CN104010631B - 包含hcv抑制剂的固体组合物 - Google Patents
包含hcv抑制剂的固体组合物 Download PDFInfo
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- CN104010631B CN104010631B CN201280064815.5A CN201280064815A CN104010631B CN 104010631 B CN104010631 B CN 104010631B CN 201280064815 A CN201280064815 A CN 201280064815A CN 104010631 B CN104010631 B CN 104010631B
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- hcv
- solid
- inhibitor
- polyoxyethylene
- solid composite
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Abstract
本发明的特征在于包含无定形形式的选定的HCV抑制剂的固体组合物。在一个实施方案中,选定的HCV抑制剂在无定形固体分散体中配制,所述无定形固体分散体包含药学上可接受的亲水性聚合物并且优选包含药学上可接受的表面活性剂。
Description
本申请要求2011年12月29日提交的美国临时专利申请系列号61/581,146和2012年5月11日提交的美国临时专利申请系列号61/645,696的优先权,其全部内容通过引用并入本文中。
发明领域
本发明涉及包含抗HCV化合物的固体组合物和使用该组合物治疗HCV感染的方法。
背景
丙型肝炎病毒(HCV)为RNA病毒,其属于黄病毒科中的丙型肝炎病毒属。在单个的、不间断的开放阅读框中,包膜HCV病毒体含有编码所有已知的病毒特异性蛋白的正链RNA基因组。所述开放阅读框包含大约9500个核苷酸并编码约3000个氨基酸的单个的、大的多蛋白。所述多蛋白包括核心蛋白、包膜蛋白E1和E2、膜结合蛋白p7和非结构蛋白NS2、NS3、NS4A、NS4B、NS5A和NS5B。
HCV感染与进行性肝脏病理,包括硬化和肝细胞癌相关。慢性丙型肝炎可以采用与利巴韦林组合的聚乙二醇干扰素-α来治疗。由于很多使用者遭受副作用,并病毒从身体中的消除通常是不充分的,因此仍然存在对功效和耐受性的显著限制。因此,需要新药物来治疗HCV感染。
发明概述
本发明的特征在于固体组合物,其包含(1)选自特拉匹韦(VX-950)、BI-201335、TMC-435(TMC-435350)、vaniprevir(MK-7009)、MK-5172、asunaprevir(BMS-650032)、daclatasvir(BMS-790052)、丹诺普韦、setrobuvir(ANA-598)、tegobuvir(GS-333126或GS-9190)、GS-9451,mericitabine (R-4048)、IDX-184、filibuvir(PF-00868554)、PSI-7977、PSI-352938、BIT-225、波普瑞韦、GS-5885或GS-9256的HCV抑制剂(下文称为“选定的HCV抑制剂”);(2)药学上可接受的亲水性聚合物;和任选地(3)药学上可接受的表面活性剂。
在一个方面,本发明的特征在于包含固体分散体的固体组合物,其中固体分散体包含(1)无定形形式的选定的HCV抑制剂、(2)药学上可接受的亲水性聚合物和(3)药学上可接受的表面活性剂,其中选定的HCV抑制剂为特拉匹韦(VX-950)、BI-201335、TMC-435(TMC-435350)、vaniprevir(MK-7009)、MK-5172、asunaprevir(BMS-650032)、daclatasvir(BMS-790052)、丹诺普韦、setrobuvir(ANA-598)、tegobuvir(GS-333126或GS-9190)、GS-9451、mericitabine(RG-7128或R-4048)、IDX-184、filibuvir(PF-00868554)、PSI-7977、PSI-352938、BIT-225、波普瑞韦、GS-5885或GS-9256。可以但不限于将表面活性剂配制在固体分散体中或单独地与固体分散体结合或混合。优选地,亲水性聚合物具有至少50℃的Tg。更优选地,亲水性聚合物具有至少80℃的Tg。高度优选地,亲水性聚合物具有至少100℃的Tg。还可以使用Tg低于50℃的亲水性聚合物,例如具有至少25℃的Tg的聚合物,和/或具有低于10的HLB值的表面活性剂。
在本发明这个方面的一个实施方案中,亲水性聚合物选自N-乙烯基内酰胺的均聚物、N-乙烯基内酰胺的共聚物、纤维素酯、纤维素醚、聚环氧烷(polyalkylene oxide)、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚乙烯醇、乙酸乙烯酯聚合物、寡糖或多糖。合适的亲水性聚合物的非限制性实例包括N-乙烯基吡咯烷酮的均聚物、N-乙烯基吡咯烷酮的共聚物、N-乙烯基吡咯烷酮和乙酸乙烯酯的共聚物、N-乙烯基吡咯烷酮和丙酸乙烯酯的共聚物、聚乙二醇/聚乙烯基己内酰胺/聚乙酸乙烯酯的接枝共聚物(例如,Soluplus)、聚乙烯吡咯烷酮、甲基纤维素、乙基纤维素、羟烷基纤维素、羟丙基纤维素、羟烷基烷基纤维素、羟丙基甲基纤维素、纤维素邻苯二甲酸酯、纤维素琥珀酸酯、纤维素乙酸邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素琥珀酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、聚环氧乙烷、聚环氧丙烷、环氧乙烷和环氧丙烷的共聚物、甲基丙烯酸/丙烯酸乙酯共聚物、甲基丙烯酸/甲基丙烯酸甲酯共聚物、甲基丙烯酸丁酯/甲基丙烯酸2-二甲氨基乙酯共聚物、聚(丙烯酸羟基烷基酯)、聚(甲基丙烯酸羟基烷基酯)、乙酸乙烯酯和巴豆酸的共聚物、部分水解的聚乙酸乙烯酯、角叉菜胶、半乳甘露聚糖或黄原胶、或其组合。在某些情况下,除了亲水性聚合物之外还可以使用糖醇,或用糖醇替代亲水性聚合物。
在本发明的这方面的另一个实施方案中,所述表面活性剂选自聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨糖醇的单脂肪酸酯、聚氧乙烯烷基醚、聚氧乙烯烷基芳基醚、聚乙二醇脂肪酸酯、烷二醇脂肪酸单酯、蔗糖脂肪酸酯、或脱水山梨糖醇脂肪酸单酯。合适的表面活性剂的非限定性实例包括聚氧乙烯甘油三蓖麻油酸酯或聚氧乙烯(5蓖麻油(Cremophor EL; BASF Corp.)或聚氧乙烯甘油氧基硬脂酸酯(polyoxyethyleneglyceroloxystearate)如聚乙二醇40氢化蓖麻油(Cremophor RH 40,也被称为聚氧乙烯40氢化蓖麻油或聚乙二醇甘油羟基硬脂酸酯(macrogolglycerol hydroxystearate))或聚乙二醇60氢化蓖麻油(Cremophor RH 60)、聚氧乙烯脱水山梨糖醇的单脂肪酸酯如聚氧乙烯(20)脱水山梨糖醇的单脂肪酸酯,例如聚氧乙烯(20)脱水山梨糖醇单油酸酯(Tween 80)、聚氧乙烯(20)脱水山梨糖醇单硬脂酸酯(Tween 60)、聚氧乙烯(20)脱水山梨糖醇单棕榈酸酯(Tween40)或聚氧乙烯(20)脱水山梨糖醇单月桂酸酯(Tween 20)、聚氧乙烯(3)月桂基醚、聚氧乙烯(5)鲸蜡基醚、聚氧乙烯(2)硬脂基醚、聚氧乙烯(5)硬脂基醚、聚氧乙烯(2)壬基苯基醚、聚氧乙烯(3)壬基苯基醚、聚氧乙烯(4)壬基苯基醚、聚氧乙烯(3)辛基苯基醚、PEG-200单月桂酸酯、PEG-200二月桂酸酯、PEG-300二月桂酸酯、PEG-400二月桂酸酯、PEG-300二硬脂酸酯、PEG-300二油酸酯、丙二醇单月桂酸酯(例如, Lauroglycol FCC)、D-α-生育酚基聚乙二醇1000琥珀酸酯、蔗糖单硬脂酸酯、蔗糖二硬脂酸酯、蔗糖单月桂酸酯、蔗糖二月桂酸酯、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯、或脱水山梨糖醇硬脂酸酯、或其组合。也可以使用其它合适的离子型或非离子型表面活性剂。
在本发明这个方面的又一个实施方案中,固体分散体为无定形固体分散体。在又一个实施方案中,固体分散体为无定形固体分散体,其包含(1)选定的HCV抑制剂、(2)亲水性聚合物和(3)表面活性剂。在另一个实施方案中,固体分散体为包含(1)选定的HCV抑制剂和(2)亲水性聚合物的固体溶液。在又一个实施方案中,固体分散体为包含(1)选定的HCV抑制剂、(2)亲水性聚合物和(3)表面活性剂的固体溶液。
在本发明这个方面的又一个实施方案中,亲水性聚合物为N-乙烯基吡咯烷酮的均聚物或共聚物。优选地,亲水性聚合物为共聚维酮。
在又一个实施方案中,表面活性剂为D-α-生育酚基聚乙二醇1000琥珀酸酯(维生素E TPGS)。在又一个实施方案中,表面活性剂为lauroglycol FCC。在又一个实施方案中,表面活性剂为维生素E TPGS和lauroglycol FCC的组合。在又一个实施方案中,表面活性剂为脱水山梨糖醇脂肪酸酯,例如脱水山梨糖醇单月桂酸酯(Span 20)。在另一个实施方案中,表面活性剂选自Tween 20、Tween 80、维生素E TPGS、lauroglycol FCC或其组合。
在又一个实施方案中,本发明的固体组合物包含无定形固体分散体或固体溶液,其包含(1)选定的HCV抑制剂、(2)共聚维酮和(3)选自维生素E TPGS、Span 20或其组合的表面活性剂。
在另一个实施方案中,本发明的固体组合物包含无定形固体分散体或固体溶液,其包含(1)选定的HCV抑制剂、(2)共聚维酮和(3)维生素E TPGS和lauroglycol FCC的组合。
在又一个实施方案中,本发明的固体组合物包含无定形固体分散体或固体溶液,其包含(1)选定的HCV抑制剂、(2)共聚维酮和(3)选自Tween 20或Tween 80的表面活性剂。
在另一个方面,本发明的特征在于制备本发明的固体组合物的方法。在一个实施方案中,所述方法包括干燥液体溶液中的挥发性溶剂,其中所述溶液包含:(1)选定的HCV抑制剂;(2)药学上可接受的亲水性聚合物;和任选地(3)药学上可接受的表面活性剂。干燥方法可以使用任何合适的溶剂蒸发技术进行,所述技术包括但不限于喷雾-干燥技术。
在另一个实施方案中,所述方法包括使熔融物凝固,所述熔融物包含:(1)选定的HCV抑制剂;(2)药学上可接受的亲水性聚合物;和任选地(3)药学上可接受的表面活性剂。
本发明的固体组合物也可含有其它添加剂或成分,例如着色剂、调味剂、润滑剂或防腐剂。本发明的固体组合物可以制备成任何合适的剂型,例如胶囊剂、锭剂、颗粒剂、粉剂或片剂。
本发明的固体组合物可以进一步包含另一种抗HCV剂,例如选自HCV解螺旋酶抑制剂、HCV聚合酶抑制剂、HCV蛋白酶抑制剂、HCV NS5A抑制剂、CD81抑制剂、亲环蛋白抑制剂或内部核糖体进入位点(IRES)抑制剂的药剂。
本发明的进一步特征在于使用本发明的固体组合物治疗HCV感染的方法。所述方法包括向需要其的患者给予本发明的固体组合物,从而降低患者中的HCV病毒的血液或组织水平。
本发明的其它特征、目的和优点在随后的详细说明中是显而易见的。然而,应当理解,详细说明尽管指示了本发明的优选实施方案,但仅以示例的方式给出,而非限制。对本领域技术人员而言,根据详细说明,在本发明范围内的各种变化和修饰将变得显而易见。
详细说明
本发明的特征在于固体组合物,其包含(1)选定的HCV抑制剂、(2)药学上可接受的亲水性聚合物和任选地(3)药学上可接受的表面活性剂,其中选定的抑制剂为特拉匹韦(VX-950)、BI-201335、TMC-435(TMC-435350)、vaniprevir(MK-7009)、MK-5172、asunaprevir(BMS-650032)、daclatasvir(BMS-790052)、丹诺普韦、setrobuvir(ANA-598)、tegobuvir(GS-333126或GS-9190)、GS-9451、mericitabine (R-4048)、IDX-184、filibuvir(PF-00868554)、PSI-7977、PSI-352938、BIT-225、波普瑞韦、GS-5885或GS-9256。将选定的HCV抑制剂配制成无定形形式可以提高固有的药物溶解度和溶解速率,从而提高所述化合物的生物利用度。
特拉匹韦(VX-950)、BI-201335、TMC-435(TMC-435350)、vaniprevir(MK-7009)、MK-5172、asunaprevir(BMS-650032)、丹诺普韦、GS-9451、波普瑞韦和GS-9256是HCV蛋白酶抑制剂;daclatasvir(BMS-790052)和GS-5885是HCV NS5A抑制剂;setrobuvir(ANA-598)、tegobuvir(GS-333126或GS-9190)、mericitabine (R-4048)、IDX-184、filibuvir(PF-00868554)、PSI-7977、PSI-352938 (PSI-938)和BIT-225是聚合酶抑制剂。这些选定的HCV抑制剂的化学结构在下面提供:
特拉匹韦
BI-201335
TMC-435 (TMC-435350)
vaniprevir(MK-7009)
MK-5172
BMS-650032
BMS-790052(daclatasvir)
丹诺普韦
ANA-598(Setrobuvir)
Tegobuvir
GS-9451
Mericitabine(R-4048)
IDX-184
Filibuvir(PF-00868554)
PSI-7977
PSI-352938
BIT-225
波普瑞韦
GS-9256
GS-5885
形成无定形形式的选定的上述HCV抑制剂的非限制性方式为通过形成含有聚合物载体的固体分散体。一种或多种亲水性聚合物和任选的一种或多种表面活性剂的存在,以及处于无定形形式的选定的HCV抑制剂在含有一种或多种聚合物的基质中的分散体可以显著提高所选化合物的溶解速率。在某些情况下,固体分散体制剂也可以有效地将选定的HCV抑制剂保持为其过饱和状态以实现更好的吸收。
如本文使用的,术语“固体分散体”定义为包含至少两种组分的固态(与液态或气态相对)的系统,其中一种组分完全分散在另一种组分或多种组分中。例如,选定的上述HCV抑制剂可以分散在由一种或多种药学上可接受的亲水性聚合物和一种或多种药学上可接受的表面活性剂组成的基质中。术语“固体分散体”涵盖具有分散于另一相中的一相的小颗粒的系统。这些颗粒的尺寸通常小于400μm,例如尺寸小于100、10或1μm。当组分的固体分散体使得整个系统为化学和物理均一的或同质的或者由单相(如热力学定义的)组成时,这样的固体分散体被称为“固体溶液”。玻璃状溶液是其中溶质溶于玻璃状溶剂的固体溶液。
术语“重量百分比”或“百分比重量”或“重量%”或“wt %”表示以组合物或混合物的重量百分数表示的组合物或混合物中单一组分的重量。
现代的新化学实体往往具有更高的分子量、更大的亲脂性和更低的水溶解度,所有这些对口服生物利用度产生负面影响。尽管有导致促成技术(enabling technologies)如基于脂质的药物递送系统(例如SEDDS)和纳米颗粒商业化的制剂进步,但由于每种方法相关的局限性,水难溶性化合物的递送仍具有挑战性。利用无定形固体分散体(ASD)是有吸引力的,不仅因为它可以增加另外的难吸收药物的药代动力学暴露,还因为可将最终产物作为片剂或胶囊递送给患者,这可提供更大的化学稳定性并且与液体剂型相比为病人提供更大的方便。
对于所有制剂方法,当务之急是要在开发开始前或开始时了解活性药物的内在理化和生物制药性质。为此,生物药剂学分类系统(BCS)已常规用于评估口服吸收并指导制剂开发。对于ASD制剂,通常考虑活性药物成分(API)的溶解度/渗透性以及无定形药物产品的长期物理稳定性。从概念上讲,有三个影响ASD物理稳定性的主要因素:热力学驱动力(在载药量和药物在基质中的溶解度方面有差异)、分子迁移率和结晶活化障碍。本发明依靠使用创新的评估工具来分级(rank)无定形药物物质的内在物理稳定性,例如,无定形API的结晶倾向。
许多人将无定形材料的分子迁移率(其通常通过弛豫时间常数或其倒数表征,分子迁移率)视为确定其物理稳定性的主要因素。无定形材料的动力学特征已经是药物领域中不断研究的主题。与玻璃态相比,无定形相的结晶在过冷液态下进行更快的事实表明分子迁移率的重要性。然而,已在不能仅通过迁移率解释的化合物中观察到结晶倾向的显著性差异。例如,一些无定形相在玻璃化温度Tg下几乎立即结晶(例如,孕酮、对羟基苯甲酸酯、对乙酰氨基酚),一些在低于Tg下在相对短的时间内结晶(例如,灰黄霉素、硝苯地平),而其他则相当稳定。对于一些更稳定的无定形相,在玻璃态下经常未观察到结晶且在高于Tg下不经引晶它不会以显著的速率发生结晶。理论上,Tg对应于无定形相的分子弛豫时间常数等于实验时间尺度(time scale)时的温度。根据这些差异,已经假定,除了迁移率之外,热力学驱动力和结晶活化障碍有助于观察这些化合物之间的物理稳定性差异。
Shamblin等,J. Phys. Chem. B 103: 4113-4121 (1999),基于热容量测量和Adam-Gibbs模型评估了无定形材料的分子迁移率。这种方法允许使用药物实验室中广泛使用的温度调制式差示扫描量热法(TMDSC)连同已用于表征其他材料(例如聚合物和陶瓷制品)的Adam-Gibbs模型来计算分子迁移率。
利用这种方法,可探究药学相关化合物的物理稳定性以试图确定临界结晶的热力学量。通过这种分析,已证实量热构型熵是确定高于Tg时的结晶倾向的重要因素。
构型熵通常是无定形相和结晶相之间构型数目差异的量度。对于在预结晶的无定形状态下的分子,它们必须聚集成具有限定构型或取向的特定晶格。因此,构型熵值越高表明分子处于聚集成晶格所需的方向的概率越低。因此,具有较大构型熵的亚稳定的无定形化合物倾向于表现出更大的物理稳定性。这与具有大量可旋转键的大分子往往更难结晶的观察结果相一致。
已假定,构型熵作为成核概率的热力学量度,而分子迁移率决定分子可改变其构型时的速率,并作为成核的动力学量度。类似的意见也可应用于晶体生长的速率。因此,这两个量可用于评估无定形API的内在物理稳定性风险。
基于不同化合物的实验性结晶观察,Baird等,J. Pharm. Sci. 99: 3787-3806(2010);和Eerdenbrugh等,J. Pharm. Sci. 99: 3826-3838(2010)提出了评估无定形系统的结晶倾向的分类系统。然而,结晶实验需要相对长的时间并且结果受内在和外在因素影响。本发明采用上述两种内在性质和不同的无定形分类系统(ACS)来评估无定形候选药物的物理稳定性。这两种内在分子性质可由单个方便的量热法测量来计算。
分子结构的灵活性和迁移率可用于预测化合物作为无定形相是否是动力学稳定的。物理稳定的无定形API可在配制的ASD的物理稳定性中起作用。
在本发明所使用的ACS中,分子可分为4类,如下:
I类:稳定的无定形固体/较差的结晶器(crystallizer),和
高构型熵和低分子迁移率
(开发ASD制剂的极佳候选物)
II类:中等无定形稳定性/结晶器,和
高构型熵但高分子迁移率
III类:中等无定形稳定性/结晶器,和
低分子迁移率但低构型熵
IV类:不稳定的无定形固体/良好的结晶器,和
低构型熵和高分子迁移率
(开发ASD制剂的较差候选物)。
迁移率高度依赖于温度但对于所有玻璃而言在Tg下是相同的。分子迁移率在过冷液态下通常用VTF方程表示且在玻璃态下用AGV方程表示,如下:
(VTF方程)
(AGV方程)
其中τ为弛豫时间常数,τ0为假定等于10-14秒的常数,D为强度参数,且T0为具有零分子迁移率(τ=∞)时的温度,即所谓的Kauzmann温度且为平衡过冷液(即理想的玻璃)具有与结晶状态相同的熵时的温度。Tf为假想温度,其为理想的玻璃在给定的温度(T)下具有与真正的玻璃相同的构型熵时的温度。值得注意的是,根据定义,在Tg时弛豫时间常数对于所有无定形系统是相同的(即τg=100秒)。强度参数D可用作T < Tg时分子迁移率的方便表示。
在玻璃化转变温度Tg下,以下关系成立,其可通过VTF方程获得:
其中τg为Tg时的弛豫时间常数。D和T0不是独立的,且为与强度参数D相关的参数。在许多理论处理中,τ0被假定为10-14秒,因此ln(τg /τ0) = ln(1016) = 36.84是常数。
假设Tg为与恒定迁移率(即τ =100秒)相关的温度,而T0为与理想玻璃的零迁移率相关的温度,则的比率并因此D值表示理想玻璃的分子迁移率随温度降低而降低的速度。D值越高,分子迁移率随温度降低而降低的速率越慢,从而有利于结晶。
对于理想玻璃可进一步显示:
其中C = ln(τg /τ0) = 36.84。假设C > 0,Tg/T > 1,因此在的范围所代表的常规温度下,预计理想玻璃的分子迁移率比具有较大D值的玻璃高。在高于Tg的过冷液态下相反的趋势是真实的。因此,强度参数为理想玻璃的分子迁移率提供方便的指示物:D值越大,迁移率越高(在相同的下)。
“理想的新鲜制备的玻璃”是指以足够高的冷却速率熔融淬灭的一个,使得在温度低于玻璃化转变温度下无结构弛豫发生。在这种“理想的新鲜制备的玻璃”中,假想温度Tf等于其玻璃化转变温度Tg。因此,“理想的新鲜制备的玻璃”的分子弛豫时间常数可基于AGV方程导出:
上面的方程表明在这些系统中与分子弛豫时间常数的温度依赖相关的Arrhenius行为。进一步注意到,在相同的值时,所有“理想的新鲜制备的玻璃”的分子弛豫时间常数或迁移率是相同的,不管系统的其它特征。乍看之下,强度参数未表现出与分子迁移率的大小相关联。
然而,在真实玻璃中排列没有完全被阻止。分子运动确实发生在较长的时间范围内,从而导致结构松弛或老化。因此,真实玻璃的分子迁移率成为老化时间的函数。在现实中,当液体被淬灭冷却时,结构松弛已在任何新鲜制备的玻璃中发生。在老化的过程中,强度参数D在分子迁移率的演变中起作用,从“理想的新鲜制备的玻璃”,其中D是不相关的,到理想玻璃,其中较高的D值与较高的迁移率相关。分子迁移率的演变揭示迁移率和强度参数之间的类似关系,即在这一演变过程中,较高的D值决定较高的分子迁移率。
Tg时的构型熵将作为此参数的良好指示物,原因有二:(1)无定形药物实际上往往在低于玻璃化转变温度下储存;(2)“理想的新鲜制备的玻璃”的构型熵在T < Tg时与温度无关。
在储存过程中,随结构松弛发生,该构型熵不断减小。然而,随时间变化熵减小变慢且远离理想玻璃中的值,即使考虑整个两年的保质期中的物理老化时。
为了确定构型熵,可将仪器例如TMDSC校准以获得热容量的精确测量。此外,传统的DSC扫描可为该热力学量提供显著的洞察力。已观察到,Tg时构型的热容量变化或Tg时简单的热容量变化,,显示出与构型熵和物理稳定性较好的相关性。因此,(其可从传统的DSC测量中获得)可作为构型熵的近似指示物或替代物。热容量通过在分子可消散热能的模式下直接测量,因此为构型的物理学上有意义的测量。在玻璃化转变温度下热容量变化直接反映由于玻璃状过冷液体转换导致可获得的构型的数量。因为典型的玻璃化转变温度范围相对较小,非谐振动的贡献可能微乎其微。因此,这种做法最大限度地减少对经热分析获得的过剩熵的实际构型源的担忧。
此外,可基于Adam-Gibbs模型和在温度高于Tg时结构热容量的双曲线温度关系的假设,用于估计玻璃的强度参数D:
基于熵的Kauzmann温度计算为:
其中Tm和△Hm分别为熔化的温度和焓。因此,强度参数可以推导为:
使用作为构型熵的估计量的优点是,该量可在不费力的程序例如确定构型熵所需要的那些下容易地测定。此外,Tg时构型熵可基于和其它相关参数进行估计:
其中△Sm为熔化熵。
因此强度参数D可用于表示无定形材料的分子迁移率,且构型熵可通过玻璃化转变温度下它的数量来表示,或更方便地,它可通过Tg时热容量的变化来表示。然后可定义每个数量的高低标准以用于ACS分配中。
稳定性的标准在不同的应用领域是不同的。医药产品往往关心典型保质期,例如2-3年内的稳定性。可通过调查一些具有已知的物理稳定性的药物化合物采用基准测试(benchmarking)方法,包括其ASD制剂已成功商业化的那些。这些化合物包括各种各样的结构特征和广泛的范围,从快速结晶器(例如对乙酰氨基酚、灰黄霉素、苯巴比妥和磺胺噻唑)到形成动力学稳定的无定形相的那些(例如伊曲康唑、酮康唑、沙奎那韦、利托那韦和洛匹那韦)。这些化合物包括利托那韦、对乙酰氨基酚、非诺贝特、蔗糖、硝苯地平、灰黄霉素、洛匹那韦、洛伐他汀、非洛地平、吲哚美辛、伊曲康唑、酮康唑、苯巴比妥、夫洛丙酮、塞来考昔、依托考昔、罗非考昔、伐地考昔、甲苯磺丁脲、奎尼丁、保泰松、磺胺噻唑、氢氯噻嗪、格列本脲、西咪替丁、阿托品、外消旋-布洛芬、水杨苷、山道年、辛伐他汀和沙奎那韦。
基于迁移率和构型熵的评估,以及上述选定的化合物在其无定形状态的已知物理稳定性,开发以下标准:
(1) D ≥ 9作为高分子迁移率标准;
(2) Sconf(Tg)/R ≥ 6 作为高构型熵的标准。或者,当 ≥ 23时可认为是高构型熵。
这些标准的选择允许在物理稳定性或结晶倾向的背景下将化合物分为四类。在很多时候,每个分子的构型特征通过的简单测量一致反映,且信息可方便地提取以用于ACS测定。的使用使得即使当无晶体形式被识别时也可进行分子的ACS分配,条件是分子迁移率可通过其他方法例如粘度测量和玻璃化转变温度的扫描速率依赖性独立地进行评价。
基于上述ACS模型,认为选定的上述HCV抑制剂是开发ASD制剂的良好候选物。
在一个方面,本发明的特征在于固体组合物,其包含(1)选定的HCV抑制剂、(2)药学上可接受的亲水性聚合物和任选地(3)药学上可接受的表面活性剂,其中选定的HCV抑制剂为特拉匹韦(VX-950)、BI-201335、TMC-435 (TMC-435350)、vaniprevir(MK-7009)、MK-5172、asunaprevir(BMS-650032)、daclatasvir(BMS-790052)、丹诺普韦、setrobuvir(ANA-598)、tegobuvir(GS-333126或GS-9190)、GS-9451、mericitabine (R-4048)、IDX-184、filibuvir(PF-00868554)、PSI-7977、PSI-352938、BIT-225、波普瑞韦、GS-5885或GS-9256。选定的HCV抑制剂和聚合物可在固体分散体中配制。表面活性剂可在相同的固体分散体中配制;或表面活性剂可单独地与固体分散体结合或混合。
在一个实施方案中,本发明的固体组合物包含无定形固体分散体,其包含(1)选定的HCV抑制剂、(2)药学上可接受的亲水性聚合物和(3)药学上可接受的表面活性剂。在另一个实施方案中,本发明的固体组合物包含固体溶液,其包含(1)选定的HCV抑制剂和(2)药学上可接受的亲水性聚合物。在又一个实施方案中,本发明的固体组合物包含固体溶液,其包含(1)选定的HCV抑制剂、(2)药学上可接受的亲水性聚合物和(3)药学上可接受的表面活性剂。在又一个实施方案中,本发明的固体组合物包含玻璃状溶液,其包括(1)选定的HCV抑制剂和(2)药学上可接受的亲水性聚合物。在另一个实施方案中,本发明的固体组合物包含玻璃状溶液,其包括(1)选定的HCV抑制剂、(2)药学上可接受的亲水性聚合物和(3)药学上可接受的表面活性剂。
本发明的固体组合物(或固体分散体)可含有例如至少1重量%的选定的HCV抑制剂,优选至少5%,包括例如至少10%。例如,本发明的固体组合物(或固体分散体)可含有1至50重量%的选定的HCV抑制剂。又如,本发明的固体组合物(或固体分散体)可含有5至30重量%的选定的HCV抑制剂。优选地,本发明的固体组合物(或固体分散体)含有5至15重量%的选定的HCV抑制剂。
本发明的固体分散体可以含有至少30重量%的药学上可接受的亲水性聚合物或这类亲水性聚合物的组合。优选地,固体分散体含有至少40重量%的药学上可接受的亲水性聚合物或这类亲水性聚合物的组合。更优选地,固体分散体含有至少50重量% (包括,例如,至少60%、70%、80%或90%)的药学上可接受的亲水性聚合物或这类聚合物的组合。本发明的固体分散体(或固体组合物)也可含有至少1重量%的药学上可接受的表面活性剂或这类表面活性剂的组合。优选地,固体分散体(或固体组合物)含有至少2重量%的药学上可接受的表面活性剂或这类表面活性剂的组合。更优选地,固体分散体(或固体组合物)含有4重量%至20重量%的一种或多种表面活性剂,例如5重量%至10重量%的一种或多种表面活性剂。
在一个实施方案中,本发明的固体分散体(或固体组合物)包含至少30重量%的药学上可接受的亲水性聚合物或这类聚合物的组合,和至少1重量%的药学上可接受的表面活性剂或这类表面活性剂的组合。在另一个实施方案中,本发明的固体分散体(或固体组合物)包含至少50重量%的药学上可接受的亲水性聚合物或这类聚合物的组合,和2重量%至20重量%的药学上可接受的表面活性剂或这类表面活性剂的组合。在又一个实施方案中,本发明的固体分散体(或固体组合物)包含50重量%至90重量%的药学上可接受的亲水性聚合物或这类聚合物的组合,和3重量%到15重量%的药学上可接受的表面活性剂或这类表面活性剂的组合。在又一个实施方案中,本发明的固体分散体(或固体组合物)包含70重量%至90重量%的药学上可接受的亲水性聚合物或这类聚合物的组合,和5重量%到10重量%的药学上可接受的表面活性剂或这类表面活性剂的组合。
优选地,本发明中使用的亲水性聚合物具有至少50℃的Tg,更优选至少60℃,高度优选至少80℃,包括但不限于80℃至180℃或100℃至150℃。用于测定有机聚合物的Tg值的方法描述于Introduction to Physical Polymer Science(第二版,L.H. Sperling编著,John Wiley & Sons,Inc.出版,1992)中。Tg值可以计算为衍生自每个独立单体的均聚物的Tg值的加权总和,即聚合物Tg = Σ Wi•Xi,其中Wi为单体i在有机聚合物中的重量%,并且Xi为衍生自单体i的均聚物的Tg值。均聚物的Tg值可以从Polymer Handboo(第二版,J.Brandrup和E.H. Immergut编著,John Wiley & Sons,Inc.出版,1975)获得。具有如上所述Tg的亲水性聚合物可以实现机械稳定的并在常规温度范围内足够温度稳定的固体分散体的制备,使得所述固体分散体可以用作无需进一步加工的剂型或压制成仅具有少量压片助剂的片剂。也可以使用具有低于50℃的Tg的亲水性聚合物。
优选地,本发明中使用的亲水性聚合物为水溶性的。本发明的固体组合物也可以包含水溶性差或水不溶性的一种聚合物或多种聚合物,例如交联聚合物。当以2%(w/v)溶解在20℃下的水溶液中时,本发明的固体组合物中包含的亲水性聚合物优选具有1至5000mPa٠s的表观粘度,更优选1至700mPa٠s且最优选5至100mPa٠s。
适用于本发明的固体组合物中的亲水性聚合物包括但不限于N-乙烯基内酰胺的均聚物或共聚物,例如N-乙烯基吡咯烷酮的均聚物或共聚物(例如,聚乙烯吡咯烷酮(PVP)或N-乙烯基吡咯烷酮和乙酸乙烯酯或丙酸乙烯酯的共聚物);纤维素酯或纤维素醚,例如烷基纤维素(例如,甲基纤维素或乙基纤维素)、羟烷基纤维素(例如,羟丙基纤维素)、羟烷基烷基纤维素(例如,羟丙基甲基纤维素)和纤维素邻苯二甲酸酯或琥珀酸酯(例如,纤维素乙酸邻苯二甲酸酯和羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素琥珀酸酯或羟丙基甲基纤维素乙酸琥珀酸酯);高分子聚环氧烷,例如聚环氧乙烷、聚环氧丙烷以及环氧乙烷和环氧丙烷的共聚物;聚丙烯酸酯或聚甲基丙烯酸酯,例如甲基丙烯酸/丙烯酸乙酯共聚物、甲基丙烯酸/甲基丙烯酸甲酯共聚物、甲基丙烯酸丁酯/甲基丙烯酸2-二甲氨基乙酯共聚物、聚(丙烯酸羟基烷基酯)和聚(甲基丙烯酸羟基烷基酯);聚丙烯酰胺;乙酸乙烯酯聚合物,例如乙酸乙烯酯和巴豆酸的共聚物,和部分水解的聚乙酸乙烯酯(也称为部分皂化的“聚乙烯醇”);聚乙烯醇;寡糖或多糖,例如角叉菜胶、半乳甘露聚糖和黄原胶;聚丙烯酸羟基烷基酯;聚甲基丙烯酸羟基烷基酯;甲基丙烯酸甲酯和丙烯酸的共聚物;聚乙二醇(PEGs);聚乙二醇/聚乙烯基己内酰胺/聚乙酸乙烯酯的接枝共聚物、或其任何混合物或组合。在某些情况下,除了亲水性聚合物之外还可以使用糖醇,或用糖醇替代亲水性聚合物。
用于本发明的优选亲水性聚合物的非限制性实例包括聚乙烯吡咯烷酮(PVP)K17、PVP K25、PVP K30、PVP K90、羟丙基甲基纤维素(HPMC) E3、HPMC E5、HPMC E6、HPMCE15、HPMC K3、HPMC A4、HPMC A15、HPMC乙酸琥珀酸酯(AS) LF、HPMC AS MF、HPMC AS HF、HPMC AS LG、HPMC AS MG、HPMC AS HG、HPMC邻苯二甲酸酯(P) 50、HPMC P 55、Ethocel 4、Ethocel 7、Ethocel 10、Ethocel 14、Ethocel 20、共聚维酮(乙烯基吡咯烷酮-乙酸乙烯酯共聚物 60/40)、聚乙酸乙烯酯、甲基丙烯酸酯/甲基丙烯酸共聚物(Eudragit) L100-55、Eudragit L100、Eudragit S100、聚乙二醇(PEG) 400、PEG 600、PEG 1450、PEG 3350、PEG4000、PEG 6000、PEG 8000、Soluplus、泊洛沙姆124、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338和泊洛沙姆407。
其中,N-乙烯基吡咯烷酮的均聚物或共聚物,例如N-乙烯基吡咯烷酮和乙酸乙烯酯的共聚物是优选的。优选的聚合物的非限制性实例为60重量%的N-乙烯基吡咯烷酮和40重量%的乙酸乙烯酯的共聚物。其它优选的聚合物包括但不限于羟丙基甲基纤维素(HPMC,在USP中也称为羟丙甲基纤维素(hypromellose)),例如羟丙基甲基纤维素E5级(HPMC-E5);和羟丙基甲基纤维素乙酸琥珀酸酯(HPMC-AS)。
本发明中使用的药学上可接受的表面活性剂优选为非离子型表面活性剂。也可以使用离子型表面活性剂。更优选地,本发明的固体组合物包含具有2-20的HLB值的药学上可接受的表面活性剂。在一个实例中,本发明的固体组合物包括药学上可接受的表面活性剂的混合物,其中至少一种表面活性剂具有不小于10的HLB值且至少另一种表面活性剂具有低于10的HLB值。HLB系统(Fiedler,H.B.,Encylopedia of Excipients,第5版,Aulendorf:ECV-Editio-Cantor-Verlag (2002))对表面活性剂赋予数值,其中亲脂性物质具有较低的HLB值并且亲水性物质具有较高的HLB值。
适合于本发明的药学上可接受的表面活性剂的非限定性实例包括聚氧乙烯蓖麻油衍生物,例如聚氧乙烯甘油三蓖麻油酸酯或聚氧乙烯35蓖麻油(Cremophor EL; BASFCorp.)或聚氧乙烯甘油氧基硬脂酸酯如聚乙二醇40氢化蓖麻油(Cremophor RH 40,也被称为聚氧乙烯40氢化蓖麻油或聚乙二醇甘油羟基硬脂酸酯)或聚乙二醇60氢化蓖麻油(Cremophor RH 60);或聚氧乙烯脱水山梨糖醇的单脂肪酸酯如聚氧乙烯(20)脱水山梨糖醇的单脂肪酸酯,例如聚氧乙烯(20)脱水山梨糖醇单油酸酯(Tween 80)、聚氧乙烯(20)脱水山梨糖醇单硬脂酸酯(Tween 60)、聚氧乙烯(20)脱水山梨糖醇单棕榈酸酯(Tween 40)、或聚氧乙烯(20)脱水山梨糖醇单月桂酸酯(Tween 20)。合适的表面活性剂的其它非限定性实例包括聚氧乙烯烷基醚,例如聚氧乙烯(3)月桂基醚、聚氧乙烯(5)鲸蜡基醚、聚氧乙烯(2)硬脂基醚、聚氧乙烯(5)硬脂基醚;聚氧乙烯烷基芳基醚,例如聚氧乙烯(2)壬基苯基醚、聚氧乙烯(3)壬基苯基醚、聚氧乙烯(4)壬基苯基醚、聚氧乙烯(3)辛基苯基醚;聚乙二醇脂肪酸酯,例如PEG-200单月桂酸酯、PEG-200二月桂酸酯、PEG-300二月桂酸酯、PEG-400二月桂酸酯、PEG-300二硬脂酸酯、PEG-300二油酸酯;烷二醇脂肪酸单酯,例如丙二醇单月桂酸酯(Lauroglycol,例如Lauroglycol FCC);蔗糖脂肪酸酯,例如蔗糖单硬脂酸酯、蔗糖二硬脂酸酯、蔗糖单月桂酸酯、蔗糖二月桂酸酯;脱水山梨糖醇脂肪酸单酯如脱水山梨糖醇单月桂酸酯(Span 20)、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯(Span 40)、或脱水山梨糖醇硬脂酸酯;D-α-生育酚基聚乙二醇1000琥珀酸酯;或其组合或混合物。其它合适的表面活性剂包括但不限于环氧乙烷和环氧丙烷的嵌段共聚物,也被称为聚氧乙烯聚氧丙烯嵌段共聚物或聚氧乙烯聚丙二醇,如泊洛沙姆124、泊洛沙姆188、泊洛沙姆237、泊洛沙姆388、或泊洛沙姆407 (BASF Wyandotte Corp.)。如上所述,表面活性剂的混合物可以用于本发明的固体组合物中。
用于本发明的优选表面活性剂的非限制性实例包括聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、Cremophor RH 40、Cremophor EL、Gelucire 44/14、Gelucire 50/13、D-α-生育酚基聚乙二醇1000琥珀酸酯(维生素E TPGS)、丙二醇月桂酸酯、十二烷基硫酸钠和脱水山梨糖醇单月桂酸酯。
在一个实施方案中,本发明的固体组合物包含无定形固体分散体或固体溶液,其包括(1)选自特拉匹韦(VX-950)、BI-201335、TMC-435(TMC-435350)、vaniprevir(MK-7009)、MK-5172、asunaprevir(BMS-650032)、daclatasvir(BMS-790052)、丹诺普韦、setrobuvir(ANA-598)、tegobuvir(GS-333126或GS-9190)、GS-9451、mericitabine(R-4048)、IDX-184、filibuvir(PF-00868554)、PSI-7977、PSI-352938、BIT-225、波普瑞韦、GS-5885或GS-9256的选定的HCV抑制剂和(2)药学上可接受的亲水性聚合物。所述固体组合物也可以包括药学上可接受的表面活性剂,其优选配制在无定形固体分散体或固体溶液中。亲水性聚合物可以选自例如N-乙烯基内酰胺的均聚物、N-乙烯基内酰胺的共聚物、纤维素酯、纤维素醚、聚环氧烷、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚乙烯醇、乙酸乙烯酯聚合物、寡糖和多糖。作为非限制性实例,亲水性聚合物选自N-乙烯基吡咯烷酮的均聚物、N-乙烯基吡咯烷酮的共聚物、N-乙烯基吡咯烷酮和乙酸乙烯酯的共聚物、N-乙烯基吡咯烷酮和丙酸乙烯酯的共聚物、聚乙烯吡咯烷酮、甲基纤维素、乙基纤维素、羟烷基纤维素、羟丙基纤维素、羟烷基烷基纤维素、羟丙基甲基纤维素、纤维素邻苯二甲酸酯、纤维素琥珀酸酯、纤维素乙酸邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素琥珀酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、聚环氧乙烷、聚环氧丙烷、环氧乙烷和环氧丙烷的共聚物、聚乙二醇/聚乙烯基己内酰胺/聚乙酸乙烯酯的接枝共聚物、甲基丙烯酸/丙烯酸乙酯共聚物、甲基丙烯酸/甲基丙烯酸甲酯共聚物、甲基丙烯酸丁酯/甲基丙烯酸2-二甲氨基乙酯共聚物、聚(丙烯酸羟基烷基酯)、聚(甲基丙烯酸羟基烷基酯)、乙酸乙烯酯和巴豆酸的共聚物、部分水解的聚乙酸乙烯酯、角叉菜胶、半乳甘露聚糖和黄原胶。优选地,亲水性聚合物选自聚乙烯吡咯烷酮(PVP) K17、PVP K25、PVP K30、PVP K90、羟丙基甲基纤维素(HPMC) E3、HPMC E5、HPMC E6、HPMC E15、HPMC K3、HPMC A4、HPMC A15、HPMC乙酸琥珀酸酯(AS) LF、HPMC AS MF、HPMC AS HF、HPMC AS LG、HPMC AS MG、HPMC AS HG、HPMC邻苯二甲酸酯(P)50、HPMC P 55、Ethocel 4、Ethocel 7、Ethocel 10、Ethocel 14、Ethocel 20、共聚维酮(乙烯基吡硌烷酮-乙酸乙烯酯共聚物60/40)、聚乙酸乙烯酯、甲基丙烯酸酯/甲基丙烯酸共聚物(Eudragit) L100-55、Eudragit L100、Eudragit S100、聚乙二醇(PEG) 400、PEG 600、PEG 1450、PEG 3350、PEG 4000、PEG 6000、PEG 8000、Soluplus、泊洛沙姆124、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338或泊洛沙姆407。更优选地,亲水性聚合物选自乙烯基吡硌烷酮的均聚物(例如,具有12至100的Fikentscher K值的PVP或具有17至30的FikentscherK值的PVP)、或30至70重量%的N-乙烯基吡咯烷酮(VP)和70到30重量%的乙酸乙烯酯(VA)的共聚物(例如,60重量%VP和40重量%VA的共聚物)。表面活性剂可以选自例如聚氧乙烯甘油三蓖麻油酸酯或聚氧乙烯35蓖麻油(Cremophor EL;BASF Corp.)或聚氧乙烯甘油氧基硬脂酸酯、聚氧乙烯脱水山梨糖醇的单脂肪酸酯、聚氧乙烯烷基醚、聚氧乙烯烷基芳基醚、聚乙二醇脂肪酸酯、烷二醇脂肪酸单酯、蔗糖脂肪酸酯和脱水山梨糖醇脂肪酸单酯。作为非限制性实例,表面活性剂选自聚乙二醇40氢化蓖麻油(Cremophor RH 40,也称为聚氧乙烯40氢化蓖麻油或聚乙二醇甘油羟基硬脂酸酯)、聚乙二醇60氢化蓖麻油(Cremophor RH 60)、聚氧乙烯(20)脱水山梨糖醇的单脂肪酸酯(例如聚氧乙烯(20)脱水山梨糖醇单油酸酯(Tween80)、聚氧乙烯(20)脱水山梨糖醇单硬脂酸酯(Tween 60)、聚氧乙烯(20)脱水山梨糖醇单棕榈酸酯(Tween 40)、或聚氧乙烯(20)脱水山梨糖醇单月桂酸酯(Tween 20))、聚氧乙烯(3)月桂基醚、聚氧乙烯(5)鲸蜡基醚、聚氧乙烯(2)硬脂基醚、聚氧乙烯(5)硬脂基醚、聚氧乙烯(2)壬基苯基醚、聚氧乙烯(3)壬基苯基醚、聚氧乙烯(4)壬基苯基醚、聚氧乙烯(3)辛基苯基醚、PEG-200单月桂酸酯、PEG-200二月桂酸酯、PEG-300二月桂酸酯、PEG-400二月桂酸酯、PEG-300二硬脂酸酯、PEG-300二油酸酯、丙二醇单月桂酸酯、D-α-生育酚基聚乙二醇1000琥珀酸酯、蔗糖单硬脂酸酯、蔗糖二硬脂酸酯、蔗糖单月桂酸酯、蔗糖二月桂酸酯、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯和脱水山梨糖醇硬脂酸酯。优选地,表面活性剂选自聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、Cremophor RH 40、Cremophor EL、Gelucire 44/14、Gelucire 50/13、D-α-生育酚基聚乙二醇1000琥珀酸酯(维生素E TPGS)、丙二醇月桂酸酯、十二烷基硫酸钠或脱水山梨糖醇单月桂酸酯。更优选地,表面活性剂选自脱水山梨糖醇单月桂酸酯、D-α-生育酚基聚乙二醇1000琥珀酸酯、丙二醇单月桂酸酯或其组合(例如,D-α-生育酚基聚乙二醇1000琥珀酸酯和lauroglycol FCC的组合)。
在另一个实施方案中,本发明的固体组合物包含无定形固体分散体或固体溶液,其包括(1)选定的上述HCV抑制剂和(2)N-乙烯基吡咯烷酮的均聚物或共聚物(例如,共聚维酮)。所述固体组合物也包含药学上可接受的表面活性剂(例如,维生素E TPGS、脱水山梨糖醇单月桂酸酯、或维生素E TPGS和lauroglycol FCC的组合),其中表面活性剂优选配制在无定形固体分散体或固体溶液中。
在又一个实施方案中,本发明的固体组合物包含无定形固体分散体或固体溶液,其包括(1)选定的上述HCV抑制剂、(2)共聚维酮和(3)药学上可接受的表面活性剂(例如,维生素E TPGS、脱水山梨糖醇单月桂酸酯、或维生素E TPGS和lauroglycol FCC的组合)。所述无定形固体分散体或固体溶液也可包括另一种药学上可接受的表面活性剂。
在又一个实施方案中,本发明的固体组合物包含无定形固体分散体或固体溶液,其包括(1) 10重量%的选定的HCV抑制剂、(2) 82重量%的共聚维酮和(3) 5重量%的维生素ETPGS和2重量%的lauroglycol FCC。所述固体组合物也可以包括1重量%的胶体二氧化硅。
在另一个实施方案中,本发明的固体组合物包含无定形固体分散体或固体溶液,其包括(1)10重量%的选定的HCV抑制剂、(2)82重量%的共聚维酮和(3)7重量%的丙二醇单辛酸酯(Capryol 90)。所述固体组合物也可以包括1重量%的胶体二氧化硅。
本发明中使用的固体分散体优选包含单相(热力学定义的)或由单相组成,其中一种或多种治疗剂(例如,与或不与另一种抗HCV剂组合的选定的上述HCV抑制剂)分子地(molecularly)分散在含有一种或多种药学上可接受的亲水性聚合物的基质中。在这样的情况下,使用差示扫描量热法(DSC)对固体分散体的热分析通常仅显示一个单一的Tg,并且所述固体分散体不含有任何可检测的晶体HCV抑制剂(通过X射线粉末衍射光谱测量的)。
本发明的固体组合物可以进一步包括一种或多种其它抗HCV剂。这些其它的抗HCV剂可以是例如HCV聚合酶抑制剂(包括核苷或非核苷类型的聚合酶抑制剂)、HCV蛋白酶抑制剂、HCV解螺旋酶抑制剂、CD81抑制剂、亲环蛋白抑制剂、内部核糖体进入位点抑制剂或HCVNS5A抑制剂。
在一个实施方案中,本发明的固体组合物包含(1)选定的上述HCV抑制剂和(2)另一种HCV蛋白酶抑制剂。在另一个实施方案中,本发明的固体组合物包含(1)选定的上述HCV抑制剂和(2)另一种HCV聚合酶抑制剂(例如,非核苷聚合酶抑制剂,或优选核苷聚合酶抑制剂)。在又一个实施方案中,本发明的固体组合物包含(1)选定的上述HCV抑制剂、(2)另一种HCV蛋白酶抑制剂和(3)另一种HCV聚合酶抑制剂(例如,非核苷聚合酶抑制剂,或优选核苷聚合酶抑制剂)。在另一个实施方案中,本发明的固体组合物包含(1)选定的上述HCV抑制剂和(2)另一种HCV NS5A抑制剂。在另一个实施方案中,本发明的固体组合物包含(1)选定的上述HCV抑制剂、(2)另一种HCV聚合酶抑制剂(例如,非核苷聚合酶抑制剂,或优选核苷聚合酶抑制剂)和(3)另一种HCV NS5A抑制剂。在另一个实施方案中,本发明的固体组合物包含(1)选定的上述HCV抑制剂、(2)另一种HCV蛋白酶抑制剂和(3)另一种HCV NS5A抑制剂。
其他蛋白酶抑制剂的非限制性实例可选自ACH-1095 (Achillion)、ACH-1625(Achillion)、ACH-2684 (Achillion)、AVL-181 (Avila)、AVL-192 (Avila)、BI-201335(Boehringer Ingelheim)、BMS-650032 (BMS)、波普瑞韦、丹诺普韦、GS-9132 (Gilead)、GS-9256 (Gilead)、GS-9451 (Gilead)、IDX-136 (Idenix)、IDX-316 (Idenix)、IDX-320(Idenix)、MK-5172(Merck)、narlaprevir、PHX-1766 (Phenomix)、特拉匹韦、TMC-435(Tibotec)、vaniprevir、VBY708(Virobay)、VX-500(Vertex)、VX-813(Vertex)、VX-985(Vertex)或其组合。并且其他HCV聚合酶抑制剂的非限制性实例可选自ABT-072(Abbott)、ABT-333(Abbott)、ANA-598(Anadys)、BI-207127(Boehringer Ingelheim)、BILB-1941(Boehringer Ingelheim)、BMS-791325(BMS)、filibuvir、GL59728(Glaxo)、GL60667(Glaxo)、GS-9669(Gilead)、IDX-375(Idenix)、MK-3281(Merck)、tegobuvir、TMC-647055(Tibotec)、VCH-759(Vertex & ViraChem)、VCH-916(ViraChem)、VX-222(VCH-222)(Vertex& ViraChem)、VX-759(Vertex)、GS-6620(Gilead)、IDX-102(Idenix)、IDX-184(Idenix)、INX-189(Inhibitex)、MK-0608(Merck)、PSI-7977(Pharmasset)、PSI-938(Pharmasset)、RG7128(Roche)、TMC64912(Medivir)、GSK625433(GlaxoSmithKline)、BCX-4678(BioCryst)或其组合。聚合酶抑制剂可以是核苷酸聚合酶抑制剂,例如GS-6620(Gilead)、IDX-102(Idenix)、IDX-184(Idenix)、INX-189(Inhibitex)、MK-0608(Merck)、PSI-7977(Pharmasset)、PSI-938(Pharmasset)、RG7128(Roche)、TMC64912(Medivir)或其组合。聚合酶抑制剂也可以是非核苷聚合酶抑制剂,例如ABT-072(Abbott)、ABT-333(Abbott)、ANA-598(Anadys)、BI-207127(Boehringer Ingelheim)、BILB-1941(Boehringer Ingelheim)、BMS-791325(BMS)、filibuvir、GL59728(Glaxo)、GL60667(Glaxo)、GS-9669(Gilead)、IDX-375(Idenix)、MK-3281(Merck)、tegobuvir、TMC-647055 (Tibotec)、VCH-759 (Vertex &ViraChem)、VCH-916 (ViraChem)、VX-222 (VCH-222) (Vertex & ViraChem)、VX-759(Vertex)或其组合。本发明还考虑在本发明的固体组合物中包含核苷酸聚合酶抑制剂和非核苷聚合酶抑制剂。其他HCV NS5A抑制剂的非限制性实例包括ACH-2928(Achillion)、AZD2836(Astra-Zeneca)、AZD7295(Astra-Zeneca)、BMS-790052(BMS)、BMS-824393(BMS)、EDP-239(Enanta)、GS-5885(Gilead)、PPI-1301(Presidio)、PPI-461(Presidio)、GSK62336805或其组合。
本发明的固体组合物优选为固体口服剂型。适合于本发明的常用固体口服剂型包括但不限于胶囊剂、锭剂、颗粒剂、丸剂、粉剂和片剂,其中胶囊剂和片剂是优选的。本发明的固体口服剂型也可以包括其它赋形剂或嵌入式稀释剂(inset diluents),例如蔗糖、乳糖或淀粉。润滑剂、着色剂、释放剂、包衣剂、甜味剂或调味剂、缓冲剂、防腐剂或抗氧化剂也可以包括在本发明的固体口服剂型中。
本发明的固体组合物可以通过多种技术制备,例如但不限于熔融-挤出、喷雾-干燥、共沉淀、冷冻干燥或其它溶剂蒸发技术,其中熔融-挤出和喷雾-干燥是优选的。熔融-挤出方法通常包括如下步骤:制备包括一种或多种活性成分、一种或多种亲水性聚合物和优选的一种或多种表面活性剂的熔融物,然后将熔融物冷却直到其凝固。熔融通常包括向液态的转变,其中一种组分可能溶解或嵌入,优选均匀溶解或嵌入其它的一种组分或多种组分中。在许多情况下,所述一种或多种聚合物组分将熔融,并且包括所述一种或多种活性成分和一种或多种表面活性剂的其它组分将溶于熔融物中,从而形成溶液。在这样的情况下,聚合物起溶剂的作用。熔融通常包括在高于所述一种或多种聚合物的软化点下加热。熔融物的制备可以采用多种方式进行。组分的混合可以在形成熔融物之前、期间或之后进行。例如,可以首先混合组分,接着熔融,或者同时混合和熔融。也可以将熔融物均质化,以便有效地分散所述一种或多种活性成分。另外,首先将所述一种或多种聚合物熔融,然后混入所述一种或多种活性成分并均质化可能是方便的。在一个实例中,将除了一种或多种表面活性剂之外的所有物质混合并进料于挤出机中,同时将所述一种或多种表面活性剂在外部熔融并在挤出过程中泵入。
在另一个实例中,熔融物包含选定的上述HCV抑制剂和一种或多种上述亲水性聚合物;并且熔融温度的范围为100至170℃,优选120至150℃,且高度优选135至140℃。熔融物也可以包括上述药学上可接受的表面活性剂。
在又一个实例中,熔融物包含选定的上述HCV抑制剂、至少另一种上述抗HCV剂和一种或多种上述亲水性聚合物。熔融物也可以包括上述药学上可接受的表面活性剂。
为了开始熔融-挤出过程,可以使用其固体形式如其各自的晶体形式的一种或多种活性成分(例如,选定的上述HCV抑制剂)。也可以使用在合适的液体溶剂中的溶液或分散体形式的一种或多种活性成分,所述液体溶剂例如醇、脂肪族烃、酯或在某些情况下为液态二氧化碳。制备熔融物后,可以例如通过蒸发除去溶剂。
各种添加剂也可以包括在熔融物中,例如流动调节剂(例如胶体二氧化硅)、粘合剂、润滑剂、填充剂、崩解剂、增塑剂、着色剂、或稳定剂(例如,抗氧化剂、光稳定剂、自由基清除剂和抗微生物攻击的稳定剂)。
熔融和/或混合可以在惯用于该目的的装置中进行。特别合适的装置是挤出机或捏合机。合适的挤出机包括单螺杆挤出机、啮合型螺杆挤出机(intermeshing screwextruders)或多螺杆挤出机,优选双螺杆挤出机,其可以是同向旋转的(corotating)或异向旋转的(counterrotating)并任选装配有捏合盘(kneading disk)。应当理解,工作温度将由使用的挤出机的类型或挤出机内的构造类型来确定。在挤出机中熔融、混合和溶解组分所需的部分能量可以由加热元件提供。然而,挤出机中物质的摩擦和剪切也可以为混合物提供大量能量并有助于所述组分的均匀熔融物的形成。
熔融物可以从稀的到糊状的到粘稠的。挤出物的成形可以通过具有两个异向旋转的滚柱的压延机方便地实现,所述滚柱在其表面上具有互相匹配的凹槽。可以将挤出物冷却并使其凝固。也可以将挤出物在凝固之前(热切)或之后(冷切)切成片。
可以将凝固的挤出产物进一步研磨、碾磨或以其它方式减小为颗粒。凝固的挤出物以及产生的每个颗粒包含一种或多种活性成分在基质中的固体分散体,优选固体溶液,所述基质由一种或多种亲水性聚合物和任选的一种或多种药学上可接受的表面活性剂组成。当所述颗粒不含有任何表面活性剂时,可以将上述药学上可接受的表面活性剂加入到颗粒中并与该颗粒混合。也可以在研磨或碾磨成颗粒之前,将所述挤出产物与一种或多种其它的活性成分和/或一种或多种添加剂混合。可以将该颗粒进一步加工成合适的固体口服剂型。
在某些情况下,直接成形技术如注塑可以与熔融挤出结合使用来制备合适的固体剂型。
在一个实例中,将共聚维酮和一种或多种表面活性剂混合并制粒,接着加入气相二氧化硅(aerosil)和选定的上述HCV抑制剂。然后研磨可以含有例如至少5重量%的选定的HCV抑制剂的混合物。然后将该混合物挤出,并可以研磨由此生成的挤出物并过筛用于进一步加工以制备胶囊剂或片剂。在该实例中使用的一种或多种表面活性剂也可以在挤出过程中经由液体给料(dosing)加入。
经由喷雾-干燥的蒸发溶剂途径提供了实现较低温度(如果需要的话)下的可加工性的优点,并实现了对该方法进行其它修饰以便进一步改善粉末性质。然后,如果需要的话,可以进一步配制喷雾干燥的粉末,并且无论期望胶囊剂、片剂或任何其它固体剂型,最终药物产品都是柔软的(flexible)。
示例性的喷雾干燥方法和喷雾-干燥设备描述于K. Masters,Spray DryingHandbook(Halstead Press,New York,第4版,1985)中。适合于本发明的喷雾-干燥设备的非限制性实例包括由Niro Inc.或GEA Process Engineering Inc.,Buchi LabortechnikAG和Spray Drying Systems,Inc.制造的喷雾干燥器。喷雾干燥方法通常包括将液体混合物破碎成小的液滴并在容器(喷雾干燥装置)中从液滴中快速除去溶剂,所述容器中存在从液滴中蒸发溶剂的强驱动力。雾化技术包括例如双流体或压力喷嘴、或旋转雾化器。用于溶剂蒸发的强驱动力可以例如通过保持喷雾干燥装置中的溶剂分压恰好低于干燥液滴的温度下溶剂的蒸气压来提供。这可以通过如下方式实现:(1)保持喷雾干燥装置中的压力为部分真空;(2)混合液滴与温的干燥气体(例如,加热的氮气);或(3)上述两者。
可以选择干燥气体的温度和流速以及喷雾干燥器的设计,以便液滴在其到达装置壁时足够干燥。这有助于确保干燥的液滴基本上是固体并可以形成细粉末并且不粘结于装置壁。可以通过人工、气动、机械或其它合适的方法移出所述物质来收集喷雾干燥的产物。实现优选的干燥水平的实际时间长度取决于液滴的尺寸、制剂和喷雾干燥器操作。凝固之后,固体粉末可以在喷雾干燥室中停留额外的时间(例如,5-60秒)以进一步从固体粉末中蒸发溶剂。当其离开干燥器时,固体分散体中的最终溶剂含量优选为足够低的水平,以便提高最终产物的稳定性。例如,喷雾干燥粉末的残留溶剂含量可以小于2重量%。高度优选地,残留溶剂含量在International Conference on Harmonization (ICH) Guidelines中设定的限度内。另外,对喷雾干燥的组合物进行进一步干燥以降低残留溶剂至甚至更低的水平可能是有用的。进一步降低溶剂水平的方法包括但不限于流化床干燥、红外线干燥、滚动干燥、真空干燥以及这些和其它方法的组合。
类似于上述固体挤出物,喷雾干燥产物含有一种或多种活性成分在由一种或多种亲水性聚合物和任选的一种或多种药学上可接受的表面活性剂组成的基质中的固体分散体,优选固体溶液。当喷雾干燥产物不含有任何表面活性剂时,可以在进一步加工之前将上述药学上可接受的表面活性剂加入到喷雾干燥产物中并与所述喷雾干燥产物混合。
在进料至喷雾干燥器之前,可以将所述一种或多种活性成分(例如,选定的上述HCV抑制剂)、所述一种或多种亲水性聚合物以及其它任选的活性成分或赋形剂例如一种或多种药学上可接受的表面活性剂溶于溶剂中。合适的溶剂包括但不限于水、烷醇(例如,甲醇、乙醇、1-丙醇、2-丙醇或其混合物)、丙酮、丙酮/水、烷醇/水混合物(例如,乙醇/水混合物)、或其组合。还可以在进料至喷雾干燥器之前预加热所述溶液。
通过熔融-挤出、喷雾-干燥或其它技术制备的固体分散体可以制备成任何合适的固体口服剂型。在一个实施方案中,通过熔融-挤出、喷雾-干燥或其它技术制备的固体分散体(例如,挤出物或喷雾干燥的粉末)可以压制成片剂。可以将固体分散体直接压制,或者在压制之前研磨或碾磨成颗粒或粉末。压制可以在压片机中进行,例如在两个移动冲压机之间的钢模中进行。当本发明的固体组合物包含选定的上述HCV抑制剂和另一种抗HCV剂时,可以分别制备每种独立活性成分的固体分散体,然后在压制之前将任选研磨或碾磨的固体分散体混合。还可以将选定的上述HCV抑制剂和其它活性成分制备在相同的固体分散体中,任选与其它添加剂研磨和/或混合,然后压制成片剂。
至少一种选自流动调节剂、粘合剂、润滑剂、填充剂、崩解剂或增塑剂的添加剂可以在压制固体分散体中使用。这些添加剂可以在压制之前与碾磨或研磨的固体分散体混合。崩解剂促进压制物在胃中快速崩解并保持释放的颗粒彼此分离。合适的崩解剂的非限制性实例为交联聚合物,例如交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠(cross-linkedsodium carboxymethylcellulose)或交联羧甲基纤维素钠(sodium croscarmellose)。合适的填充剂(也称为“增量剂”)的非限制性实例为一水合乳糖、磷酸氢钙、微晶纤维素(例如,Avicell)、硅酸盐,特别是二氧化硅、氧化镁、滑石、马铃薯或玉米淀粉、异麦芽酮糖醇(isomalt)或聚乙烯醇。合适的流动调节剂的非限制性实例包括高度分散的二氧化硅(例如,胶体二氧化硅如Aerosil)和动物或植物脂肪或蜡。合适的润滑剂的非限制性实例包括聚乙二醇(例如,具有1000至6000的分子量)、硬脂酸镁和硬脂酸钙、硬脂酰富马酸钠等。
各种其它添加剂也可以在制备本发明的固体组合物中使用,例如染料如偶氮染料、有机或无机颜料如氧化铝或二氧化钛、或天然来源的染料;稳定剂如抗氧化剂、光稳定剂、自由基清除剂、抗微生物攻击的稳定剂。
根据本发明的某些实施方案的固体组合物可以含有若干层,例如层压片剂或多层片剂。它们可以为开放或封闭形式。“封闭剂型”为其中一层被至少另一层完全环绕的那些。
为了促进固体剂型的摄取,赋予剂型合适的形状是有利的。因此,可以舒适地吞服的大片剂优选为细长形而非圆形。
片剂上的薄膜衣进一步有助于其被吞咽时的舒适性。薄膜衣还改善了味道并提供了精致的外观。薄膜衣通常包括聚合成膜材料如羟丙基甲基纤维素、羟丙基纤维素和丙烯酸酯或甲基丙烯酸酯共聚物。除了成膜聚合物之外,薄膜衣可以进一步包含增塑剂例如聚乙二醇、表面活性剂例如聚山梨醇酯和任选的颜料例如二氧化钛或氧化铁。薄膜衣也可以包含作为防粘剂的滑石。优选地,薄膜衣占本发明药物组合物的小于5重量%。
在另一个方面,本发明的特征在于使用本发明的固体组合物治疗HIV感染的方法。所述方法包括向需要其的患者给予本发明的固体组合物。本发明的固体组合物可以单独给药,或者与一种或多种其它抗HCV剂(例如上述那些)联合给药。用于任何特定患者的具体抑制剂量将取决于多种因素,包括HCV感染的严重性;一种或多种活性成分在特定患者中的活性;所用的具体固体组合物;患者的年龄、体重、一般健康状况、性别和饮食;给药时间和排泄速率;治疗的持续时间;与选定的上述HCV抑制剂联合或同时使用的药物;和医学领域中熟知的类似因素。
在一个实施方案中,本发明的方法包括向需要其的患者给予本发明的固体组合物和至少另一种抗HCV剂,其中所述另一种抗HCV剂选自HCV聚合酶抑制剂(例如,核苷或非核苷HCV聚合酶抑制剂)、HCV蛋白酶抑制剂、HCV解螺旋酶抑制剂、CD81抑制剂、亲环蛋白抑制剂、内部核糖体进入位点抑制剂或HCV NS5A抑制剂。优选地,所述另一种抗HCV剂为HCV聚合酶抑制剂(例如,核苷或非核苷HCV聚合酶抑制剂)或HCV蛋白酶抑制剂。还优选地,所述另一种抗HCV剂为干扰素或利巴韦林,或优选其组合。所述干扰素优选为α-干扰素,并更优选为聚乙二醇化的干扰素-α,如PEGASYS(聚乙二醇干扰素α-2a)。本发明的固体组合物和另外的一种或多种抗HCV剂的给药可以同时或顺序进行。
本发明的特征还在于本发明的固体组合物在制备用于治疗HCV感染的药物中的用途。
在一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为特拉匹韦(VX-950)。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为BI-201335。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为TMC-435(TMC-435350)。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为vaniprevir(MK-7009)。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为MK-5172。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为asunaprevir(BMS-650032)。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为daclatasvir(BMS-790052)。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为丹诺普韦。优选地,丹诺普韦与利托那韦联合使用以改善丹诺普韦的药代动力学。更优选地,丹诺普韦在本发明的固体组合物中与利托那韦共同配制。例如,本发明的固体组合物中的丹诺普韦和利托那韦可在相同的固体分散体或不同的固体分散体中进行配制。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为setrobuvir(ANA-598)。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为tegobuvir(GS-333126或GS-9190)。优选地,该实施方案的固体组合物进一步包含GS-9256、GS-9451或GS-5885。还优选地,该实施方案的固体组合物进一步包含GS-9451和GS-5885。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为GS-9451。优选地,该实施方案的固体组合物进一步包含tegobuvir或GS-5885。还优选地,该实施方案的固体组合物进一步包含tegobuvir和GS-5885。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为mericitabine(R-4048)。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为IDX-184。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为filibuvir(PF-00868554)。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为PSI-7977。优选地,该实施方案的固体组合物进一步包含GS-5885或daclatasvir。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为PSI-352938。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为BIT-225。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为波普瑞韦。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为GS-5885。优选地,该实施方案的固体组合物进一步包含PSI-7977、GS-9451或tegobuvir。还优选地,该实施方案的固体组合物进一步包含GS-9451和tegobuvir。
在另一个实施方案中,在上文所述的任何方面、实施方案、实施例或特征中使用的选定的HCV抑制剂为GS-9256。优选地,该实施方案的固体组合物进一步包含tegobuvir。
也可以采用其它制剂方法(例如基于液体的制剂、简单溶液、纳米颗粒、结晶固体、盐或共结晶以及传统的立即释放制剂)配制选定的HCV抑制剂,无论是单独地或与其它抗HCV剂联合。
本发明的上述描述提供了例示和描述,但不意欲是穷尽的或将本发明限定为所公开的具体一项。在参照上述教导的情况下可以进行修改和变化,或可以从本发明的实践中获得所述修改和变化。因此,应注意,本发明的范围由权利要求及其等价物来限定。
Claims (2)
1.一种固体口服剂型,其包含固体溶液,所述固体溶液包括至少1重量%的下列化合物:
至少30重量%的共聚维酮,和
任选药学上可接受的表面活性剂。
2.权利要求1的固体口服剂型,其进一步包含另一种抗HCV剂。
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