CN102911166B - 顺-ftc的多晶型物及其它晶型 - Google Patents
顺-ftc的多晶型物及其它晶型 Download PDFInfo
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- CN102911166B CN102911166B CN201210146877.2A CN201210146877A CN102911166B CN 102911166 B CN102911166 B CN 102911166B CN 201210146877 A CN201210146877 A CN 201210146877A CN 102911166 B CN102911166 B CN 102911166B
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Abstract
本申请提供了顺‑FTC的多晶型物及其它晶型,提供了被称作无定形(‑)‑FTC和II型及III型(‑)‑顺‑FTC的(‑)‑顺‑FTC固体相,它们在X射线粉末衍射图、热性质和制备方法方面与I型不同。还提供了(±)‑顺‑FTC(即,外消旋的顺‑FTC)的一种水合晶型及该水合物的脱水形式,类似地可根据X射线粉末衍射图、热性质及制备方法与FTC的其它晶型区分。这些FTC晶型可用于制备其它晶型的FTC,或用于药物组合物中。这些晶型的特别优选的用途是用于治疗HIV或乙型肝炎。
Description
本申请是申请号为02808285.0、申请日为2002年3月1日的发明专利申请的分案申请。
技术领域
本发明涉及(-)-和(±)-顺-FTC(4-氨基-5-氟-1-(2-(羟甲基)-1,3-氧硫杂环戊烷-5-基)-2(1H)-嘧啶酮)的多晶型物及其它晶型,其药物组合物及这些组合物的应用。
背景技术
各种合成核苷(例如AZT、D4T、DDI和DDC)在体内或体外抑制HIV复制的成功导致研究人员在20世纪80年代后期设计和试验用杂原子取代核苷的3′-位碳原子得到的核苷。Norbeck等公开了(±)-1-[顺-(2,4)-2-(羟甲基)-4-二氧杂环戊烷基]胸腺嘧啶(称作(±)-二氧杂环戊烷-T)具有适度的抗HIV活性(EC50为20μm,ATH8细胞),而且在200μm的浓度对于未感染的对照细胞无毒性。Tetrahedron Letters 30(46),6246(1989)。授予BioChemPharma,Inc.,的欧洲专利申请337713和美国专利5,041,449公开了具有抗病毒活性的外消旋的2-取代-4-取代-1,3-二氧杂环戊烷。PCT申请PCT US9I/09124和PCT US 93/08044公开了用于治疗HIV感染的分离的β-D-1,3-二氧杂环戊烷基核苷。WO 94/09793公开了使用分离的β-D-1,3-二氧杂环戊烷基核苷治疗HBV感染。
美国专利5,047,407和欧洲专利申请0382526(也是授予BioChem Pharma,Inc.)披露一些外消旋的2-取代-5-取代-1,3-氧硫杂环戊烷核苷具有抗病毒活性,而且特别提到2-羟甲基-5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷(下面称作BCH-189)的外消旋混合物有与AZT近似相同的抗HIV活性,但毒性较小。称作3TC的BCH-189的(-)对映异构体(美国专利5,539,116,Liotta等)现已在美国市场销售,用于治疗人类中的HIV。还参见EP 513200B1。
还已披露,(-)-(顺)-FTC(4-氨基-5-氟-1-(2-(羟甲基)-1,3-氧硫杂环戊烷-5-基)-2(1H)-嘧啶酮(2R-顺)或β-L-2-羟甲基-5-(5-氟胞嘧啶-1-基)-1,3-氧硫杂环戊烷)具有强有力的HIV活性。参见Schinazi,et al.,“Selective Inhibition of HumanImmunodeficiency Viruses by Racemates and Enantiomers of cis-5-Fluoro-1-[2-(Hydfoxymethyl)-1,3-Oxathiolane-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolane-5-y l]Cytosine”Antimicrobial Agents and Chemotherapy1992年11月号,2423-2431页。还可参见美国专利5,814,639、5,914,331、5,210,085、5,204,446,WO 91/11186和WO 92/14743。(-)-顺-FTC的化学结构示出如下:
C8H10FN3O3S
分子量:247.25
由于1,3-氧硫杂环戊烷核苷(例如FTC)的商业重要性,在专利和科学文献中已描述了它们的一些制备方法。在1,3-氧硫杂环戊烷核苷的手性碳上的取代基(指定的嘌呤或嘧啶碱,称作C5取代基)和CH2OH上的取代基(称作C2取代基)相对于氧硫杂环戊烷环系可以是顺式(在同一侧)或反式(在对面两侧)。顺式和反式外消旋物都由一对旋光异构体组成。因此,每种化合物有四个个别的旋光异构体。这四种旋光异构体用以下构型表示(将氧硫杂环戊烷部分定向在水平平面中,于是-S-CH2-部分是在背面):(1)顺式(也称作β),两个基因“在上”,这是天然存在的L-顺式构型;(2)顺式,两个基团“在下”,这是非天然存在的β-顺式构型;(3)反式(也称作α-构型),C2取代基“在上”,而C5取代基“在下”;和(4)反式,C2取代基“在下”,而C5取代基“在上”。两种顺式对映体合起来被称作β-对映体外消旋混合物,而两种反式对映体合起来被称作α-对映体的外消旋混合物。一般,能将顺式外消旋旋光异构体对与反式外消旋旋光异构体对分开是相当普通的。要分开或者得到顺式构型的个别的对映体则是困难得多的挑战。对于3TC和FTC,所要的立体化学构型是β-L-异构体。
FTC中的1,3-氧硫杂环戊烷环的编号给出如下:
1,3-氧硫杂环戊烷环与被保护的碱缩合的途径
美国专利5,204,466公开了一种用氯化钖作为Lewis酸使1,3-氧硫杂环戊烷与被保护的嘧啶碱缩合的方法,实现了基本上完全的β-立体选择性。还参见Choi等,“In SituComplexation Directs the Stereochemistry of N-Glycosylation in the synthesisof Oxathiolanyl and Dioxolanyl Nucleoside Analogues,”J.Am Chem.Soc.1991,213,9377-9379。氯化钖的使用在反应期间产生了难以去除的不良残余物和副产物。
一些美国专利公开了通过在环的2-位上有手性酯的1,3-氧硫杂环戊烷中间体与被保护的碱在硅基Lewis酸存在下缩合制备1,3-氧硫杂环戊烷核苷的方法。随后必须将该2-位上的酯还原成相应的羟甲基以得到终产物。见美国专利5,663,320、5,864,164、5,693,787、5,696,254、5,744,596和5,756,706。
美国专利5,763,606公开了一种制备主要是顺-2-羧酸或硫代羧酸1,3-氧硫杂环戊烷核苷的方法,该方法包括使所需要的事先甲硅烷基化的嘌呤或嘧啶碱与一种双环中间体在Lewis酸存在下偶合。美国专利5,272,151描述了一种制备1,3-二氧杂环己烷核苷的方法,包括使2-O-保护的-5-O-酰化的1,3-二氧杂环戊烷与氧或氮被保护的嘌呤或嘧啶碱在钛催化剂存在下反应。
Choi等在“In Situ Complexation Directs the Stereochemistry of N-Glycosylation in the synthesis of Oxathiolanyl and Dioxolanyl NucleosideAnalogues,”J.Am Chem.Soc.1991,213,9377-9379中报道,1,3-氧硫杂环戊烷与被保护的嘧啶碱在用HgCl2、Et2AlCl或TiCl2(O-异丙基)2时不发生偶合(见脚注2)。Choi还报道,在端基异构的1,3-氧硫杂环戊烷乙酸酯与甲硅烷基化的胞嘧啶及除氯化钖之外的基本上任何常用的Lewis酸之间的反应均导致形成N-糖基化的端基差向异构体的无法分离的混合物。
美国专利5,922,867公开了一种制备二氧杂环戊烷核苷的方法,其中包括用2-保护的氧甲基-4-卤-1,3-二氧杂环戊烷将嘌呤或嘧啶碱糖基化。
美国专利5,914,331、5,700,937、5,827,727和5,892,025(Liotta等)描述了其中公开的1,3-氧硫杂环戊烷与甲硅烷基化的5-氟胞嘧啶在SnCl4存在下偶合形成FTC的β(-)异构体,并可任选地除去保护基。(得到具有所要的立体构型的1,3-氧硫杂环戊烷核苷的方法)
在授予Liotta等的美国专利5,914,331、5,700,937、5,827,727和5,892,025中描述了制备具有所要立体构型的基本上纯形式的FTC的具体方法。在一项实施方案中,核苷外消旋物混合物的C5′-羟基与酰基化合物反应,形成C5′-酯,其中核苷位于酯的“甲醇”末端。通过用能将所要的对映体水解的酶处理(随后用极性溶剂萃取极性水解产物),或者用能将不要的对映体水解的酶处理(随后用极性溶剂除去不要的对映体),可以将所要的对映体分离。催化1,3-氧硫杂环戊烷嘧啶核苷的水解的酶包括猪肝酯酶、猪胰酯酶、Amano PS-800酯酶、枯草杆菌蛋白酶和α-糜蛋白酶。
胞苷-脱氧胞苷脱氨基酶可以用来拆分2-羟甲基-5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷及其衍生物(包括2-羟甲基-5-(5-氟胞嘧啶-1-基)-1,3-氧硫杂环戊烷)的外消旋混合物。该酶对于胞嘧啶部分去氨基化形成尿苷起催化作用。1,3-氧硫杂环戊烷核苷的对映异构体之一是用于胞苷-脱氧胞苷脱氨基酶的一种优选底物。未被转化成尿苷的这种对映体(因此仍为碱性)用酸性溶液从溶液中萃取出来。胞苷-脱氧胞苷脱氨基酶可以从鼠肝或从人肝中分离得到,或者由重组序列表达在原核生物体系的大肠肝菌中。
也可以用手性层析法拆分顺式FTC对映体。例如,美国专利5,892,025(Liotta等)公开了一种使顺-FTC流过一根乙酰化的β-环糊精手性柱来拆分顺-FTC对映体混合物的方法。
多晶型鉴定
化合物以不同的晶体结构存在的能力称作同质多晶现象。这些不同的晶型被称作“多晶型变体”或“多晶型物”。多晶型物有相同的化学结构,但它们在堆积排列和几何排列方面不同,而且显示出不同的物理性质,例如熔点、形状、颜色、密度、硬度、可变形性、稳定性、溶解性等。根据它们的温度-稳定性关系,两种多晶型物可以是单向转变的或是互变性的。对于单向转变体系,两个固体相之间的相对稳定性不随温度而变。相反,在互变体系中存在一个过渡温度,在该温度下两相的稳定性逆转(Theory and Origin of Polymorphismin“Polymorphism in Pharmaceutical Solids”(1999)I SBN:)-8247-0237。
已经报道许多化合物显示出同质多晶现象。作为较早的例子,Go rdom等在美国专利4,476,248中公开并要求保护药物布洛芬的一种新晶型及其制备方法。该新晶型据称改善了布洛芬的可制造性。还报道一种与FTC更密切相关的结构3TC((-)-顺-4-氨基-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮,拉米夫定)存在多种晶型。Jozwiakowski,M.J.,Nguyen,N.T.,Sisco,J.M.,Spancake,C.W.“Solubility Behavior ofLamivudine Crystal Forms in Recrystallization Solvents”,J.Pharm.Sci.,85,2,p.193-199(1996)。还可参见Roberts等题为“Crystalline Oxathiolane Derivatives”的美国专利5,905,082(1999年5月18日颁布)及其PCT对应物PCT/EP92/01213,其中描述了3TC的两种多晶型物。Roberts等披露,一种多晶型物是当3TC由水溶液中结晶时得到的。第二种多晶型物是当3TC由非水介质中结晶,或第一种晶型熔化后冷却,或第一种晶型被研磨时得到。两种多晶型物都显示出特有的吸收带、溶化温度和结晶能。
用上述方法制备的(-)-顺-FTC具有特殊的晶型,本申请中称其为I型(-)-顺-FTC。示于图7的I型FTC的粉末X射线衍射图的特征峰的角度位置(2θ)是:14.1°±0.1°,19.9°±0.1°,20.2°±0.1°,20.6°±0.1°,21.0°±0.1°,22.4°±0.1°,28.5°±0.1°,29.5°±0.1°,和32.6°±0.1°。
FTC的其它多晶型物及其它晶型可能在制造及其它应用中有商业价值。因此本发明的一个目的是提供FTC的新的多晶型物和其它晶型。
另一目的是提供制备和分离FTC多晶型物和其它晶型的新方法。
本发明的再一目的是提供FTC多晶型物及其它晶相的医疗用途。
发明概述
提供了被称作无定形(-)-FTC和II型及III型(-)-顺-FTC的(-)-顺-FTC的固体相,它们可根据X射线粉末衍射图、热性质及制备方法与I型(-)-顺-FTC区分。还提供了(±)-顺-FTC(即,外消旋的顺-FTC)的一种水合晶型和该水合物的脱水形式,并可类似地根据X-射线粉末衍射图、热性质及制备方法与顺-FTC的其它晶型区分。这些FTC晶型可用来制备其它晶型的FTC或用于药物组合物。这些晶型的特别优选的用途是治疗HIV或乙型肝炎。
II型(-)-顺-FTC可以通过I型(-)-顺-FTC熔化后在接近I型熔点的温度下重结晶来得到。将II型(-)-顺-FTC冷至II型与III型的热力学转变温度之下,可以得到III型(-)-顺-FTC。将液态的(-)-顺-FTC快速冷却,可以得到无定形(-)-顺-FTC。(±)-顺-FTC的水合晶型是一种倍半水合物,可通过将(±)-顺-FTC溶于水并重结晶FTC得到。该倍半水合物的脱水形式可通过从倍半水合物中除去水化的水得到。
附图简介
图1是I型(-)-顺-FTC的典型的DSC(“差示扫描量热法”)热分析图,吸热151℃,以10℃/分的加热速度得到。
图2是以1℃/分的加热速度得到的I型(-)-顺-FTC的DSC热分析图。
图3是以2℃/分的加热速度得到的I型(-)-顺-FTC的DSC热分析图。
图4是以5℃/分的加热速度得到的I型(-)-顺-FTC的DSC热分析图。
图5是II型和III型(-)-顺-FTC的DSC热分析图。
图6是显示II型至I型的可逆转变的DSC热分析图。
图7是I型(-)-顺-FTC的PXRD(粉末X射线衍射)图。
图8是II型(-)-顺-FTC的PXRD图。
图9是III型(-)-顺-FTC的PXRD图。
图10是(±)-顺-FTC的倍半水合物的PXRD图。
图11是外消旋的顺-FTC倍半水合物的脱水形式的PXRD图。
图12是(±)-顺-FTC倍半水合物和(-)-顺-FTC的DSC热分析图。
图13是(±)-顺-FTC的倍半水合物的TGA(热解重量分析)扫描曲线。
图14是(-)-(顺)-FTC的三种多晶型物(I、II和III型)的自由能-温度关系。稳定相用实线表示,虚线代表介稳相。
图15是通过将(-)-顺-FTC晶态样品熔融和冷冻得到的无定型(-)-顺-FTC的DSC热分析图。最终加热速度为10℃/分。
发明详述
提供了两种新的(-)-顺-FTC多晶型物,(-)-顺-FTC的无定形相,(±)-顺-FTC的一种新的水合晶型和该(±)-顺-FTC水合物的脱水形式,根据X射线衍射图、热性质及其制备方法可以将其与(-)-顺-FTC和(±)-顺-FTC的其它晶相区分。FTC的这些晶型及无定形相可以作为制备FTC的中间体,或配制成药物组合物,用于治疗H I V或乙型肝炎。
本发明的(-)-顺-FTC的两种多晶型物被称作II型和III型(-)-顺-FTC,以图8和9中的X射线粉末衍射图为特征。这些晶型与I型(-)-顺-FTC不同,后者是用本申请书的背景部分所述方法制备的(-)-顺-FTC的多晶型物。I型(-)-顺-FTC可根据图7所示的X射线粉末衍射图,或根据本申请书背景部分给出的峰值衍射角来鉴定。
(±)-顺-FTC的水合晶型以图10所示的X射线粉末衍射图为特征。此晶型应与先有技术中制备的(±)-顺-FTC对比。各种晶型的热性质总结于下表中:
于是,本发明提供了:
a)由X射线粉末衍射分析、物理性质及制备方法表征的(-)-顺-FTC的两种多晶型物和一种无定形相;
b)由X-射线粉末衍射分析、物理性质及制备方法表征的(±)-顺-FTC的水合晶型;
c)制备(-)-顺-FTC相及(±)-顺-FTC晶型的方法
d)(-)-顺-FTC相和(±)-顺-FTC晶型的治疗和/或药物组合物,可任选地有可药用的载体存在;和
e)(-)-顺-FTC相和(±)-顺-FTC晶型的新颖的治疗用途,尤其是用于治疗病毒性疾病,例如HIV和乙型肝炎。
II型(-)-顺-FTC
当I型(-)-顺-FTC熔化后重结晶时,观察到II型(-)-顺-FTC。象所有的多晶型物一样,II型可以根据进行粉末X射线晶体分析时显示出的粉末衍射图鉴定。示于图8的II型(-)-顺-FTC的粉末X射线衍射图中特征峰的角度位置(2θ)是:14.7°±0.1°,16.7°±0.1°,19.6°±0.1°,21.1°±0.1°,21.8°±0.1°,24.6°±0.1°,和25.6°±0.1°。
II型(-)-顺-FTC也可由其熔化温度和/或熔化热鉴定。II型(-)-顺-FTC在大气压下的熔化温度约为166℃,熔化热通常为约15-19KJ/mol。已知熔化热会随实验条件而变。
或者是,II型(-)-顺-FTC可以根据其互变性和制备方法判定。II型(-)-顺-FTC与(-)-顺-FTC的I型和III型多晶型物是互变性的,即,存在一个转变温度,在低于和高于该温度时稳定性的次序逆转。由于这种互变性,II型(-)-顺-FTC可以由I型或III型(-)-顺-FTC制备。在本申请书列出的实施例中,II型(-)-顺-FTC是用以下方法得到:
(1)将(-)-顺-FTC(I型)加热至其熔点之上(对于I型约为151℃),并保持在此升高的温度。在缓慢冷却时,熔化的(-)-顺-FTC重结晶成II型,并且在温度高于II型与III型间的热力学转变温度时采取II型晶型。
(2)将III型(-)-顺-FTC加热至II型和III型的热力学转变温度之上,这大约为96至112℃(因为II型与III型(-)-顺-FTC是互变性体系)。
于是,当将I型(-)-顺-FTC熔化并保持熔体温度低于II型的熔化温度但高于II型和III型间的热力学转变温度时,可以得到II型(-)-顺-FTC。值得注意的是,当将II型加热至其熔点(约166℃)以上并缓慢冷却时,观察不到II型的类似转变,而是II型简单地重结晶成II型。然而,如果急骤冷却,则从同一熔体中结晶不出II型,而是形成无定形相。
因此,在本发明的一项实施方案中提供了如上述任何方法所表征的II型(-)-顺-FTC,优选是基本上纯的形式。在另一实施方案中本发明提供了其中基本上不存在I型(-)-顺-FTC的II型(-)-顺-FTC。在又一项实施方案中,本发明提供了基本上不含III型(-)-顺-FTC的II型(-)-顺-FTC。在另一项实施方案中,本发明提供了一种含有II型(-)-顺-FTC和可药用载体的药物组合物。
III型(-)-顺-FTC
因为II型(-)-顺-FTC发生向III型(-)-顺-FTC的固态转化,所以当II型(-)-顺-FTC的温度降至低于约96-112℃的转变温度时,由II型(-)-顺-FTC得到III型。III型(-)-顺-FTC是(-)-顺-FTC的另一种多晶型物,可以根据进行粉末X射线晶体分析时的粉末衍射图鉴别。III型(-)-顺-FTC的粉末X射线衍射图(示于图9)中特征峰的角度位置(2θ)为:14.5°±0.1°,16.7°±0.1°,19.6°±0.1°,20.4°±0.1°,21.4°±0.1°,21.7°±0.1°,25.2°±0.1°,和26.2°±0.1°。
III型(-)-顺-FTC也可以根据其制备方法鉴定。因为III型与II型是互变性体系,所以III型(-)-顺-FTC可以通过将II型(-)-顺-FTC冷却至低于II型和III型的固态转变温度,引起II型(-)-顺-FTC的固态转变,从II型(-)-顺-FTC制得。当然,III型(-)-顺-FTC也可以直接由I型(-)-顺-FTC制备,以II型作为中间体,将I型熔化并缓慢地将熔体冷却至II型和III型的固态转变温度之下。因为低于其固态转变温度时的这种稳定性,III型(-)-顺-FTC也可由显示固态转变的温度范围鉴定,但最好是在此范围的低端(即,大气压下约96℃)鉴定。
因此,在一项实施方案中本发明提供了III型(-)-顺-FTC,优选为基本上纯的形式。在另一实施方案中,本发明提供了基本上不含I型(-)-顺-FTC的III型(-)-顺-FTC。在又一实施方案中,本发明提供了基本上不含II型(-)-顺-FTC的III型(-)-顺-FTC。在另一实施方案中,本发明提供了一种含有III型(-)-顺-FTC和可药用载体的药物组合物。
(±)-顺-FTC倍半水合物
(±)-顺-FTC倍半水合物是外消旋顺-FTC的一种晶型,它由(±)-顺-FTC溶于水中并重结晶得到。值得指出的是,该水化物只由顺-FTC的外消旋物生成,而不由纯的(-)-顺-FTC生成。(±)-顺-FTC倍半水合物可以用进行粉末X射线晶体分析时得到的粉末衍射图鉴定。示于图10的(±)-顺-FTC倍半水合物的粉末衍射图中特征峰的角度位置(2θ)是:11.5°±0.1°,13.4°±0.1°,19.1°±0.1°,20.3°±0.1°,20.8°±0.1°,21.5°±0.1°,21.9°±0.1°,和30.9°±0.1°。
TGA分析证实是(±)-顺-FTC的倍半水合物。该倍半水合物在大气压下于30℃左右开始失去其水化水。
(±)-顺-FTC倍半水合物也可以根据其制备方法之一鉴定。(±)-顺-FTC倍半水合物优选简单地制备如下:将(±)-顺-FTC溶于水中,将溶解的FTC重结晶成水合晶体形式。在溶解期间可以加热以提高FTC的溶解量。(±)-FTC可以以顺-FTC的纯外消旋混合物的形式,或是以主要含(+)-顺-FTC或(-)-顺-FTC的组合物的杂质形式存在。当作为杂质存在时,(±)-FTC优选构成(+)-顺-FTC或(-)-顺-FTC组合物重量的至少约4%(即,如果作为(-)-顺-FTC的杂质,该FTC优选含至少2%重量的(+)对映异构体,而如果作为(+)-顺-FTC的杂质,则该FTC优选含至少2%重量的(-)对映异构体)。
(±)-顺-FTC的DSC热分析图示于图12。如DSC、TGA和PXDR分析所示,重结晶的FTC是倍半水合物。
因此,在一项实施方案中,本发明提供了(±)-顺-FTC倍半水合物,优选是基本上纯的形式。在另一实施方案中,本发明提供了基本上不含I型(-)-顺-FTC,或基本上不含外消旋的顺-FTC、(-)-顺-FTC或(+)-顺-FTC的其它水合和脱水晶型的(±)-顺-FTC。在又一实施方案中,本发明提供了一种含有(±)-顺-FTC倍半水合物和可药用载体的药物组合物。
在(±)-顺-FTC倍半水合物中的水化水蒸发时,形成外消旋的顺-FTC的脱水晶型。这样得到的外消旋的顺-FTC可以由粉末X-射线晶体分析得到的粉末衍射图鉴定。脱水的外消旋顺-FTC的粉末X射线衍射图(图11)中特征峰的角度位置(2θ)是:12.3°±0.1°,14.0°±0.1°,20.7°±0.1°,22.6°±0.1°,23.3°±0.1°和25.5°±0.1°。脱水的外消旋顺-FTC在大气压下熔化温度为约190℃,溶化热为约23KJ/mol。
图12中的DSC热分析图是(±)-顺-FTC倍半水合物的。如由TGA分析所证实的,在约80℃时的大的吸热峰来自(±)-顺-FTC倍半水合物失去其水化水。在190℃的第二个吸热峰来自脱水的外消旋顺-FTC的溶化。
于是,本发明的另一实施方案提供了本发明的脱水的(±)-顺-FTC。在其它实施方案中本发明提供了这种脱水的(±)-顺-FTC,其中基本上不含I型(-)-顺-FTC,或基本上不含外消旋顺-FTC、(-)-顺-FTC或(+)-顺-FTC的其它水合晶型和脱水晶型。在另一实施方案中,本发明提供了一种含有本发明的脱水的(±)-顺-FTC及可药用载体的药物组合物。
无定形(-)顺-FTC
当熔化的(-)-顺-FTC快速骤冷至低于40或50℃,从而越过向II型或III型(-)-顺-FTC的任何转变时,得到无定形的(-)-顺-FTC。图15展示了无定形(-)-顺-FTC的DSA热分析图,此图表明该相的玻璃化转变温度为67℃。
因此,在另一实施方案中,本发明提供了无定形的(-)-顺-FTC,优选是基本上纯的形式。在另一实施方案中本发明提供了基本上不含I、II和/或III型(-)-顺-FTC的无定形的(-)-顺-FTC。在又一实施方案中本发明提供了含有无定形(-)-顺-FTC和可药用载体的药物组合物。
定义
本文所用的“基本上纯的”一词,当用于FTC的一相或晶型时,是指FTC的一相或晶型的纯度大于约95%。这意味着FTC的多晶型物或水合形式含有的任何其它化合物不多于约5%,在一项实施方案中,FTC的任何其它晶相或晶型(无论是外消旋物、(+)、(-)、顺式或反式)的含量不多于约5%。在其它实施方案中,术语“基本上纯的”是指FTC的相或晶型的纯度大于约96%。在又一实施方案中,术语“基本上纯”是指FTC的相或晶型的纯度大于约97%或99%。
类似地,“基本上不含第二组分”在用于FTC的相或晶型时,是指FTC的相或晶型中第二组分的含量不大于约5%。更优选的是,“基本上不含第二组分”一词表示FTC的相或晶型中第二组分的含量不多于约4%,更优选第二组分的含量不多于约3%或1%。
对于晶型的特征粉末X射线衍射峰位置,按照在±0.1°的容许误差之内的角度位置(2θ)报道。此容许误差是由美国药典1843-1844页(1995)指定的。±0.1°的误差打算在比较两个粉末X射线衍射图时使用。实际上,如果一张图的某个衍射峰被指定了作为测定的峰位置±0.1°的一定的角度位置范围(2θ),而另一张图的一个衍射峰被指定了作为测定的峰值位置±0.1°的另一角度位置范围(2θ),而且如果这些峰值范围重叠,则这两个峰被认为有相同的角度位置(2θ)。例如,如果一张图的衍射峰经测定位于5.20°,对比较来说,容许误差使该峰值可被指定在5.10°-5.30°的范围。若是另一衍射图的对照峰经测定位于5.35°,对比较来说,容许误差使该峰被指定在5.25°-5.45°的范围。因为两个峰位范围之间存在重叠,故比较的两个峰被认为有相同的角度位置(2θ)。
在整篇说明书中,“含有”一词或其变型,例如“包含”或“含”,应理解为包括所述的要素、整体或步骤,或要素组、整体组或步骤组,而不排除任何其它的要素、整体或步骤,或要素组、整体组或步骤组。
实施例
材料和方法
除非另外说明,所有试验中的(-)-顺-FTC均通过两批(-)-顺-FTC如下组合和处理得到。在烧瓶内装入1109g(-)-顺-FTC和2750m l乙酸乙酯。将该浆体在室温下搅拌2小时,过滤并用550m l乙酸乙酯洗。将滤饼在真空烘箱中于50℃和约2mmHg柱下干燥。所有溶剂均是HPLC级,使用前未再纯化。起始物(-)-顺-FTC的HPLC分析指示纯度为98.8%。
示差扫描量热法(DSC):DSC实验用以下仪器之一进行:
用一台TA Instruments DSC 2920(带有冷冻设备)进行DSC研究。将约5mg样品放入密封的铝盘内。DSC池用30ml/分的氮吹洗。除非另外说明,加热速度为10℃/分。温度校正和热流动校正用铟标准在同一实施条件下进行。
用装有数据分析器(STARe,Mettler Instrument)的MettlerDS30(MettlerInstrument,Hightstowm,NJ)进行DSC测定。将样品(约2-5mg)密封在标准的40μL铝盘中,盘的盖上穿一个孔。使用该样品类型的空盘作为对照。将样品在1-10℃/分下扫描,并用50mL/分的干燥氮气吹洗。此DSC进行热流动和温度校正。
热重量分析(TGA):TGA研究用TA Instruments TGA 2950进行。将大约5mg样品放入开口铂盘中,以10℃/分的加热速度对样品加热。
变温PXRD:衍射仪(XDS 2000,Scintag,Sunnyvale,CA)包括一个4-KW发电机(电压45kV,电流40mA),铜阳极管,液氮冷却的Ge检测器(GLP-10195/07-S,EG&G ORTEC,OakRidge,TN),数据分析器(Micro Vax 3100,Digital Equipment Corporation,Ontario,Canada),加热台(Scintag)和温度控制器(Microstar,Research Inc.,Minneapolis,MN)。将样品以薄层形式放入样品座内,以每分钟1°的速度扫描,不旋转。
热台显微镜(HSM):用一台装有Mettlor-Toledo FP82HT热台的Olympus BX60显微镜进行偏振光显微镜观察。一薄层样品放在载片上,以10℃/分的速度加热。受热情况用软件记录。
重结晶法:将约5g(-)-顺-FTC放在园底烧瓶中,在155-160℃的温度下搅拌加热30分钟。在环境条件下将烧瓶内的样品冷却至室温。
平衡溶解度:为得到平衡溶解度值,用过量的固体在具塞烧瓶中于控温水浴内在25℃摇动52小时。平衡后用热台显微镜和PXRD鉴定残余固体物质。将上清液经0.45μm滤膜过滤,然后稀释用于HPLC分析。
研磨:(-)-顺-FTC在Fitzpatrick磨中以高速(4000RPM)研磨,前向锤磨,000-级筛。药物通过滤器一次并收集在塑料袋中。
水合物形成:在50℃下配制I型的过饱和溶液。将此溶液冷却至室温并搅拌约2小时。沉淀的固体抽气过滤并空气干燥。将该固体用HPLC、DSC、PXRD和TGA分析。此分析表明该固体是(±)-顺-FTC的倍半水合物。
结晶:将(-)-顺-FTC溶于以下溶剂之一:甲醇、乙酸乙酯、水、四氢呋喃和丙酮。每种悬浮液都煮沸约15分钟,立即经0.45μm尼龙滤膜过滤。在室温下搅拌清液直至结晶。在结晶时,将悬浮液过滤以收集滤饼。将滤饼置于玻璃皿内,盖上无纤维屑的纸巾,在通风橱内于环境条件下放置2天。
实施例1:I型和II型(-)-顺-FTC的DSC鉴定
在10、1、2和5℃/分的加热速度下,观察I型(-)-顺-FTC多晶型物的受热情况。这些DSC热分析图分别示于图1、2、3和4中。样品大小分别为6.8400mg,5.290mg,5.0430mg或5.1500mg。
在151℃的吸热相应于I型(-)-顺-FTC的熔化温度。在所研究的所有加热速度下均存在此吸热峰。与此相的熔体相关的熔化热为25KJ/mol。这一熔化之后是重结晶形成熔点更高的II型固体。高温吸热峰(162℃)的存在取决于加热速度。具体地说,随着加热速度减小,出现高温吸热峰的几率升高。另外,高温吸热峰的熔化热值随加热速度减小而增加。这些观察与加热速度较慢时液体重结晶的程度较大这一事实相一致。这一依赖于加热速度的吸热表明I型在151℃熔化后会发生重结晶,而形成的晶体在约162℃时熔化。在162℃熔化的相被称作“II型(-)-顺-FTC”。
实施例2:II型和III型(-)-顺-FTC的DSC鉴定
利用DSC观察(I)型(-)-顺-FTC在熔化和随后冷却至室温时的热量情况。将5.5500mg I型(-)-顺-FTC样品加热至160℃,这刚好在I型的熔化温度之上,然后冷却到25℃。当采用10℃/分的加热速度在DSC中重新加热时,I型(-)-顺-FTC在151℃时的吸热不出现。然而,如图5所示,在102℃和162℃处出现了吸热峰。102℃的吸热是如图6所示的III型(-)-顺-FTC向II型(-)-顺-FTC的固态转变。在高于和低于102℃转变温度下收集的PXRD数据(图7和9)证实了该DSC解释。在162℃的吸热是II型(-)-顺-FTC的熔化。HPLC证实加热未引起效能变化。
实施例3:无定形(-)-顺-FTC的DSC鉴定
将7.315mg的I型FTC在DSC试验中以5℃/分的速度加热至180℃,然后以-20℃/分将样品骤冷至-20℃。此样品在以10℃/分重新加热时显示出基线移动,玻璃化转变温度为~67℃,这一基线移动在加热和冷却循环中均存在,证实它是由于玻璃化转变。无定形(-)-顺-FTC的DSC热分析图包括在图15内。
实施例4:I、II和III型(-)-顺-FTC的HSM观察
基于DSC分析期间观察到的热量变化对I、II、III型的指认和HSM观察相一致。在显微镜下,I型物质在室温下看起来为片状。在10℃/分下加热至160℃时,I型熔化成透明的液体。在将该液体冷却时,由熔体中析出针形结晶,其外观比I型要黑。重新加热时,这些针状物发出双折射变化,在约102℃开始,约115℃结束。该针形物最终在166℃熔化。
实施例5:研磨对晶型的影响
制备了两批研磨的I型(-)-顺-FTC:一批以研杵和缽用手研磨5分钟,另一批在Fitzpatrick磨中研磨。虽未作定量测定,但光学显微镜观察表明,手研磨的(-)-顺-FTC的粒度看来最小,其次是用Fitzpatrick得到的,然后是未研磨的(-)-顺-FTC。用Fitzpatrick磨研磨的样品和未经研磨的(-)-顺-FTC的DSC曲线只在151℃有一个吸热峰。手研磨的(-)-顺-FTC在151℃和162℃有两个吸热峰。手研磨的(-)-顺-FTC在室温下的PXRD图与I型的相同,表明在DSC实验期间发生从I型到II型的转变。总之,这些数据表明,当从I型出发时,按照所述条件研磨不影响(-)-顺-FTC的晶型。
实施例6:热对晶型的影响
III型在25℃和95℃的PXRD图示于图9。但是,此样品在120℃下得到的PXRD图与在95℃得到的图不同。PXRD图在这一温度范围内的变化与由DSC分析得到的在约102℃处的吸热峰(图6)是一致的,并证实了102℃的吸热是由固态转变或晶体结构的变化引起的。
在120℃测得的PXRD图与在160℃测得的相同。然而,在样品冷却回到25℃时,PXRD图与III型(-)-顺-FTC的相同。在102℃以上存在并在162℃熔化的晶型经鉴定为II型。I型物质的PXRD图直到其熔化温度151℃不发生变化。
实施例7:热力学稳定性分析
表1总结了I、II和III(-)-顺-FTC的熔化数据。根据这一数据确定了I型和II型间的热力学关系。这些晶型是互变相关的,计算出的转变温度为130℃。
表I:(-)-顺-FTC的四种晶型的转变温度数据
*III型不发生熔化而是在约112℃发生固态转变,因此熔化热未知。
这些晶型之间的热力学稳定性关系图示于图14中。
实施例8:溶解度
由图14显然可见,低于130℃时,I型是最稳定相。因此,在130℃以下,I型是溶解最少的相。I型在25℃下在水中的平衡溶解度为0.482M(119mg/mL)。溶解度数值大于100mg/mL的化合物被认为是高度可溶的,I型(-)-顺-FTC属于这一范畴。本申请中所述的其它晶型的(-)-顺-FTC的溶解度比I型更大。
实施例9:结晶研究
用于所有结晶研究的(-)-顺-FTC起始物,根据PXRD测定,均为I型(-)-顺-FTC。I型(-)-顺-FTC自水、甲醇、四氢呋喃、乙酸乙酯和丙酮的溶液中重结晶。所有得自重结晶实验的样品均用PXRD和DSC分析。自乙酸乙酯和丙酮中结晶的(-)-顺-FTC在151℃和162℃显示吸热峰,而且PXRD图与I型(-)-顺-FTC的相同。
在50℃制备I型的过饱和溶液(0.5g/mL),然后将该溶液冷却至室温并搅拌2小时。沉淀出的固体经抽气过滤和空气干燥。对该固体进行HPLC、DSC、PXRD和TGA分析。此实验指示该固体是(±)-顺-FTC的倍半水合物。该倍半水合物在25℃下的平衡溶解度为0.34M(93mg/mL)。其DSC热分析图示于图12中。在低温时的大的吸热是由于(±)-顺-FTC倍半水合物失去水化水,这由TGA(图13)得到证实。190℃的吸热是由于脱水的水合物熔化。该脱水的水合物随后被指定一个特有的约190℃的熔化温度(图12)。对于该脱水的水合物还收集了特有的PXRD图(见图11)。
药物组合物
患有HIV和HBV的人可以通过向该患者施用与可药用载体或稀释剂一起存在的有效数量的本发明各种化合物(即,I、II和III型(-)-顺-FTC、外消旋的顺-FTC倍半水合物及外消旋的顺-FTC倍半水合物的脱水形式),或其前药或盐,得到治疗。该活性可以通过任何合适的途径,例如,口服、非肠道或静脉内,以液体或固体形式给药。
用于HIV或HBV的化合物的优选剂量为每天每kg体重1-75mg,优选1至50或20mg,更一般的是每天每kg服药者体重0.1至约100mg。可药用盐和前药的有效剂量范围可以根据要释出的母体核苷的重量计算。如果盐或前药本身具有活性,则有效剂量可以用盐或前药的重量如上估算,或按照本领域技术人员已知的其它方法估算。
化合物可以方便地以任何合适剂型的单元形式给药,包括但不限于每单位剂型含7-3000mg,优选70-1400mg活性成分。50-1000mg的口服剂型通常是合适的。
最好是活性组分的给药能实现约0.2-70μm、优选1.0-10μm的活性化合物峰值血浆浓度。这可以通过例如静脉注射0.1-5%的活性组分溶液(任选地在盐水中)或以活性组分大丸剂的形式给药来达到。
活性化合物在药物组合物中的浓度取决于该药物的吸收、失活和排泄速度,以及本领域技术人员了解的其它因素。应当指出,剂量值还随要减轻的病症的严重程度而变。还要清楚,对于任何特定的对象,具体的剂量方案应根据个别需要和管理或指导组合物给药的人士的专业判断而随时调整,而且上述的浓度范围只是示例性的,并非是要限制要求保护的组合物的范围或实用。活性组分可以一次用药,也可以分成多个较小剂量以不同的时间间隔用药。
活性化合物的一种优选的给药方式是口服。口服组合物一般包括惰性稀释剂或可食性载体。它们可以包封在明胶胶囊中或压制成片剂。就经口的治疗给药而言,可以将活性化合物与赋形剂掺混并以片剂、锭剂或胶囊剂的形式使用。可以包含药学上相容的粘合剂和/或辅助物质作为组合物的一部分。
片剂、丸剂、胶囊剂、锭剂等可以含有任何以下成分或类似本质的化合物:粘合剂,例如微晶纤维素、黄蓍胶或明胶;赋形剂,例如淀粉或乳糖;崩解剂,例如藻酸、Primogel或玉米淀粉;润滑剂,例如硬脂酸镁或Sterotes;滑动剂,例如胶体二氧化硅;甜味剂,例如蔗糖或糖精;或者风味剂,例如薄荷、水杨酸甲酯或桔子香精。当剂量单元形式是胶囊时,除了上述类型的物质以外,还可以含一种液态载体,例如脂肪油。此外,剂量单元形式可以含有调节剂量单元物理形式的其它物质,例如糖、虫胶或其它肠溶剂的包衣。
化合物可以作为酏剂、悬浮剂、浆剂、糯米纸囊剂、咀嚼剂等的一个组分给药。浆剂中除活性化合物外,还可含有蔗糖作为甜味剂,以及一些防腐剂、染料和着色剂以及香料。
化合物或其可药用的前药或盐也可以与不损害所期望作用的其它活性物质,或与补充所期望作用的物质混合,例如:抗生素,抗真菌剂,消炎剂,或其它抗病毒剂,包括其它的核苷化合物。用于非肠道、皮内、皮下或局部旋用的溶液剂或悬浮剂可以包括以下组分:无菌的稀释剂,例如注射用水、盐溶液、不挥发性油类、聚乙二醇、甘油、丙二醇或其它的合成溶剂;抗菌剂,例如苯甲醇或羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐;以及用于调节渗透压的试剂,例如氯化钠或葡萄糖。非肠道制剂可以封装在安瓿瓶、一次性针管或由玻璃或塑料制成的多剂量小瓶中。
如果静脉内给药,优选的载体是生理盐水或磷酸盐缓冲盐水(PBS)。
在一项优选的实施方案中,活性化合物是与保护该化合物不被身体快速排除的载体一起配制,例如控释制剂,包括植入剂和微胶囊释放体系。可以使用可生物降解的、生物相容的聚合物,例如乙烯乙酸乙烯酯共聚物、聚酐、聚羟基乙酸、胶原、聚原酸酯和聚乳酸。这些制剂的制备方法对于本领域的技术人员是显而易见的。这些材料也可以由AlzaCorporation购得。
脂质体悬浮液(包括以带有病毒抗原的单克隆抗体的受感染细胞为目标的脂质体)也优选作为可药用载体。它们可按照本领域技术人员已知的方法,例如美国专利4,522,811(在本申请中全文引用作为参考)中所述的方法制备。例如,脂质体制剂可以制备如下:将合适的脂质(例如硬脂酰磷脂酰乙醇胺,硬脂酰磷脂酰胆碱,花生酰磷脂酰胆碱和胆固醇)溶于有机溶剂中然后蒸发,在容器的表面上留下干燥的脂质薄膜。然后向容器中加入活性化合物或其一磷酸盐、二磷酸盐和/或三磷酸盐衍生物的水溶液。用手旋动容器使脂质脱离容器边壁并将脂质聚集体分散,从而得到脂质体悬浮液。
在整篇申请中,引用了各式各样的出版物。这些出版物的公开内容都全文并入本申请作为参考,以便更充分地描述本发明所属领域的现有技术。
对于本领域的技术人员,显然可以在不偏离本发明的范围或精神的情况下对本发明作出各种修改和变动。根据这里公开的对说明书的讨论和本发明的实施,本发明的其它实施方案对于本领域技术人员是显而易见的。本说明书和实施例应被看作仅供示例说明,本发明的真正范围和精神由以下的权利要求表明。
Claims (2)
1.一种制备(-)-顺-FTC的多晶型物的方法,包括:
(a)将I型(-)-顺-FTC加热至151℃之上;
(b)将所述(-)-顺-FTC保持在此升高的温度;和
(c)缓慢冷却所述熔化的(-)-顺-FTC,以获得多晶型的结晶的(-)-顺-FTC,所述多晶型的结晶的(-)-顺-FTC是II型(-)-顺-FTC,其特征在于图8中所示的粉末X射线衍射图和熔点为162-167℃;
其中所述I型(-)-顺-FTC的特征在于图7中所示的粉末X射线衍射图和熔点为148-153℃。
2.权利要求1的方法,其中步骤(a)包含将I型(-)-顺-FTC加热至160℃之上。
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