨的组合以及6HP和拉米夫定的组合在抑制HIV-1繁殖方面表现出协同作用。
当病毒在所述情况下传代时，发现与单独使用6HP相比，在存在拉米夫定或恩曲他滨的情况下6HP的有效浓度下降发生在60-70天后。比较实验中6HP的浓度是相同的。
Claims (12)
1.用于HIV感染治疗的组合，其包含(i)5'-氨基羰基膦酸酯-3'-叠氮基-3'-脱氧胸苷铵盐和(ii)选自恩曲他滨和拉米夫定的胞苷类似物，药剂(i)与药剂(ii)的重量比为从250:1至1:250。
2.根据权利要求1的组合，其中添加了药学上可接受的载体。
3.根据权利要求1或2的组合，其中药剂(i)与药剂(ii)的质量比为从1:50至50:1。
4.根据权利要求1或2的组合，其中药剂(i)与药剂(ii)的质量比为从1:10至10:1。
5.根据权利要求1或2的组合，其中它旨在口服施用。
6.根据权利要求5的组合，其中它是片剂形式，包括用于放置在泡罩包装中的那些。
7.根据权利要求5的组合，其中它是胶囊剂形式，包括用于放置在泡罩包装中的那些。
8.根据权利要求1或2的组合，其中它被设计用于同时施用药剂(i)和(ii)。
9.根据权利要求1或2的组合，其中它被设计用于顺序施用药剂(i)和(ii)。
10.用于治疗HIV感染的试剂盒，其中使用根据权利要求1-9中任一项的组合并且提供了用于使用所述组合的说明书。
11.治疗包括人的哺乳动物中的HIV感染的方法，所述方法通过向有此需要的哺乳动物施用治疗有效量的权利要求1-9所公开的组合。
12.根据权利要求11的方法，其中哺乳动物是人。
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