CN102670629B - 用于联合抗病毒治疗的组合物和用途 - Google Patents
用于联合抗病毒治疗的组合物和用途 Download PDFInfo
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- CN102670629B CN102670629B CN201210094391.9A CN201210094391A CN102670629B CN 102670629 B CN102670629 B CN 102670629B CN 201210094391 A CN201210094391 A CN 201210094391A CN 102670629 B CN102670629 B CN 102670629B
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- emtricitabine
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Abstract
本发明涉及用于联合抗病毒治疗的组合物和用途,具体涉及含有[2-(6-氨基-嘌呤-9-基)-1-甲基-乙氧基甲基]-膦酸二异丙氧基羰基氧基甲基酯(替诺福韦地索普西富马酸盐,)和(2R,5S,顺式)-4-氨基-5-氟-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮(恩曲他滨,EmtrivaTM,(-)-顺式FTC)及其生理学功能衍生物的治疗联合物。所述联合物可用于治疗HIV感染,包括被对核苷和/或非核苷抑制剂具有耐药性的HIV突变株感染。本发明还涉及含有所述替诺福韦地索普西富马酸盐和恩曲他滨、及其生理学功能衍生物的联合物的药物组合物和制剂,以及使用这类组合物和制剂的治疗方法。
Description
本申请是申请号为200480002190.5、申请日为2004年1月13日、发明名称为“用于联合抗病毒治疗的组合物和方法”的专利申请的分案申请。
本非临时申请要求2003年1月14日提交的临时申请60/440,246和60/440,308的权益,它们在此将其引入作为参考。
技术领域
本发明总的来说涉及含有具抗病毒活性(更具体地说是具有抗HIV特性)的化合物的联合物。特别地,本发明涉及含有具不同结构的抗病毒剂的化学稳定联合物。
背景技术
人类免疫缺陷病毒(HIV)感染以及相关疾病是全球范围内主要的公共健康问题。人类免疫缺陷病毒1型(HIV-1)编码至少三种病毒复制所必需的酶:逆转录酶(RT)、蛋白酶(Prt)和整合酶(Int)。尽管靶向逆转录酶和蛋白酶的药物已经被广泛使用并且也显示出具有疗效,特别是当联合应用时,但是毒性和耐药性菌株的出现使其应用受到限制(Palella等人,N.Engl.J.Med.(1998)338:853-860;Richman,D.D.Nature(2001)410:995-1001)。人类免疫缺陷病毒1型(HIV-1)蛋白酶(Prt)对于病毒的复制具有重要作用,因而是被认可的抗病毒药物的有效靶点。HIVPrt裂解病毒Gag和Gag-Pol多聚蛋白质得到病毒结构蛋白(pl7、p24、p7和p6)以及三种病毒酶。已经证实,使用各种RT抑制剂进行联合治疗可以在持续的时间内将病毒复制高度有效地抑制在无法量化的水平内。另外,使用RT和Prt抑制剂(PI)进行联合治疗在抑制HIV复制方面已经显示出协同效应。然而遗憾的是,由于出现耐药性、不能依从复杂化的给药方案、药物代谢动力学的相互作用、毒性反应以及缺乏效果导致目前高百分比(通常为30-50%)的患者不能接受这种联合治疗。因此,需要一类可以有效对抗突变型HIV菌株、具有截然不同的耐药性曲线、副作用更少、给药方案更简单、同时口服有效的新HIV-1抑制剂。特别地,需要一种更简单化的给药方案,例如每天口服给药一次,最好是服用尽可能少的药丸。
化合物的联合应用可以在降低毒性反应的同时获得相当的抗病毒效果、或者是获得增强的药物疗效。总的给药剂量越低越可以降低HIV耐药性变异体的出现几率。很多种不同方法被用于测量含有各种化合物的联合物在不同测定系统中的合并作用效果(FurmanWO02/068058)。如果药丸负荷降低、给药方案更加简化的话,以及任选如果各种化合物之间还表现为协同作用的话,那么剂量越低就意味着患者的依从性越好(Loveday,C.″Nucleosidereversetranscriptaseinhibitorresistance″(2001)JAIDSJournalofAcquiredImmuneDeficiencySyndromes26:S10-S24)。据证实,AZT(齐多夫定TM,3′-叠氮,3′-脱氧胸苷)与那些作用于HIV-1复制步骤而不是逆转录步骤的药剂联合时具有协同的抗病毒活性,这类药剂包括重组可溶性CD4castanospermine和重组干扰素-α。然而,需要注意的是,化合物联合物可能导致毒性反应增强。例如,AZT和重组干扰素-α对于正常人的骨髓原始细胞具有增强的毒性作用。
抗病毒剂联合物的化学稳定性是联合制剂成功的一个重要方面,本发明就提供了这种联合物的实例。
为了治疗被某些病毒例如HIV感染的患者,需要一类新的口服活性药物的联合物,这类联合物可以提供加强的治疗安全性和有效性,同时产生较低的耐药性,并且预期具有较高的患者依从性。
发明内容
发明概述
本发明提供了抗病毒化合物的联合物,具体地说是用于抑制HIV的组合物和方法。在示例性方面,本发明包括一种具有抗HIV活性的含替诺福韦地索普西富马酸盐(tenofovirdisoproxilfumarate)和恩曲他滨(emtricitabine)的组合物。含有替诺福韦DF和恩曲他滨的所述组合物不仅在化学上是稳定的,并且还具有协同作用和/或可以降低单独的替诺福韦DF和恩曲他滨或者两者的副作用。考虑到药丸负荷的降低和给药方案的简化,这样的组合物可能会增加患者的依从性。
本发明涉及含有[2-(6-氨基-嘌呤-9-基)-1-甲基-乙氧基甲基]-膦酸二异丙氧基羰基氧基甲基酯富马酸酯(替诺福韦地索普西富马酸盐,替诺福韦DF,TDF,)和(2R,5S,顺式)-4-氨基-5-氟-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮(恩曲他滨,EmtrivaTM,(-)-顺式FTC)的治疗联合物,及其在包括被对核苷和/或非核苷抑制剂具有耐药性的HIV突变株感染在内的HIV感染的治疗中的应用。本发明还涉及含有所述替诺福韦地索普西富马酸盐和恩曲他滨的联合物的药物组合物和制剂。本发明另一方面在于含有替诺福韦地索普西富马酸盐的生理学功能衍生物或恩曲他滨的生理学功能衍生物的药物制剂。
本发明的治疗联合物和药物组合物以及制剂含有PMEA或PMPA(替诺福韦)化合物与恩曲他滨或(2R,5S,顺式)-4-氨基-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮(3TC,拉米夫定,EpivirTM)的联合物,及其在HIV感染的治疗中的应用。
本发明一方面在于一种治疗或预防受感染动物中HIV感染的症状或影响的方法,它包括向所述动物施用(即用于治疗)治疗有效量的含有[2-(6-氨基-嘌呤-9-基)-1-甲基-乙氧基甲基]-膦酸二异丙氧基羰基氧基甲基酯富马酸盐(替诺福韦DF,TDF)或其生理学功能衍生物、和(2R,5S,顺式)-4-氨基-5-氟-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮(恩曲他滨)或其生理学功能衍生物的联合物。
本发明另一方面在于含有替诺福韦地索普西富马酸盐和恩曲他滨、或其生理学功能衍生物的联合物的单位剂型。可以配制该单元剂型供口服或其它途径给药,并且就这类具有不同结构的组分的特性而言,所述单位剂型具有出人意料的化学稳定性。
本发明另一方面涉及含有替诺福韦地索普西富马酸盐和恩曲他滨的抗病毒组合物的化学稳定的联合物。在本发明又一方面,所述含有替诺福韦地索普西富马酸盐和恩曲他滨的化学稳定的联合物进一步含有第三种抗病毒剂。在所述三组分混合物中,为了保证与第三种抗病毒剂联合,利用了替诺福韦地索普西富马酸盐和恩曲他滨所具有的独特的化学稳定性。具体的可使用的第三种药物示例性而非限制性地包括表A中的药物。所述第三组分优选为适用于抗病毒用途的药物,更优选为NNRTI或蛋白酶抑制剂(PI),进一步更优选为NNRTI。在一具体优选实施方案中,本发明涉及含有替诺福韦地索普西富马酸盐和恩曲他滨以及依法韦仑的化学稳定混合物的联合物。
本发明另一方面在于一种患者用药包,它含有选自替诺福韦地索普西富马酸盐和恩曲他滨中的至少一种、通常为两种、以及任选三种活性成分和其它抗病毒剂,以及含有关于联合使用替诺福韦地索普西富马酸盐和恩曲他滨的说明的信息插页。
本发明另一方面在于一种制备前述联合物的方法,它包括将联合物中的替诺福韦DF和恩曲他滨混和成为药物以获得抗病毒效果。在本发明又一方面,提供了本发明的联合物在制备用于治疗任意一种前述病毒感染或病症的药物中的应用。
发明详述
尽管是结合所列举的权利要求对本发明进行说明,但是应该理解这并不意味着将本发明限制于这些权利要求中。相反,本发明意在涵盖落入如权利要求书定义的本发明范围之内的所有变型、修饰、和等同替换。
定义
除非另有说明,本文所使用的下列术语和短语具有下面的含义:
当本文中使用商标时,申请人意在单独包括该商标产品以及该商标产品中的(各种)活性药物成分。
术语“化学稳定性”是指联合物中的两种主要抗病毒剂基本上保持稳定而不发生化学降解。优选它们在物理混和时保持足够稳定,从而允许在商业上可以利用该联合产品所具有的贮存寿命。通常,“化学稳定”是指当两种组分被物理混和形成药物剂型时,第一种组分不会作用于第二种组分而使其降解。更典型地,“化学稳定”是指第一种组分所具有的酸性不会催化或加速第二种组分的酸分解。举例来说(并非限制),在本发明一个方面中,“化学稳定”是指替诺福韦地索普西富马酸盐基本上不会由于恩曲他滨具有酸性而发生降解。上下文中的“基本上”是指当该产品为药物剂型时,替诺福韦地索普西富马酸盐在24小时内发生的酸降解作用至少大约低于10%,优选低于1%,更优选低于0.1%,进一步更优选低于0.01%。
术语“协同”和“协同作用”是指同时使用化合物所获得的效果高于单独使用这些化合物所获得的效果总和,也就是高于根据单独施用这两种活性成分所能预期的效果。当化合物为下述情形时可以获得协同效应:(1)以联合制剂的形式联合配制并给药或递送;(2)以单独制剂的形式交替或平行递送;或者(3)通过某些其它方案进行给药。当在交替疗法中递送时,如果这些化合物被例如以单独的片剂、药丸或胶囊剂、或者容纳在分别的注射器中的不同注射剂的形式连续进行给药或递送的话,可以获得协同效应。一般来说,在交替疗法中,各种活性成分的有效剂量是被连续也就是依次施用的,而在联合疗法中,两种或更多种活性成分的有效剂量是被同时施用的。协同的抗病毒效果是指比由联合物中的各个化合物效果进行单纯加和所预期得到的效果高的抗病毒效果。
术语“生理学功能衍生物”是指当与本发明联合物中的其它药物活性化合物联合施用时,具有与替诺福韦DF或恩曲他滨相当或者近似相当的生理功能的药物活性化合物。本文所使用的术语“生理学功能衍生物”包括任意一种下述形式:生理学上可接受的盐、醚、酯、前药、溶剂化物、立体异构体包括对映异构体、非对映异构体或立体异构富集或外消旋混合物、以及经患者服用后能够提供(直接或间接)上述化合物或其抗病毒活性代谢物或残余物的任意一种其它化合物。
“生物利用度”是指将药剂引入至体内后,药物活性剂被目标组织利用的程度。提高药物活性剂的生物利用度可以为患者提供更有效率和更有效的治疗,这是因为对于既定剂量而言,更多的药物活性剂在目标组织位点上被获得利用。
本发明联合物中的化合物可被称作“活性成分”或“药物活性剂”。
本文所使用的术语“前药”是指当向生物学系统施用时,由于(各种)自发化学反应、(各种)酶催化化学反应、和/或(各种)代谢化学反应而生成药物物质即活性成分的任意一种化合物。
“前药基团”是指在全身、或细胞内代谢过程中通过水解、酶裂解、或者通过某些其它途径与活性抑制剂化合物分开的不稳定官能基团(Bundgaard,Hans,″DesignandApplicationofProdrugs″,Drug DesignandDevelopment(1991),P.Krogsgaard-Larsen和H.Bundgaard,Eds.HarwoodAcademicPublishers,第113-191页)。前药基团可以起提高溶解性、吸收性和亲脂性的作用,从而优化药物的递送、生活利用度和效能。因此,“前药”是指治疗活性化合物的共价修饰类似物。
“烷基”是指除去母系烷烃、烯烃、或炔烃中单个碳原子上的一个氢原子后得到的饱和或不饱和、支链、直链、链状或环状烃基。常见的烷基由1-18个饱和和/或不饱和碳组成,例如正、伯、仲或环碳原子。其实例包括但并不仅仅限于:甲基、Me(-CH3)、乙基、Et(-CH2CH3)、乙炔基(-C≡CH)、乙烯基、乙烯基(-CH=CH2)、1-丙基、正-Pr、正丙基(-CH2CH2CH3)、2-丙基、异-Pr、异丙基(-CH(CH3)2)、烯丙基(-CH2CH=CH2)、炔丙基(-CH2C≡CH)、环丙基(-C3H5)、1-丁基、正-Bu、正丁基(-CH2CH2CH2CH3)、2-甲基-1-丙基、异-Bu、异丁基(-CH2CH(CH3)2)、2-丁基、仲-Bu、仲丁基(-CH(CH3)CH2CH3)、2-甲基-2-丙基、叔-Bu、叔丁基(-C(CH3)3)、1-戊基、正-戊基(-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、环戊基(-C5H9)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、5-己烯基(-CH2CH2CH2CH2CH=CH2)、1-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、环己基(-C6H11)、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、以及3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3。
“芳基”是指除去母系芳香环系中单个碳原子上的一个氢原子后得到的具有6-20个碳原子的单价芳族烃基。常见的芳基包括但并不仅仅限于由苯、取代苯、萘、蒽、联苯等衍生得到的基团。
“芳烷基”是指其中一个与碳原子(通常为末端或sp3碳原子)相连的氢原子被芳基替代的脂肪族烷基。常见的芳烷基包括但并不仅仅限于苄基、2-苯基乙-1-基、2-苯基乙烯-1-基、萘甲基、2-萘基乙-1-基、2-萘基乙烯-1-基、萘基苄基、2-萘基苯基乙-1-基等。芳烷基例如具有6-20个碳原子,该芳烷基中的烷基部分包括烷烃基、烯烃基或炔烃基具有1-6个碳原子,芳基部分具有5-14个碳原子。
“取代的烷基”、“取代的芳基”、和“取代的芳烷基”分别指其中一个或多个氢原子各自独立地被取代基取代的烷基、芳基、和芳烷基。常见的取代基包括但并不仅仅限于-X、-R、-O-、-OR、-SR、-S-、-NR2、-NR3、=NR、-CX3、-CN、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、=N2、-N3、NC(=O)R、-C(=O)R、-C(=O)NRR-S(=O)2O-、-S(=O)2OH、-S(=O)2R、-OS(=O)2OR、-S(=O)2NR、-S(=O)R、-OP(=O)O2RR、-P(=O)O2RR-P(=O)(O)2、-P(=O)(OH)2、-C(=O)R、-C(=O)X、-C(S)R、-C(O)OR、-C(O)O-、-C(S)OR、-C(O)SR、-C(S)SR、-C(O)NRR、-C(S)NRR、-C(NR)NRR,其中各X独立地表示卤素:F、Cl、Br、或I;以及各R独立地表示-H、烷基、芳基、杂环、或前药基团。
“杂芳基”和“杂环”是指其中一个或多个环原子为例如氮、氧、和硫的杂原子的环系。杂环描述在:Katritzky,AlanR.,Rees,C.W.,和Scriven,E.ComprehensiveHeterocyclicChemistry(1996)PergamonPress;Paquette,LeoA.;PrinciplesofModernHeterocyclic ChemistryW.A.Benjamin,NewYork,(1968),特别是第1、3、4、6、7、和9章;″TheChemistryofHeterocyclicCompounds,AseriesofMonographs″(JohnWiley&Sons,NewYork,1950至今),尤其是第13、14、16、19、和28卷。示例性杂环包括但并不仅仅限于各种取代基,即由吡咯、吲哚、呋喃、苯并呋喃、噻吩、苯并噻吩、2-吡啶基、3-吡啶基、4-吡啶基、2-喹啉基、3-喹啉基、4-喹啉基、2-咪唑、4-咪唑、3-吡唑、4-吡唑、哒嗪、嘧啶、吡嗪、嘌呤、噌啉、pthalazine、喹唑啉、喹喔啉、3-(1,2,4-N)-三唑基、5-(1,2,4-N)-三唑基、5-四唑基、4-(1-O,3-N)-唑、5-(1-O,3-N)-唑、4-(1-S,3-N)-噻唑、5-(1-S,3-N)-噻唑、2-苯并唑、2-苯并噻唑、4-(1,2,3-N)-苯并三唑和苯并咪唑衍生的基团。
本文所使用的立体化学定义和转化通常是根据S.P.Parker编著,McGraw-HillDictionaryofChemicalTerms(1984)McGraw-HillBookCompany,NewYork;以及Eliel,E.和Wilen,S.,StereochemistryofOrganicCompounds(1994)JohnWiley&Sons,Inc.,NewYork。很多有机化合物存在旋光形式,也就是说它们有能力使平面偏振光所处的平面发生旋转。在描述旋光化合物时,前缀D和L或者R和S用来表示分子在其(多个)手性中心附近的绝对构型。前缀d和l或者(+)和(-)用来表示平面偏振光被化合物旋转的方向,其中(-)或l表示该化合物为左旋的。具有前缀(+)或d的化合物为右旋的。对于指定的化学结构而言,被称作立体异构体的这些化合物除了它们彼此呈镜像之外,其余均相同。特定的立体异构体又被称作对映异构体,这类异构体的混合物通常被称作对映混合物。对映异构体的50∶50混合物被称作外消旋混合物或外消旋体。术语“外消旋混合物”和“外消旋体”是指两种对映异构物质的等摩尔混合物,不具旋光性。
术语“手性”是指对其镜像伙伴(partner)具有非重叠特性的分子,而“非手性”是指对其镜像伙伴是可重叠的分子。
术语“立体异构体”是指具有相同化学结构,但是原子或基团的空间排列不同的化合物。
“非对映异构体”是指具有两个或更多个手性中心的立体异构体,其分子彼此不呈镜像。非对映异构体具有不同的物理性质,例如熔点、沸点、光谱特性、和反应活性。非对映异构体可以通过高分辨率分析方法例如电泳法和色谱法分离。
“对映异构体”是指化合物的两种立体异构体,它们彼此呈非可重叠镜像。
联合物中的活性成分
本发明提供了同时使用两种或更多种活性成分的新联合物。在部分实施方案中获得了协同的抗病毒效果。在其它实施方案中获得了化学稳定的联合物。所述联合物包括至少一种选自(1)替诺福韦地索普西富马酸盐及其生理学功能衍生物的活性成分、以及至少一种选自(2)恩曲他滨及其生理学功能衍生物的活性成分。术语“协同的抗病毒效果”是指比由联合物中的单独组分(a)和(b)的效果进行单纯加和所预期得到的效果高的抗病毒效果。
替诺福韦地索普西富马酸盐(也被称作替诺福韦DF,替诺福韦地索普西,TDF,Bis-POC-PMPA(美国专利号5935946、5922695、5977089、6043230、6069249)是替诺福韦的一种前药,具有下面的结构:
并且包括富马酸盐(HO2CCH2CH2CO2 -)。
替诺福韦地索普西的化学名称包括:[2-(6-氨基-嘌呤-9-基)-1-甲基-乙氧基甲基]-膦酸二异丙氧基羰基氧基甲基酯;9-[(R)-2-[[双[[(异丙氧基羰基)氧基]甲氧基]氧膦基]甲氧基]丙基]腺嘌呤;和2,4,6,8-四氧杂-5-磷壬烷二酸,5-[[(1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基-,双(1-甲乙基)酯,5-氧化物。CAS登记号包括:201341-05-1;202138-50-9;206184-49-8。应该注意的是,替诺福韦的乙氧基甲基单元具有手性中心。这里示出了R(rectus,右手构型)对映异构体。然而,本发明也包括其S异构体。本发明包括替诺福韦(PMPA)及其生理学功能衍生物的所有对映异构体、非对映异构体、外消旋物、以及富集的立体异构体混合物。
PMPA或替诺福韦(美国专利号4808716、5733788、6057305)具有下面的结构:
PMPA即替诺福韦的化学名称包括:(R)-9-(2-膦酰基甲氧丙基)腺嘌呤;和膦酸,[[(1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基]。其CAS登记号为147127-20-6。
替诺福韦地索普西富马酸盐(DF)是一种核苷酸逆转录酶抑制剂,于2001年在美国被批准与其它抗逆转录酶病毒剂联合用于治疗HIV-1感染。替诺福韦地索普西富马酸盐或(GileadScience,Inc.)是替诺福韦地索普西的富马酸盐。可以命名为:9-[(R)-2-[[双[[(异丙氧基羰基)氧基]甲氧基]氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(1∶1);或者2,4,6,8-四氧杂-5-磷壬二酸,5-[[(1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲乙氧基]甲基]-,双(1-甲乙基)酯,5-氧化物,(2E)-2-丁烯二酸酯(1∶1)。其CAS登记号为202138-50-9。
替诺福韦地索普西富马酸盐的生理学功能衍生物包括PMEA(阿德福韦,9-((R)-2-(膦酰基甲氧基)乙基)腺嘌呤)和PMPA化合物。示例性联合物包括与恩曲他滨或3TC联合的PMEA或PMPA化合物。PMEA和PMPA化合物具有下面的结构:
其中PMEA(R3是H),PMPA(R3是C1-C6烷基、被取代的C1-C6烷基、或CH2OR8,其中R8是C1-C6烷基、C1-C6羟烷基或C1-C6卤烷基)。R6和R7独立地是H或C1-C6烷基。R4和R5独立地是H、NH2、NHR或NR2,其中R是C1-C6烷基。R1和R2独立地是H、C1-C6烷基、被取代的C1-C6烷基、C6-C20芳基、被取代的C6-C20芳基、C6-C20芳烷基、被取代的C6-C20芳烷基、酰氧基甲基酯-CH2OC(=O)R9(例如POM)或酰氧基甲基碳酸酯-CH2OC(=O)OR9(例如POC),其中R9是C1-C6烷基、被取代的C1-C6烷基、C6-C20芳基或者被取代的C6-C20芳基。例如R1和R2可以是新戊酰氧基甲氧基、POM、-CH2OC(=O)C(CH3)3;-CH2O(=O)OC(CH3)3;或POC、-CH2OC(=O)OCH(CH3)2。另外,还例如具有下述结构的替诺福韦,其中R3是CH3,R1、R2、R4、R5、R6和R7是H。二烷基膦酸酯可以根据下面的方法制备:Quast等人(1974)Synthesis490;Stowell等人(1990)TetrahedronLett.3261;美国专利号5663159。
PMPA化合物可以是对映富集或对映纯(单一立体异构体)的,其中携带有R3的碳原子可以是R或S对映异构体。PMPA化合物可以是外消旋物,即R和S立体异构体的混合物。
阿德福韦(9-(2-膦酰基甲氧基乙基)腺嘌呤,其中R1-R7=H)是一种示例性PMEA化合物(美国专利号4808716,4724233)。作为双-新戊酸盐前药,阿德福韦dipivoxil也被称作双-POMPMEA(R3-R7=H,R1和R2=-CH2OC(=O)C(CH3)3、匹伏基(pivoxil)、POM、新戊酰氧基甲氧基),它可以有效对抗HIV和乙型肝炎B感染(美国专利号5663159、6451340)。据证实,与具有抗HIV活性的其它化合物联用的阿德福韦dipivoxil具有小至中等程度的对HIV复制的协同抑制作用,这类其它化合物包括PMPA、d4T、ddC、那非那韦(nelfinavir)、利托那韦和沙奎那韦(Mulato等人(1997)AntiviralResearch36:91-97)。
本发明包括PMEA和PMPA、及其生理学功能衍生物的所有对映异构体、非对映异构体、外消旋物和富集的立体异构体混合物。
恩曲他滨((-)-顺式-FTC,EmtrivaTM)为FTC的单一对映异构体,它是一种被批准用于治疗HIV的强效核苷逆转录酶抑制剂(美国专利号5047407、5179104、5204466、5210085、5486520、5538975、5587480、5618820、5763606、5814639、5914331、6114343、6180639、6215004;WO02/070518)。该单一对映异构体恩曲他滨具有下面的结构:
恩曲他滨的化学名称包括:(-)-顺式-FTC;β-L-羟甲基-5-(5-氟胞嘧啶-1-基)-1,3-氧硫杂环戊烷;(2R,5S)-5-氟-1-[2-(羟甲基)-1,3-氧硫杂环戊烷-5-基]胞嘧啶;和4-氨基-5-氟-1-(2-羟甲基-[1,3]-(2R,5S)-氧硫杂环戊烷-5-基)-1H-嘧啶-2-酮。其CAS登记号包括:143491-57-0;143491-54-7。应该注意的是,FTC在氧硫杂环戊烷环的2和5位上具有两个手性中心,因此它可以以两对光学异构体(即对映异构体)及其混合物包括外消旋混合物的形式存在。所以,FTC既可以是顺式又可以是反式异构体或其混合物。顺式和反式异构体的混合物是具有不同物理性质的非对映异构体。每种顺式和反式异构体可以以两种对映异构体中的一种或其混合物包括外消旋物的形式存在。本发明包括恩曲他滨及其生理学功能衍生物的所有对映异构体、非对映异构体、外消旋物、以及富集的立体异构体混合物。例如,本发明包括生理学功能衍生物例如对映异构体(2R,5S,顺式)-4-氨基-5-氟-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮(恩曲他滨)及其镜像(2S,5R,顺式)-4-氨基-5-氟-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮的1∶1外消旋混合物、或者这两种对映异构体以任何相对含量组成的混合物。本发明还包括顺式和反式形式的FTC的混合物。
恩曲他滨的生理学功能衍生物包括具有下述结构的1,3-氧硫杂环戊烷核苷:
在上述1,3-氧杂环戊烷核苷结构中,B是核碱(nucleobase),包括任意一种能够与补偿核碱或核碱类似物例如嘌呤、7-脱氮嘌呤或嘧啶配对形成Watson-Crick氢键的含氮杂环基团。B的实例包括天然形式的核碱:腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶、胸腺嘧啶、以及天然形式的核碱的少量组分和类似物,例如7-脱氮腺嘌呤、7-脱氮鸟嘌呤、7-脱氮-8-氮杂鸟嘌呤、7-脱氮-8-氮杂腺嘌呤、肌苷、水粉蕈素、硝基吡咯、硝基吲哚、2-氨基嘌呤、2-氨基-6-氯嘌呤、2,6-二氨基嘌呤、次黄嘌呤、假尿苷、5-氟胞嘧啶、5-氯胞嘧啶、5-溴胞嘧啶、5-碘胞嘧啶、假胞嘧啶、假异胞嘧啶、5-炔丙基胞嘧啶、异胞嘧啶、异鸟嘌呤、7-脱氮鸟嘌呤、2-硫代嘧啶、6-硫代鸟嘌呤、4-硫代胸腺嘧啶、4-硫代尿嘧啶、O6-甲基鸟嘌呤、N6-甲基腺嘌呤、O4-甲基胸腺嘧啶、5,6-二氢胸腺嘧啶、5,6-二氢尿嘧啶、4-甲基吲哚、吡唑并[3,4-D]嘧啶(美国专利号6,143,877和6,127,121;WO01/38584)、以及乙烯化腺嘌呤(Fasman(1989)PracticalHandbookofBiochemistryandMolecularBiology,第385-394页,CRCPress,BocaRaton,Fl)。
核碱B可以以天然形式的核酸构型通过嘌呤的N-9例如腺嘌呤-9-基和鸟嘌呤-9-基、或者嘧啶的N-1例如胸腺嘧啶-1-基和胞嘧啶-1-基与1,3-氧硫杂环戊烷相连(Blackburn,G.和Gait,M.编.″DNAandRNAstructure″inNucleicAcidsinChemistryandBiology,第二版,(1996)OxfordUniversityPress,第15-81页)。.
另外,在上述1,3-氧硫杂环戊烷核苷结构中,R是H、C1-C18烷基、被取代的C1-C18烷基、C2-C18链烯基、被取代的C2-C18链烯基、C2-C18链炔基、被取代的C2-C18链炔基、C6-C20芳基、被取代的C6-C20芳基、C2-C20杂环、被取代的C2-C20杂环、膦酸酯、磷酸膦酸酯、二磷酸膦酸酯、磷酸酯、二磷酸酯、三磷酸酯、聚乙烯氧基或前药基团。
恩曲他滨的生理学功能衍生物还包括3TC(拉米夫定,),它是一种被美国批准与商品名为的AZT(GlaxoSmithKline)联合用于治疗HIV-1感染的逆转录酶抑制剂。参见美国专利号5859021;5905082;6177435;5627186;6417191。拉米夫定(美国专利号5587480、5696254、5618820、5756706、5744596、568164、5466806、5151426)具有下面的结构:
譬如为了某些治疗用途,3TC可以是与替诺福韦DF或替诺福韦DF的生理学功能衍生物联合的恩曲他滨的生理学功能衍生物。
应该理解的是,替诺福韦DF和恩曲他滨、及其生理学功能衍生物可以以酮-烯醇互变异构形式存在,因此任意一种上述互变异构形式均落入本发明范围内。通常情况下,在本发明联合物中使用基本上不存在相应对映异构体的替诺福韦DF和恩曲他滨,也就是说存在不超过大约5%w/w的相应对映异构体。
前药
本发明包括替诺福韦和恩曲他滨的任何前药。替诺福韦的示例性前药是替诺福韦地索普西富马酸盐(TDF,)。对于磷酸而言,已经描述了很多结构多样化的前药(Freeman和Ross,ProgressinMedicinalChemistry34:112-147(1997)。常用的一类前药是酰氧基烷基酯,它最初是用于羧酸的前药策略中,后来被Farquhar等人应用到磷酸酯和膦酸酯上(1983)J.Pharm.Sci.72:324;以及美国专利号4816570、4968788、5663159和5792756。接下来,酰氧基烷基酯被用于跨细胞膜递送膦酸以提高口服生物利用度。类似的各种酰氧基烷基酯策略、烷氧基羰氧基烷基酯也可以用作本发明联合物中的化合物上的前药基团以提高生物利用度。含磷基团的芳基酯,特别是苯基酯被报道可以提高口服生物利用度(DeLambert等人(1994)J.Med.Chem.37:498)。已经描述过含有位于磷酸酯邻位的羧酸酯的苯基酯(KhamneiandTorrence,(1996)J.Med.Chem.39:4109-4115)。据报道,苄基酯生成母体膦酸。在某些情形中,位于邻位或对位的取代基可以加快水解。具有酰化苯酚或烷基化苯酚的苄基类似物可以通过酶作用生成酚类化合物,例如酯酶、氧化酶等,酚类化合物接着在苄型C-O键上发生裂解,生成膦酸和醌甲基化物中间体。这类前药的实例描述在Mitchell等人(1992)J.Chem.Soc.PerkinTrans.I2345;Brook等人WO91/19721中。还描述了与苄型亚甲基相连的含有羧酸酯基团的其它苄型前药(Glazier等人WO91/19721)。含硫前药被报道可用于细胞内递送膦酸酯药物。这类前药酯含有乙硫基,其中硫醇基被酰基酯化或者与另一个硫醇基结合形成二硫化物。将二硫化物脱酯化或还原生成游离的含硫中间体,其随后断开得到磷酸和环硫化物(Puech等人(1993)AntiviralRes.,22:155-174;Benzaria等人(1996)J.Med.Chem.39:4958)。环状膦酸酯也被报道可以用作含磷化合物的前药。
根据本发明的前药独立地选自:(1)替诺福韦或恩曲他滨的单-、二-、三-磷酸酯,或者经患者人服用后能够提供(直接或间接地)所述单-、二、或三磷酸酯的任意其它化合物;(2)羧酸酯;(3)磺酸酯,例如烷基或芳烷基磺酸酯(如甲磺酰基);(4)氨基酸酯(例如丙氨酸、L-缬氨酰基或L-异亮氨酰基);(5)膦酸酯;以及(6)膦酰胺酯。
酯基团(1)-(6)可以被下述基团取代:直链或支链C1-C18烷基(如甲基、正丙基、叔丁基、或正丁基);C3-C12环烷基;烷氧基烷基(如甲氧基甲基);芳烷基(如苄基);芳氧基烷基(如苯氧基甲基);C5-C20芳基(如任选被例如卤素、C1-C4烷基、C1-C4烷氧基或氨基取代的苯基;酰氧基甲基酯-CH2OC(=O)R9(如POM)或酰氧基甲基碳酸酯-CH2OC(=O)OR9(如POC),其中R9是C1-C6烷基、被取代的C1-C6烷基、C6-C20芳基或者被取代的C6-C20芳基。例如,酯基团可以是:-CH2OC(=O)C(CH3)3,-CH2OC(=O)OC(CH3)3或-CH2OC(=O)OCH(CH3)2。
存在于这类酯中的示例性芳基包括苯基或被取代的苯基。很多磷酸酯前药基团描述在美国专利号6312662;Jones等人(1995)AntiviralResearch27:1-17;Kucera等人(1990)AIDSRes.Hum.RetroViruses6:491-50;Piantadosi等人(1991)J.Med.Chem.34:1408-14;Hosteller等人(1992)Antimicrob.AgentsChemother.36:2025-29;Hostetler等人(1990)J.Biol.Chem.265:611127;以及Siddiqui等人(1999)J.Med.Chem.42:4122-28中。
可药用前药是指通过酶作用或普通酸或碱溶剂分解作用在寄主中代谢例如水解或氧化形成活性成分的化合物。本发明联合物中活性成分的典型示例性在该活性化合物的官能基团上具有生物学不稳定的保护基。前药包括可被氧化、还原、氨化、脱氨化、酯化、脱酯化、烷基化、脱烷基化、酰化、脱酰化、磷酸化、脱磷酸化的化合物,或者是可发生涉及形成或断开前药化学键的其它官能基团变化或转化的化合物。
药物制剂的化学稳定性
活性成分在药物制剂中的稳定性包括尽量减少杂质的生产和保证足够的贮藏寿命。本发明制剂中的活性成分即替诺福韦地索普西富马酸盐和恩曲他滨具有相对较低的pKa值,这表明可能引起活性成分发生酸水解。Pka为2.65的恩曲他滨(EmtrivaProductInsert,GileadSciences,Inc.2003,可由gilead.Com得到)经5-氟胞嘧啶核碱水解脱氨基作用后形成5-氟尿苷核碱。PKa为3.75的替诺福韦地索普西富马酸盐(YuanL.等人″DegradationKineticsofOxycarbonyloxymethylProdrugsofPhosphonatesinSolution″,PharmaceuticalResearch(2001)Vol.18,No.2,234-237)也容易使腺嘌呤核碱的外环胺水解脱氨基化,同时使一个或两个POC酯基团水解(美国专利号5922695)。理想的是,将替诺福韦地索普西富马酸盐和恩曲他滨、及其生理学功能衍生物配制成含有最低量的杂质和具有足够的稳定性的治疗联合物。
本发明的联合物提供了对下述组分的酸降解表现为化学稳定的联合药物剂型:(1)第一组分(例如替诺福韦地索普西富马酸盐、及其生理学功能衍生物);(2)第二组分(例如恩曲他滨、及其生理学功能衍生物);和(3)任选的具有抗病毒活性的第三组分。所述第三组分包括抗HIV剂,包括:蛋白酶抑制剂(PI)、核苷逆转录酶抑制剂(NRTI)、非核苷逆转录酶抑制剂(NNRTI)和整合酶抑制剂。与第一和第二组分联合施用的示例性第三活性成分如表A所示。第一和第二组分定义在前面部分标题为:联合物中的活性成分中。
盐
本发明组合物中的任何一种化合物还包括其生理学上可接受的盐。替诺福韦DF、恩曲他滨及其生理学功能衍生物的生理学上可接受的盐包括由适宜碱例如碱金属(如钠)、碱土金属(如镁)、铵和NX4 +(其中X是C1-C4烷基),或者有机酸例如富马酸、乙酸、琥珀酸衍生得到的盐。氢原子或氨基的生理学上可接受的盐包括有机羧酸例如乙酸、苯甲酸、乳酸、富马酸、酒石酸、马来酸、丙二酸、苹果酸、羟乙基磺酸、乳二酸和琥珀酸;有机磺酸例如甲磺酸、乙磺酸、苯磺酸和对甲苯磺酸;以及无机酸例如盐酸、硫酸、磷酸和氨基磺酸的盐。
羟基化合物的生理学上可接受的盐包括与适宜阳离子例如Na+和NX4 +(其中X独立地选自H或C1-C4烷基)联合的所述化合物的阴离子。
对于治疗应用,本发明联合物中的活性成分的盐应该是生理学上可接受的,即它们应该是由生理学上可接受酸或碱衍生得到的。当然,不是生理学生可接受的酸或碱的盐也具有其应用,例如用于制备和纯化生理学上可接受的化合物。所有盐(不论其是否是由生理学上可接受酸或碱衍生得到的)均落入本发明范围之内。
制剂的给药
尽管联合物中的各种活性成分可以单独作为单一治疗剂分开给药,但是优选的是将其作为药物联合制剂的形式给药。可以同时或连续施用两组分或三组分的联合物。当连续施用时,该联合物可以分成一次、两次或三次给药。
优选地,两组分或三组分联合物以单一的药物剂型给药。更优选地,两组分联合物以单一的口服剂型给药,而三组分联合物以两种相同的口服剂型给药。其实例包括替诺福韦地索普西富马酸盐和恩曲他滨的单一片剂、或者替诺福韦地索普西富马酸盐、恩曲他滨和依法韦仑的双片剂。
应该理解的是,联合物中的化合物可以按照下述方式给药:(1)联合联合制剂中的各化合物同时给药或者(2)交替给药,即将化合物以单独的药物制剂形式依次、连续、平行或同时进行递送。在交替疗法中,施用第二、以及任选的第三活性成分的延迟时间应当不至于使联合这些活性成分所具有的协同治疗有益效果受到损失。借助于给药方法(1)或(2),理想的情况是,所述联合物的给药应当使每种活性成分获得血浆浓度峰值。通过每天一次一片的给药方案服用联合制剂可能适用于某些HIV阳性患者。联合物中的活性成分所具有的有效血浆浓度峰值应该落入大约为0.001-100μM的范围内。对于特定患者而言,通过针对其个体的制剂和给药方案可以获得最佳的血浆浓度峰值。应该理解的是,同时或连续给药的替诺福韦DF和恩曲他滨或其中之一的生理学功能衍生物可以单独、或以多单元形式或者任意一种联合形式给药。总的来说,在交替疗法(2)中,各化合物的有效剂量是连续进行给药的,而在联合制剂疗法(1)中,两者或更多种化合物的有效剂量是一起进行给药的。
联合物制剂
当联合物中的各单独组分被分开给药时,通常它们是以各自的药物制剂形式存在的。除非另有限定,下文中的制剂均是指含有该联合物或其组分化合物的制剂。应该理解的是,将本发明的联合物通过患者用单层药包、或者各种制剂的患者用药包的方式(其中含有提醒患者正确使用本发明的药品说明书)给药构成了本发明理想的附加特征。本发明还包括一种双层药包,它含有合并形式的供分开服用的替诺福韦地索普西富马酸盐和恩曲他滨、或者它们中的一种或两种的生理学功能衍生物的制剂。
本发明的联合疗法包括:(1)替诺福韦DF和恩曲他滨的联合物或者(2)含有它们中的一种或两种的生理学功能衍生物的联合物。
可以将该联合物配制成含有固定含量的各种活性药物成分的单元剂量制剂以定期例如每天一次或多次施用这种活性成分。
根据本发明的药物制剂含有根据本发明的联合物和一种或更多种可药用载体或赋型剂以及任选的其它治疗剂。含有活性成分的药物制剂可以为适合希望给药方法的任意形式。当用于口服给药时,可以制备成例如片剂、药片、锭剂、水或油混悬剂、可分散散剂或颗粒剂、乳剂、硬或软胶囊剂、糖浆剂或酏剂(Remington′sPharmaceutical Sciences(MackPublishingCo.,Easton,PA)。希望用于口服给药的组合物可以根据本领域已知的任意一种药物组合物制备方法制备,为了获得可口的制剂,这类组合物可以含有一种或更多种辅剂,包括抗氧化剂、甜味剂、芳香剂、着色剂和防腐剂。含有与适合用于制备片剂的无毒性可药用赋型剂相混和的活性成分的片剂是令人满意的。这些赋型剂可以是,例如惰性稀释剂如碳酸钙或碳酸钠、乳糖、乳糖单水合物、交联羧甲基纤维素钠、聚维酮、磷酸钙或磷酸钠;粒化和崩解剂如玉米淀粉、或藻酸;粘合剂如纤维素、微晶纤维素、淀粉、明胶或阿拉伯树胶;以及润滑剂如硬脂酸镁、硬脂酸或滑石。片剂可以不包衣,也可以按照已知方法包衣,包括微囊化以延迟在胃肠道中的崩解和吸收,从而在较长时间内提供持续释放作用。例如可以使用时间延迟材料如单独或者与蜡混合的甘油单硬脂酸酯或甘油二硬脂酸酯。
用于口服给药的制剂还可以被制成将活性成分与惰性固体稀释剂例如预凝胶化淀粉、磷酸钙或高岭土混和的硬明胶胶囊,或者制成其中活性成分与水或油性基质如花生油、液体石蜡或橄榄油混和的软明胶胶囊剂。
本发明的水混悬剂含有与适合用于制造水混悬剂的赋型剂混合的活性物质。这类赋型剂包括助悬剂如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶,分散或润湿剂如天然形式的磷脂(如卵磷脂)、环氧烷烃与脂肪酸的缩合产物(如聚氧乙烯硬脂酸酯)、环氧乙烷和长链脂肪醇的缩合产物(如十七亚乙基氧十六烷醇)、环氧乙烷和由脂肪酸和己糖醇酸酐部分酯化得到的酯的缩合产物(如聚氧乙烯山梨糖醇酐单油酸酯)。水混悬剂还可以含有一种或更多种防腐剂例如乙基或正丙基对羟基苯甲酸酯、一种或更多种着色剂、一种或更多种芳香剂以及一种或更多种甜味剂如蔗糖、sucralose或糖精。
配制油混悬剂可以通过将活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油、或者矿物油如液体石蜡中。口服混悬剂可以含有增稠剂,例如蜂蜡、硬石蜡和十六烷醇。为了获得可口的口服制剂,可以加入上述的甜味剂和芳香剂。这些组合物可以通过加入抗氧化剂例如抗坏血酸、BHT等进行贮藏。
通过向适合用于制备水混悬剂的本发明可分散散剂和颗粒剂中加入水,使得活性成分与分散或润湿剂、助悬剂以及一种或更多种防腐剂形成混合物。适宜的分散或润湿剂和助悬剂在前面已被例举。还可以存在其它赋型剂,例如甜味剂、芳香剂和着色剂。
本发明的药物组合物还可以为油或水乳剂或者脂质体制剂形式。油相可以是植物油例如橄榄油或花生油,矿物油例如液体石蜡,或者它们的混合物。适宜的乳化剂包括天然形式的树胶例如阿拉伯树胶和黄蓍胶、天然形式的磷脂例如大豆卵磷脂、由脂肪酸和己糖醇酸酐衍生得到酯或部分酯例如脱水山梨糖醇单油酸酯、以及这些部分酯与环氧乙烷的缩合产物例如聚氧乙烯山梨糖醇酐单油酸酯。乳剂还可以含有甜味和芳香剂。糖浆剂和酏剂还可以用甜味剂例如甘油、山梨糖醇或蔗糖配制。这类制剂还可以含有缓和剂、防腐剂、芳香剂或着色剂。
本发明的药物组合物可以为灭菌可注射制剂的形式,例如灭菌可注射水或油性混悬剂。所述混悬剂可以根据已知方法,使用上面已经提及过的适宜分散或润湿剂和助悬剂进行配制。灭菌可注射制剂还可以是在无毒性肠胃外可接受稀释剂或溶剂中的灭菌可注射溶液剂或混悬剂,例如在1,3-丁烷-二醇中的溶液剂,或者制备成冻干粉末的形式。在可接受的媒质中,可使用的溶剂是水、Ringer′s溶液和等渗氯化钠溶液。另外,灭菌固定油通常也可用作溶剂或悬浮媒介。为了实现上述目的,可以使用任意一种温和的固定油,包括合成甘油单酯或二酯。此外,类似地,脂肪酸例如油酸也可用于制备注射剂。
本发明的药物组合物可以在肠胃外注射,例如静脉内、腹膜内、鞘内、心室内、胸骨内、颅内、肌内或皮下注射,或者它们也可以通过输注方法给药。它们最好是以含有其它物质的灭菌水溶液剂形式使用,其它物质例如使得溶液与血液等渗的足够的盐或葡萄糖。如果需要的话,可以将水溶液剂适当缓冲(优选其pH为3-9)。适宜的非肠道制剂在灭菌条件下的制备可以方便地通过本领域技术人员熟知的标准药学技术完成。
本发明的药物组合物也可以通过鼻内或吸入给药,以及还可以方便地以干粉吸入剂或气雾剂喷雾形式从加压容器或雾化器中借助于适当的推进剂进行递送,推进剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氢氟烷烃例如1,1,1,2-四氟乙烷(HFC134a)、二氧化碳或其它适宜气体。在加压气雾剂的情形中,通过提供计量量的递送阀门来确定剂量单元。加压容器或雾化器可以含有例如利用乙醇和推进剂的混合物作为溶剂的本发明组合物的溶液剂或混悬剂,它还可以含有润滑剂例如脱水山梨糖醇三油酸酯。可以将用于吸入器或吹入器中的胶囊剂和药筒(例如由明胶制备的)配制成含有式(I)化合物的粉末混合物和适宜的粉末基质例如蔗糖或淀粉的形式。优选调节气雾剂或干粉制剂使得向患者给药时各计量剂量或“一次喷雾”含有20μg至20mg组合物。气雾剂总的日剂量可以为20μg至20mg,在一天内它们可以以单剂量给药、或者更通常的是以分剂量给药。
活性成分与载体材料合并得到单剂型,其用量取决于接受治疗的宿主以及给药的具体模型。例如,准备供人口服的随时间释放制剂(time-release)可以含有大约1-1000mg活性物质化合物以及适当和常规用量的载体材料,其用量可以占总组成的大约5至大约95%(重量∶重量)。可以制备得到在服用时容易对含量进行检测的药物组合物。例如,为了实现以大约30mL/小时的速度输注合适的体积,准备供静脉内输注的水溶液剂可以含有大约3-500μg活性成分/毫升溶液剂。如上所述,适合口服给药的本发明制剂可以被制备成各自含有预定含量的活性成分的离散单位形式例如胶囊剂、扁囊剂或片剂;散剂或颗粒剂;在水或非水液体中的溶液剂或混悬剂;或者水包油乳剂或油包水液体乳剂。活性成分还可以以一次性推注、药糖剂或糊剂的形式给药。
本发明的联合物可以方便地制成单位剂型的药物制剂。常规单位剂型制剂各自含有含量为1mg至1g(例如但并不仅仅限于10mg至300mg)的活性成分。在宽泛的比例下均可以获得替诺福韦DF与恩曲他滨联合的协同效果,例如为1∶50至50∶1(替诺福韦DF∶恩曲他滨)。在一实施方案中,该比例为大约1∶10至10∶1。在另一实施方案中,联合配制的联合物剂型(例如丸剂、片剂、小胶囊或胶囊剂)中替诺福韦与恩曲他滨的重量/重量比例大约为1,也就是说,含有大致相当用量的替诺福韦DF和恩曲他滨。在其它示例性联合制剂中,替诺福韦可以多于或少于FTC。例如,300mg替诺福韦DF和200mg恩曲他滨可以以1.5∶1(替诺福韦DF∶恩曲他滨)的比例联合配制。在一实施方案中,各化合物可以以单独使用时显示抗病毒活性的用量用于联合物中。示例性制剂A、B、C、D、E和F(实施例)具有12∶1至1∶1的比例(替诺福韦DF∶恩曲他滨)。示例性制剂A、B、C、D、E和F所使用的替诺福韦DF和恩曲他滨的用量为25mg至300mg。所述联合物中各化合物的其它比例和用量也落入本发明范围之内。
单位剂型还可以进一步含有替诺福韦DF和恩曲他滨、或其中任意一种的生理学功能衍生物、以及可药用载体。
本领域技术人员应该理解,用于治疗中的本发明联合物所需的各活性成分的用量取决于各种因素,包括接受治疗的症状性质、患者年龄和情况,其最终由主治医生或卫生保健从业人员决定。需要考虑的因素包括给药方式和制剂性质、动物体重、年龄和大致情况以及接受治疗的疾病性质和严重程度。例如,在恩曲他滨的I/II期单疗法研究中,患者所服用的剂量为25mg至200mg,每天两次,持续两周。在高于或等于200mg的各给药方案中,观察到对病毒具有98%(1.75log10)或更高的抑制效果。每天一次、剂量为200mg的恩曲他滨将病毒负荷平均降低了99%(1.92log10)。300mg口服片剂形式的(替诺福韦DF)已被FDA批准用于治疗和预防HIV感染。200mg口服片剂形式的EmtrivaTM(恩曲他滨)已被FDA批准用于治疗HIV。
还可以将单位剂型中的任意两种活性成分与第三活性成分联合以同时或连续给药。所述三组分联合物可以同时或连续给药。当连续进行给药时,所述联合物可以分成两次或三次给药。第三活性成分具有抗HIV活性,其包括蛋白酶抑制剂(PI)、核苷逆转录酶抑制剂(NRTI)、非核苷逆转录酶抑制剂(NNRTI)以及整合酶抑制剂。可与替诺福韦DF、恩曲他滨、及其生理学功能衍生物联合用于治疗的示例性第三活性成分如表A所示。
表A
5,6-二氢-5-氮杂胞苷
5-氮杂2′脱氧胞苷
5-氮杂胞苷
5-基-碳环2′-脱氧鸟苷(BMS200,475)
9(阿拉伯呋喃糖基)鸟嘌呤;9-(2′脱氧呋喃核糖基)鸟嘌呤
9-(2′-脱氧2′氟呋喃核糖基)-2,6-二氨基嘌呤
9-(2′-脱氧2′氟呋喃核糖基)鸟嘌呤
9-(2′-脱氧呋喃核糖基)-2,6-二氨基嘌呤
9-(阿拉伯呋喃糖基)-2,6-二氨基嘌呤
阿巴卡维,
阿昔洛韦,ACV;9-(2-羟乙氧基甲基)鸟嘌呤
阿德福韦dipivoxil,
amdoxivir,DAPD
安普那韦(Amprenavir),
araA;9-β-D-阿拉伯呋喃糖基腺嘌呤(阿糖腺苷)
atazanivir硫酸盐
AZT;3′-叠氮-2′,3′-二脱氧胸苷,齐多夫定,
BHCG;(.+-.)-(1a,2b,3a)-9-[2,3-双(羟甲基)环丁基]鸟嘌呤
BMS200,475;5-基-碳环2′-脱氧鸟苷
布昔洛韦;(R)9-(3,4-二羟丁基)鸟嘌呤
BvaraU;1-β-D-阿拉伯呋喃糖基-E-5-(2-溴乙烯基)尿嘧啶(索立夫定)
CalanolideA
卡泊韦林(Capravirine)
CDG;碳环2′-脱氧鸟苷
西多福韦,HPMPC;(S)-9-(3-羟基-2-膦酰基甲氧丙基)胞嘧啶
Clevudine,L-FMAU;2′-氟-5-甲基-β-L-阿拉伯呋喃糖基尿嘧啶(拉米夫定/齐多夫定)
Cytallene;[1-(4′-羟基-1,2-丁二烯基)胞嘧啶]
d4C;3′-脱氧-2′,3′-二脱氢胞苷
DAPD;(-)-β-D-2,6-二氨基嘌呤二氧戊环
ddA;2′,3′-二脱氧腺苷
ddAPR;2,6-二氨基嘌呤-2′,3′-二脱氧核糖苷
ddC;2′,3′-二脱氧胞苷(扎西他滨)
ddI;2′,3′-二脱氧肌苷,去羟肌苷,(EC)
地拉韦啶,
去羟肌苷,ddI,2′,3′-二脱氧肌苷
DXG;二氧戊环鸟苷
E-5-(2-溴乙烯基)-2′-脱氧尿苷
依法韦仑,
Enfuvirtide,
F-ara-A;氟阿拉伯糖基腺苷(氟达拉滨)
FDOC;(-)-β-D-5-氟-1-[2-(羟甲基)-1,3-二氧戊环]胞嘧啶
FEAU;2′-脱氧-2′-氟-1-β-D-阿拉伯呋喃糖基-5-乙基尿嘧啶
FIAC;1-(2-脱氧-2-氟-β-D-阿拉伯呋喃糖基)-5-碘胞嘧啶
FIAU;1-(2-脱氧-2-氟-(3-D-阿拉伯呋喃糖基)-5-碘尿苷
FLG;2′,3′-二脱氧-3′-氟鸟苷
FLT;3′-脱氧-3′-氟胸苷
氟达拉滨;F-ara-A;氟阿拉伯糖基腺苷
FMAU;2′-氟-5-甲基-β-L-阿拉伯呋喃糖基尿嘧啶
FMdC
膦甲酸;膦甲酸,PFA
FPMPA;9-(3-氟-2-膦酰基甲氧丙基)腺嘌呤
更昔洛韦,GCV;9-(1,3-二羟基-2-丙氧甲基)鸟嘌呤
GS-7340;9-[R-2-[[(S)-[[(S)-1-(异丙氧羰基)乙基]氨基]-苯氧基氧膦基]甲氧基]丙基]腺嘌呤
HPMPA;(S)-9-(3-羟基-2-膦酰基甲氧丙基)腺嘌呤
HPMPC;(S)-9-(3-羟基-2-膦酰基甲氧丙基)胞嘧啶(西多福韦)
羟基脲,
茚地那韦,
(洛匹那韦/利托那韦)
拉米夫定,3TC,EpivirTM;(2R,5S,顺式)-4-氨基-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮
L-d4C;L-3′-脱氧-2′,3′-二脱氢胞苷
L-ddC;L-2′,3′-二脱氧胞苷
L-Fd4C;L-3′-脱氧-2′,3′-二脱氢-5-氟胞苷
L-FddC;L-2′,3′-二脱氧-5-氟胞苷
洛匹那韦
那非那韦,
奈韦拉平,
核苷类似物A(OxetanocinA);9-(2-脱氧-2-羟甲基-β-D-赤式-oxetanosyl)腺嘌呤
核苷类似物G(OxetanocinG);9-(2-脱氧-2-羟甲基-β-D-赤式-oxetanosyl)鸟嘌呤
喷昔洛韦
PMEDAP;9-(2-膦酰基甲氧乙基)-2,6-二氨基嘌呤
PMPA,替诺福韦;(R)-9-(2-膦酰基甲氧丙基)腺嘌呤
PPA;膦酰基乙酸
利巴韦林;1-β-D-呋喃核糖基-1,2,4-三唑-3-甲酰胺
利托那韦,
沙奎那韦,
索立夫定,BvaraU;1-β-D-阿拉伯呋喃糖基-E-5-(2-溴乙烯基)尿嘧啶
司他夫定,d4T,2′,3′-二脱氢-3′-脱氧胸苷
三氟胸苷,TFT;三氟胸苷
(阿巴卡维硫酸盐/拉米夫定/齐多夫定)
阿糖腺苷,araA;9-β-D-阿拉伯呋喃糖基腺嘌呤
扎西他滨,ddC;2′,3′-二脱氧胞苷
齐多夫定,AZT,3′-叠氮基-2′,3′-二脱氧胸苷
Zonavir;5-丙炔基-1-阿拉伯糖基尿嘧啶
本发明另一方面涉及一种三组分联合物,它含有替诺福韦DF、FTC、以及具有下述结构的9-[(R)-2-[[(S)-[[(S)-1-(异丙氧羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤(在本文也被称作GS-7340):
GS-7340是替诺福韦的一种前药,同时也是申请于2001年7月20日的未决待审美国申请序列号09/909,560、和Becker等人的WO02/08241的主题。
例如,三组分单位剂量可以含有1mg至1000mg替诺福韦地索普西富马酸盐、1mg至1000mg恩曲他滨、和1mg至1000mg第三活性成分。作为本发明进一步的特征,单位剂型还可以进一步含有替诺福韦DF、恩曲他滨、第三活性成分、或者这三种活性成分的生理学功能衍生物、以及可药用载体。
本发明的联合物能够使患者无须接受多剂量的给药方案,减轻患者需要记住和依从复杂的每日给药时间和给药方案的负担。通过将替诺福韦地索普西富马酸盐和恩曲他滨合并进入单一的剂型中,可以以每天服用单剂量或者两次或更多次分剂量的形式完成理想的每日给药方案。联合配制的替诺福韦DF和恩曲他滨的联合物可以作为单丸剂每天服用一次。
本发明另一方面涉及一种患者用药包,它含有至少一种活性成分:替诺福韦地索普西富马酸盐、恩曲他滨、或者该联合物中的任意一种的生理学功能衍生物以及含有关于本发明联合物使用方法的说明的信息包装和产品插页。
活性成分在药物散剂和颗粒剂中的分聚(segregation)现象是公认的技术难题,它可能导致活性成分在最终的剂型中分散不均匀。引起分聚现象的某些主要因素归因于颗粒大小、形状和密度。在配制含有具不同密度和不同粒径的多种活性成分的单一均匀片剂时,分聚现象尤其棘手。助流剂通过减少微粒之间的摩擦,是传统上用来改善颗粒剂和散剂流动特性的物质。参见Lieberman,Lachman,&Schwartz,PharmaceuticalDosageForms:Tablets,第1卷,第177-178页(1989),在此将其引入作为参考。通常在片剂压制之前,向药物组合物中加入助流剂以促进粒状物质在片剂制片机死穴中的流动。助流剂包括:胶体二氧化硅、无石棉滑石、硅酸铝钠、硅酸钙、粉末纤维素、微晶纤维素、玉米淀粉、苯甲酸钠、碳酸钙、碳酸镁、金属硬脂酸盐、硬脂酸钙、硬脂酸镁、硬脂酸锌、stearowetC、淀粉、淀粉1500、十二烷基硫酸镁以及氧化镁。示例性片剂制剂A中含有胶体二氧化硅(实施例)。助流剂可被用于提高和改善抗HIV药物制剂中的组分混合均匀度(美国专利号6113920)。为了在片剂压片之前的加工过程中使各活性成分获得并保持均匀性,本发明的新组合物中可以含有助流剂。
本发明提供了将各种活性成分即替诺福韦DF和恩曲他滨、或其生理学功能衍生物合并得足够均匀的药物制剂,以及使用这种药物制剂的方法。本发明目的之一在于利用助流剂减少药物组合物中的各种活性成分在压片前的物料加工过程中发生的分聚现象。本发明另一目的在于提供一种药物制剂,它合并有各种活性成分即替诺福韦DF和恩曲他滨、或其生理学功能衍生物以及可药用载体,得到其特征在于具有药学上可接受的均匀度的混合物。
制剂包括那些适合用于口服、直肠、鼻内、局部(包括经皮、颊和舌下)、阴道或非肠道(包括皮下、肌内、静脉内和皮内)给药的制剂。这些制剂可以方便地按照药学领域熟知的任意方法制成单位剂型。这些方法代表了本发明的另一特征,包括将各种活性成分与由一种或更多种助剂构成的载体混和,然后维持其化学稳定性。通常,通过将这些活性成分与液体载体或细分固体载体或者两者进行均匀且致密的混和,然后如果需要的话使产品成型,这样就制备得到了所述制剂。
可以将适合用于口服给药的本发明制剂制成下面的离散单位形式:各自含有预定含量的活性成分的胶囊、小胶囊、扁囊剂或片剂;散剂或颗粒剂;在水或非水液体中的溶液剂或混悬剂;或者水包油液体乳剂或油包水液体乳剂。这些活性成分还可以为大药丸、药糖剂或糊剂形式。
片剂可以通过任选使用一种或更多种助剂进行压制或模制得到。压制片剂可以通过将为自由流动(free-flowing)形式的各种活性成分(例如粉末或颗粒)任选与粘合剂(例如聚维酮、明胶、羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如淀粉羟乙酸钠、交联聚维酮、交联羧甲基纤维素钠)、表面活性剂或分散剂进行混和在适宜的机器中压制得到。模制片剂可以通过将用惰性液体稀释剂润湿的粉末化合物在适宜的机器中成型得到。这些片剂可以任选被包衣或刻痕,以及为了让其中的活性成分缓慢或持续释出,还可以使用例如各种比例的纤维素醚衍生物(如羟丙基甲基纤维素)或甲基丙烯酸酯衍生物进行制剂以获得所需释出曲线。为了实现在肠部分而不是在胃部释出,可以任选给片剂提供肠包衣。
适合在口中局部给药的制剂包括在芳香基质(通常是蔗糖和阿拉伯树胶或黄蓍胶)含有活性成分的锭剂;在惰性基质例如明胶和甘油、或蔗糖和阿拉伯树胶中含有活性成分的锭剂;以及在适宜液体载体中含有活性成分的漱口水。可以将直肠给药制剂利用含有例如可可油或水杨酸酯的适宜基质制成栓剂。局部给药还可以通过透皮电离子透入装置进行给药。
适合阴道给药的制剂可以被制成阴道栓剂、棉塞、乳剂、凝胶剂、糊剂、泡沫剂或喷雾剂,它们除了含有这些活性成分之外,还含有本领域已知的适宜载体。
用于预防或治疗用途的适合阴茎给药的制剂可以被制成避孕套、乳剂、凝胶剂、糊剂、泡沫剂或喷雾剂,它们除了含有这些活性成分之外,还含有本领域已知的适宜载体。
其中载体为固体的适合直肠给药的药物制剂最优选被制成单位剂量的栓剂。适宜的载体包括可可油和本领域常用的其它材料。通过将活性联合物与软化或融化的(各种)载体混合,然后在模具中冷却并成型,这样可以方便地形成栓剂。
适合非肠道给药的制剂包括水和非水等渗灭菌注射溶液剂,它可以含有抗氧化剂、缓冲剂、抑菌剂以及控制制剂与服药患者血液等渗的溶质;和可以含有助悬剂和增稠剂的水和非水灭菌混悬剂;以及将化合物指定作用于某些血液组分或者一种或更多种器官的脂质体或其它微粒系统。这些制剂可以呈现在含有单位剂量或多剂量的密封容器例如安瓿和小瓶中,同时还可以贮存于冻干条件下,在使用之前只需要向其中加入灭菌液体载体例如注射用水即可。临时注射溶液剂和混悬剂可以由在上面详细描述过的灭菌散剂、颗粒剂和片剂制备得到。
示例性单位剂量制剂有这样的制剂,它们含有日剂量或每日分剂量或者其中部分剂量的上述活性成分。应该理解的是,除了上面所特别提及的成分之外,本发明制剂还可以含有本领域常用的其它成分,这取决于所考虑制剂的类型,例如适合口服给药的制剂可以含有其它成分例如甜味剂、增稠剂和芳香剂。
本发明联合物中的各化合物可以按照本领域技术人员已知的常规方法获得。替诺福韦地索普西富马酸盐可以按照描述在例如美国专利号5977089中的方法制备得到,制备FTC的方法描述在WO92/14743中,在此将其引入作为参考。
组合物用途
可以将本发明的组合物按照上面所描述的既安全又有效的用量向人或其它哺乳动物施用。所述既安全又有效的用量取决于接受治疗的哺乳动物的类型和大小以及治疗所希望达到的结果。本领域技术人员所知晓的任意一种用于包装片剂、小胶囊或适合口服给药的其它固体剂型的方法,只要这种方法不会使本发明中的各种组分发生降解,都适合在包装中使用。联合物可以包装在玻璃或塑料瓶中。片剂、小胶囊或适合口服给药的其它固体剂型可以被包装并容纳在各种包装材料中,同时任选含有干燥剂例如硅胶。包装可以为单位剂量的泡罩包装形式。例如一个包装里可以含有一种替诺福韦DF的泡罩板以及恩曲他滨丸剂、片剂、小胶囊或胶囊剂的另一种泡罩板。患者可以从两个泡罩板各服用一个剂量例如丸剂。或者,包装品也可以含有由替诺福韦DF和恩曲他滨联合配制成的单一丸剂、片剂、小胶囊或胶囊剂联合物的泡罩板。对于其它的联合物以及其包装品,本发明的联合物包括替诺福韦DF和FTC的生理学功能衍生物。
包装材料还可以具有印刷在材料上面的有关药物组合物的标签和信息。另外,制成品可以含有涉及产品有关信息的小册子、报告、注意事项、手册或插页。这种形式的药品信息在制药工业领域被称作“包装插页”。包装插页可以附在药物制品上或包括在药物制品中。包装插页以及任意一种制品标签提供了有关其中药物组合物的信息。这些信息和标签提供了可被保健从业人员和患者利用的各种形式的信息,它们对这种组合物、其剂型以及监管机构例如美国食品和药物监督管理局所要求的各种其它参数进行了描述。
联合物的测定
根据为测试抗HIV化合物而开发的标准测定方法(例如WO02/068058和美国专利号6475491中描述的测定方法),可以测得本发明的联合物抗HIV的体外活性和灵敏性及其对实验室中所用细胞系例如MT2和外周血管单核细胞(PBMC)中的细胞毒性。通过连续稀释,在具有各种浓度的联合物化合物中测量EC50,从而完成联合物的测定。
制剂实例
下面的实施例进一步描述和解释了落入本发明范围之内的具体实施方案。相关方法和制剂通常可以参见Remington′s PharmaceuticalSciences(MackPublishingCo.,Easton,PA)。所例举的实施例仅仅是出于示例的目的,因此不应将其理解为构成限制,这是因为只要不偏离本发明的主旨和范围,进行各种变型是完全可能的。下面的实施例仅仅是用于解释说明,而并不意味着以任何方式限制本发明的范围。″活性成分″表示替诺福韦地索普西富马酸盐、恩曲他滨、或它们中任意一种的生理学功能衍生物。
片剂
通过将各成分用水溶液进行湿法制粒,然后加入超颗粒(extragrannlar)组分,再加入硬脂酸镁并压制,从而制备得到下面的示例性制剂A、B、C、D、E、和F。
制剂A:
制剂B:
制剂C:
制剂D:
制剂E:
制剂F:
制剂G(对照释放制剂):
通过将各种成分用水溶液进行湿法制粒,然后加入硬脂酸镁并压制制备得到所述制剂G。
药物在大约6-8小时后开始释出,在12小时后完全释出。
胶囊剂
制剂H:
通过将各种成分进行混合,然后填入嵌入式硬凝胶(two-parthardgelatin)或羟丙基甲基纤维素胶囊中,制备得到胶囊剂。
制剂I(对照释放胶囊剂):
通过将各种成分a、b、和c使用挤压机进行挤压,压出物圆形化并干燥,然后再将干燥后的球状物用控释膜(d)包衣,填入嵌入式硬凝胶或羟丙基甲基纤维素胶囊中,从而制备得到下面的对照释出胶囊剂。
制剂J(口服混悬剂):
将活性成分与其它各种成分混合,然后将其作为干燥粉末填充。在使用之前加入纯化水充分混合。
制剂K(栓剂):
将五分之一的WitepsolH15在蒸汽套管锅中于最高温度为45℃下熔融。活性成分通过200微米筛过筛,使用装备有刻纹头的Silverson将其搅拌加入至该熔融基质中,直到获得平滑的分散体。保持混合物处于45℃,向混悬液中加入剩余的WitepsolH15,搅拌以保证均匀混合。将全部混悬液通过250微米的不锈钢筛,连续搅拌,然后冷却至40℃。在38℃至40℃的温度下,将2.02g所得混合物填入适宜的2ml塑料模具中。栓剂冷却至室温。
固定剂量的联合物片剂
使用湿法制粒/流化床干燥法按照常规方法制备得到含有替诺福韦地索普西富马酸盐(TDF)300mg/恩曲他滨200mg的固定剂量的联合物片剂。参见:US5935946;L.Young(编辑).TabletingSpecificationManual第5版,AmericanPharmaceuticalAssociation,Washington,DC,(2001);L.Lachman,H.Lieberman(编辑).PharmaceuticalDosageForms:Tablets(第2卷),MarcelDekkerInc.,NewYork,185-202(1981);J.T.Fell和J.M.Newton,J.Pharm.Pharmacol.20,657-659(1968);美国药典24-NationalFormulary19,″TabletFriability″,第<1216>章,第2148页(2000)。
研究了制粒水含量水平(40%至50%w/w)和湿法混合时间对于最终粉末混合物的物化性质以及其对混合均匀度和可压制性(片剂成型性)的影响。另外,还评价了TDF/恩曲他滨的固定剂量联合物片剂的含量均匀度、测定结果、稳定性以及溶出度性质。
制剂装置
包括下述装置:装备有高压锅和喷雾嘴以加入制粒水的高剪切混合器、流化床干燥器、碾磨机、滚式混合器、旋转式压片机以及片剂除尘器。
制剂方法
将干燥后的碾碎粉末与超颗粒微晶纤维素和交联羧甲基纤维素钠混合,然后再与硬脂酸镁混合。在与硬脂酸镁混合之后除去粉末样本。评价混合物样本的堆密度、筛分试验和可压制性。将混合有硬脂酸镁的该粉末混合物在压片装置上压制成片剂。
物料
下表1列出了TDF/恩曲他滨片剂的定量组成情况。
表1
a实际重量是根据替诺福韦地索普西富马酸盐和恩曲他滨的药物含量因子(DCF)进行调整的。
b在干燥过程中除去的水。
表征装置
通过干燥失重利用加热灯/平衡系统测量水分含量。将粉末样本用装备有隔室的采样器采样以测定粉末的混合均匀度。在搅拌机的几个不同位置取出双份样本。对来自各个位置的一个样本进行混合均匀度分析。
使用声波筛使数克样本通过过滤筛,对最终粉末混合物的粒径进行测定。通过在测试前后分别计算筛和细分收集器之间的重量差异,从而测定得到残留在各筛上以及细分收集器中的最终粉末混合物的量。通过将筛分的分布的重量取对数,计算得到几何平均直径粒径。
通过将量筒用最终的粉末混合物进行填充,然后测量每单位体积的空心量筒和实心量筒之间的重量差异,从而确定堆密度。
使用粉碎机、硬度测试器、装备有打印机的厚度测微计、以及重量天平对片剂的易碎性进行表征。
使用装备有平面、斜面打孔机的旋转式压片机测量最终重量为400mg的片剂的可压制性。粉末混合物使用目标上模冲打孔机进行压制,压力为大约100-250MPa。测量外部校准喷射力,然后对片剂厚度和直径进行校准。
片剂硬度使用硬度测试器进行测量。片剂厚度使用测微计测量,片剂重量使用顶加载天平测量。
湿法制粒
将粉末混合在制粒机中,然后用水制粒。在制粒和湿法混合操作中,将叶轮和切碎器的速度恒定保持在较低水平。加水后,停止叶轮和切碎器转动,打开制粒机口观察制粒的均匀度和纹理。关闭盖子,然后进行湿法混合期。可接受的颗粒分别含有40%w/w和60%w/w的水。
湿法碾磨
为了改善干燥步骤的均匀性,将各湿法粒状物用装备有筛子和叶轮的混合器解聚。将碾碎的湿颗粒在湿法碾磨之后立刻装料入流化床干燥器中。
流化床干燥
将碾碎的湿颗粒用入口空气设定温度为大约70℃、气流为大约100cfm的空气干燥。目标LOD为大约1.0%,范围不超过(NMT)1.5%。总的流化床干燥时间为53-75分钟。对于所有干燥的批次而言,最后的LOD为0.4%至0.7%。所有批次的最后排气温度为47℃至50℃。
干法碾磨
全部干燥颗粒通过多孔板筛碾碎。碾碎机装备有方形叶轮并进入操作。各批次碾磨后手工转移至V混合器中。
混合
各试样使用V混合器进行混合。在三组分制剂的情形中,最初为12kg物料混合,混合后所得到的最终可用于压制的粉末混合物为10.5kg(87.5%)至11.1kg(92.5%)。最终的粉末混合物堆密度为0.48-0.58g/cc,几何平均直径粒径为112-221μm。水百分数和湿法混合时间影响了最后的粉末混合物的粒径和堆密度。
替诺福韦DF和恩曲他滨的粉末混合物所得到的对于替诺福韦DF的平均(n=10)强度值为试样目标强度的100.6%至102.8%,相对标准偏差(RSD)为0.5%至1.7%。相对于恩曲他滨的平均(n=10)强度值为试样目标强度的101.3%至104.1%,相对标准偏差(RSD)为0.6%至1.7%。最后的粉末混合物湿度为0.8%至1.1%LOD。
片剂压制
将最终的混合物用旋转式压片机压片,然后片剂用薄膜包衣。
在装备有1-L槽的制粒机中对三批300gm制剂(表2)进行制粒。颗粒内组分的用量以300g总批次大小为基础。批次1和2的区别在于微晶纤维素的含量分别为30%与20%w/w。批次2和3除了粘合剂不同之外,其余均相同。批次2含有5%w/w的预凝胶化淀粉作为粘合剂,而批次3含有5%w/w的聚维酮作为粘合剂。
表2
成分 | 批次1%w/w | 批次2%w/w | 批次3%w/w |
替诺福韦地索普西富马酸盐 | 30.0 | 30.0 | 30.0 |
恩曲他滨 | 20.0 | 20.0 | 20.0 |
预凝胶化淀粉,NF/EP | 5.0 | 5.0 | N/A |
聚维酮,USP/NF(C-30) | N/A | N/A | 5.0 |
交联羧甲基纤维素钠,NF/EP | 6.0 | 6.0 | 6.0 |
乳糖单水合物,NF/EP | 8.0 | 18.0 | 18.0 |
微晶纤维素,NF/EPa | 30.0 | 20.0 | 20.0 |
硬脂酸镁,NF/EP | 1.0 | 1.0 | 1.0 |
纯化水,USP/EP | a | a | a |
总量 | 100.0 | 100.0 | 100.0 |
a在干燥过程中除去的水。
加水后,停止叶轮和切碎器,打开制粒槽观察颗粒的均匀度和纹理。为了获得相似的制粒均匀度,将批次1、2和3分别用45%、40%和30%w/w的水制粒。关闭盖子进行湿法混合。全部批次进行30秒钟的湿法混合,得到可接受的颗粒。所有取自各试样的湿颗粒通过筛子手工过筛以解聚。所得到的颗粒物在60℃的对流炉中干燥大约20小时,使得LOD<1.0%。再将所有取自各试样的干燥颗粒通过筛子手工过筛。为了将颗粒填入小容量(300mL)的V混合器中,调节最后的混合物批次大小为100g。将来自批次1的一部分即81g所得混合物与15g微晶纤维素、3g交联羧甲基纤维素钠和1g硬脂酸镁混合。将来自批次2和批次3的86g所得颗粒各自与10g微晶纤维素、3g交联羧甲基纤维素钠和1g硬脂酸镁混合。
通过反向HPLC(高效液相色谱法)进行纯度分析。在表2中的三种试样配制前后分别对松散的API(活性药物成分)中与替诺福韦地索普西富马酸盐和恩曲他滨相关的杂质进行量化和测量。所述杂质包括由替诺福韦地索普西富马酸盐和恩曲他滨的外环氨基发生水解的副产物、以及替诺福韦地索普西富马酸盐的地索普西(POC)酯发生水解的副产物。在各批次中,与替诺福韦地索普西富马酸盐和恩曲他滨相关的杂质总量在配制成片剂之后低于1%。
通过可见的外观、水含量、标示强度、纯度和降解产物的含量以及片剂溶出度评价替诺福韦地索普西富马酸盐和恩曲他滨的片剂的物化性质。对包装在与临床和商业密封容器系统相同的密封容器系统中的药物产品进行稳定性研究。在稳定性研究过程中,没有发现变色现象或片剂裂化现象。当薄膜包衣的替诺福韦地索普西富马酸盐和恩曲他滨片剂用硅胶干燥剂在40℃/75%RH(相对湿度)下包装并贮存长达六个月后,其仍然具有令人满意的稳定性。当用硅胶干燥剂在40℃/75%RH下包装并贮存六个月后,发现替诺福韦DF或恩曲他滨的%标示强度没有明显降低(将其定义为≥5%的降解度)。当在40℃/75%RH下用3克干燥剂包装并贮存六个月后,总的降解产物对于替诺福韦DF而言增加了1.5%,对于恩曲他滨而言增加了0.6-0.7%。
本文中引用的所有出版物和专利申请在此均按照相同的程度引入作为参考,就好似每篇单独的出版物或专利申请被具体和单独地引入作为参考一样。
尽管在上面对某些实施方案进行了详细描述,但是本领域普通技术人员应当清楚理解的是,只要不偏离这些教导。可以在权利要求书范围内进行各种变型。所有的这些变型均被包括在本发明范围之内。
本发明实施方案:
A1.一种药物组合物,它联合含有有效量的下式化合物或其生理学功能衍生物:
其中R1和R2独立地选自H、C1-C6烷基、被取代的C1-C6烷基、C6-C20芳基、被取代的C6-C20芳基、C6-C20芳烷基、被取代的C6-C20芳烷基、酰氧基甲基酯-CH2OC(=O)R9和酰氧基甲基碳酸酯-CH2OC(=O)OR9,其中R9是C1-C6烷基、被取代的C1-C6烷基、C6-C20芳基和被取代的C6-C20芳基;
R3选自H、C1-C6烷基、被取代的C1-C6烷基、或CH2OR8,其中R8是C1-C6烷基、C1-C6羟烷基或C1-C6卤烷基;
R4和R5独立地选自H、NH2、NHR或NR2,其中R是C1-C6烷基;以及
R6和R7独立地选自H和C1-C6烷基;
和有效量的下式化合物或其生理学功能衍生物:
其中B选自腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶、胸腺嘧啶、7-脱氮腺嘌呤、7-脱氮鸟嘌呤、7-脱氮-8-氮杂鸟嘌呤、7-脱氮-8-氮杂腺嘌呤、肌苷、水粉蕈素、硝基吡咯、硝基吲哚、2-氨基嘌呤、2-氨基-6-氯嘌呤、2,6-二氨基嘌呤、次黄嘌呤、假尿苷、5-氟胞嘧啶、5-氯胞嘧啶、5-溴胞嘧啶、5-碘胞嘧啶、假胞嘧啶、假异胞嘧啶、5-炔丙基胞嘧啶、异胞嘧啶、异鸟嘌呤、7-脱氮鸟嘌呤、2-硫代嘧啶、6-硫代鸟嘌呤、4-硫代胸腺嘧啶、4-硫代尿嘧啶、O6-甲基鸟嘌呤、N6-甲基腺嘌呤、O4-甲基胸腺嘧啶、5,6-二氢胸腺嘧啶、5,6-二氢尿嘧啶、4-甲基吲哚、以及吡唑并[3,4-D]嘧啶;以及
R选自H、C1-C18烷基、被取代的C1-C18烷基、C2-C18链烯基、被取代的C2-C18链烯基、C2-C18链炔基、被取代的C2-C18链炔基、C6-C20芳基、被取代的C6-C20芳基、C2-C20杂环、被取代的C2-C20杂环、膦酸酯、磷酸膦酸酯、二磷酸膦酸酯、磷酸酯、二磷酸酯、三磷酸酯、聚乙烯氧基;
以及可药用载体。
B2.实施方案A1的组合物,其中在式1中,R1和R2各自独立地选自H、C1-C6烷基、被取代的C1-C6烷基、C6-C20芳基、被取代的C6-C20芳基、C6-C20芳烷基、被取代的C6-C20芳烷基、酰氧基甲基酯-CH2OC(=O)R9和酰氧基甲基碳酸酯-CH2OC(=O)OR9,其中R9是C1-C6烷基、被取代的C1-C6烷基、C6-C20芳基和被取代的C6-C20芳基;以及R3、R4、R5、R6和R7独立地是H或C1-C6烷基。
C3.实施方案A1的组合物,其中在式2中,B是胞嘧啶或5-卤代胞嘧啶。
D4.实施方案A1的联合物,其中在式1中,R1和R2独立地选自H、C1-C6烷基、被取代的C1-C6烷基、C6-C20芳基、被取代的C6-C20芳基、C6-C20芳烷基、被取代的C6-C20芳烷基、酰氧基甲基酯-CH2OC(=O)R9和酰氧基甲基碳酸酯-CH2OC(=O)OR9,其中R9是C1-C6烷基、被取代的C1-C6烷基、C6-C20芳基和被取代的C6-C20芳基;以及R3、R4、R5、R6和R7独立地是H或C1-C6烷基;在式2中,B是胞嘧啶或5-卤代胞嘧啶。
E5.实施方案D4的组合物,其中在式1中,R1和R2独立地选自H、酰氧基甲基酯-CH2OC(=O)R9和酰氧基甲基碳酸酯-CH2OC(=O)OR9,其中R9是C1-C6烷基;以及R3、R4、R5、R6和R7独立地是H或C1-C6烷基;在式2中,B是胞嘧啶或5-卤代胞嘧啶且R是H。
F6.实施方案E5的组合物,其中在式1中,R1和R2独立地选自H和-CH2OC(=O)OCH(CH3)2;R3是CH3;以及R4、R5、R6和R7是H;在式2中,B是5-氟胞嘧啶且R是H。
G7.一种药物组合物,它含有药学有效量的[2-(6-氨基-嘌呤-9-基)-1-甲基-乙氧基甲基]-膦酸二异丙氧基羰基氧基甲基酯富马酸盐(替诺福韦地索普西富马酸盐)或其生理学功能衍生物和药学有效量的(2R,5S,顺式)-4-氨基-5-氟-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮(恩曲他滨)或其生理学功能衍生物;以及可药用载体。
H8.实施方案A1至G7的药物制剂,它进一步还含有选自蛋白酶抑制剂、核苷或核苷酸逆转录酶抑制剂、非核苷逆转录酶抑制剂和整合酶抑制剂的第三种活性成分。
I9.实施方案A1至H8的药物制剂,它为单位剂型。
J10.治疗或预防受感染动物中HIV感染的症状或影响的方法,它包括向所述动物施用实施方案A1至I9的药物组合物。
Claims (18)
1.一种薄膜包衣的包含核心的片剂,其中所述核心由如下成分组成:30%重量/重量的替诺福韦地索普西富马酸盐、20%重量/重量的恩曲他滨、5%重量/重量的预胶化淀粉、6%重量/重量的交联羧甲基纤维素钠、8%重量/重量的乳糖单水合物、30%重量/重量的微晶纤维素和1%重量/重量的硬脂酸镁,其中当用硅胶干燥剂在40℃/75%相对湿度下包装并贮存六个月后,观察到替诺福韦地索普西富马酸盐或恩曲他滨的百分比标示强度降低少于5%。
2.权利要求1的片剂在制备用于治疗动物中HIV感染的症状或影响的药物中的用途。
3.根据权利要求2的用途,其中所述的动物为人。
4.一种薄膜包衣的包含核心的片剂,其中所述核心由如下成分组成:300毫克替诺福韦地索普西富马酸盐、200毫克恩曲他滨、50毫克预胶化淀粉、60毫克交联羧甲基纤维素钠、80毫克乳糖单水合物、300毫克微晶纤维素和10毫克硬脂酸镁,其中当用硅胶干燥剂在40℃/75%相对湿度下包装并贮存六个月后,观察到替诺福韦地索普西富马酸盐或恩曲他滨的百分比标示强度降低少于5%。
5.权利要求4的片剂在制备用于治疗动物中HIV感染的症状或影响的药物中的用途。
6.根据权利要求5的用途,其中所述的动物为人。
7.一种薄膜包衣的包含核心的片剂,其中所述核心由如下成分组成:30%重量/重量的替诺福韦地索普西富马酸盐、20%重量/重量的恩曲他滨、5%重量/重量的预胶化淀粉、6%重量/重量的交联羧甲基纤维素钠、18%重量/重量的乳糖单水合物、20%重量/重量的微晶纤维素和1%重量/重量的硬脂酸镁,其中当用硅胶干燥剂在40℃/75%相对湿度下包装并贮存六个月后,观察到替诺福韦地索普西富马酸盐或恩曲他滨的百分比标示强度降低少于5%。
8.权利要求7的片剂在制备用于治疗动物中HIV感染的症状或影响的药物中的用途。
9.根据权利要求8的用途,其中所述的动物为人。
10.一种薄膜包衣的包含核心的片剂,其中所述核心由如下成分组成:300毫克替诺福韦地索普西富马酸盐、200毫克恩曲他滨、50毫克预胶化淀粉、60毫克交联羧甲基纤维素钠、180毫克乳糖单水合物、200毫克微晶纤维素和10毫克硬脂酸镁,其中当用硅胶干燥剂在40℃/75%相对湿度下包装并贮存六个月后,观察到替诺福韦地索普西富马酸盐或恩曲他滨的百分比标示强度降低少于5%。
11.权利要求10的片剂在制备用于治疗动物中HIV感染的症状或影响的药物中的用途。
12.根据权利要求11的用途,其中所述的动物为人。
13.一种薄膜包衣的包含核心的片剂,其中所述核心由如下成分组成:30%重量/重量的替诺福韦地索普西富马酸盐、20%重量/重量的恩曲他滨、5%重量/重量的聚维酮、6%重量/重量的交联羧甲基纤维素钠、18%重量/重量的乳糖单水合物、20%重量/重量的微晶纤维素和1%重量/重量的硬脂酸镁,其中当用硅胶干燥剂在40℃/75%相对湿度下包装并贮存六个月后,观察到替诺福韦地索普西富马酸盐或恩曲他滨的百分比标示强度降低少于5%。
14.权利要求13的片剂在制备用于治疗动物中HIV感染的症状或影响的药物中的用途。
15.根据权利要求14的用途,其中所述的动物为人。
16.一种薄膜包衣的包含核心的片剂,其中所述核心由如下成分组成:300毫克替诺福韦地索普西富马酸盐、200毫克恩曲他滨、50毫克聚维酮、60毫克交联羧甲基纤维素钠、180毫克乳糖单水合物、200毫克微晶纤维素和10毫克硬脂酸镁,其中当用硅胶干燥剂在40℃/75%相对湿度下包装并贮存六个月后,观察到替诺福韦地索普西富马酸盐或恩曲他滨的百分比标示强度降低少于5%。
17.权利要求16的片剂在制备用于治疗动物中HIV感染的症状或影响的药物中的用途。
18.根据权利要求17的用途,其中所述的动物为人。
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