CN102414186A - Abt-263的盐和其固体形式 - Google Patents
Abt-263的盐和其固体形式 Download PDFInfo
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- CN102414186A CN102414186A CN2010800185934A CN201080018593A CN102414186A CN 102414186 A CN102414186 A CN 102414186A CN 2010800185934 A CN2010800185934 A CN 2010800185934A CN 201080018593 A CN201080018593 A CN 201080018593A CN 102414186 A CN102414186 A CN 102414186A
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Abstract
ABT-263二-HCl和其晶体多晶型物是药物组合物的合适的活性药物组分,用于治疗以一或多种抗凋亡Bcl-2家族蛋白的超表达为特征的疾病,例如癌症。
Description
本申请要求美国临时申请系列61/174,274(2009年4月30日申请)的优先权。
交叉引用下列共同申请的美国申请(包括与本申请相关的主题)∶系列号12/___,___,标题“Lipid
formulation of apoptosis promoter”,要求美国临时申请系列61/174,245(2009年4月30日申请)的优先权;系列号12/___,___,标题“Stabilized lipid formulation of apoptosis promoter”,要求美国临时申请系列61/174,299(2009年4月30日申请)和系列61/289,254(2009年12月22日申请)的优先权;系列号12/___,___,标题“Solid
oral formulation of ABT-263”,要求美国临时申请系列61/174,318(2009年4月30日申请)的优先权;和系列号12/___,___,标题“Formulation for oral administration of apoptosis promoter”,要求上面说到的美国临时申请系列61/174,274、系列61/174,299、系列61 / 174,318和系列61/289,254以及系列61/185,105(2009年6月8日申请)、系列61/185,130(2009年6月8日申请)、系列61/218,281(2009年6月18日申请)和系列61/289,289(2009年12月22日申请)的优先权。
将上面每个申请的全部公开内容结合到本文中作为参考。
本发明的领域
本发明涉及细胞程序死亡(apoptosis)-促进剂ABT-263和其用于治疗疾病的方法,该疾病以抗凋亡(anti-apoptotic)Bcl-2家族蛋白的超表达为特征。更尤其是,本发明涉及ABT-263的新的盐和其固体形式,例如,在制备用于给予需要其的患者ABT-263的药物组合物中用作活性药物组分(API)。
本发明的背景
细胞程序死亡的回避是癌症的特点(Hanahan & Weinberg(2000)Cell
100:57-70)。癌细胞必须克服由细胞应激反应所造成的连续冲击,例如,导致正常细胞进行细胞程序死亡的DNA损伤、致癌基因活化、异常细胞周期进程和苛刻的微环境。癌细胞逃避细胞程序死亡的一种主要方法是上调Bcl-2家族的抗凋亡蛋白。
已经描述了占据Bcl-2蛋白的BH3结合沟的化合物,例如,Bruncko等人(2007)J.
Med. Chem. 50:641-662。 这些化合物包括N-(4-(4-((4′-氯-(1,1′-联苯)-2-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(二甲基氨基)-1-((苯基硫基)甲基)丙基)氨基)-3-硝基苯-磺酰胺,或者称为ABT-737,其具有下式∶
ABT-737与Bcl-2家族的蛋白(具体地说,Bcl-2,Bcl-X L 和Bcl-w)进行高亲合性(<1 nM)结合。其针对小细胞肺癌(SCLC)和淋巴恶性肿瘤显示出单一药剂活性,并且增强其它化疗剂的促凋亡效果。ABT-737和相关的化合物和制备这种化合物的方法公开在Bruncko等人的美国专利申请公开2007/0072860中。
近年来,对Bcl-2家族蛋白具有高结合亲合性的其它系列化合物已经得到了鉴定。 这些化合物和制备它们的方法公开在Bruncko等人的美国专利申请公开2007/0027135(本文中的“'135公开”)中,本文以引证的方式引入其全部内容,并且可以从它们的化学式可以看出它们与ABT-737结构上是相关的。
确定为'135公开中“实施例1”的一种化合物是N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-环己-1-烯-1-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(吗啉-4-基)-1-((苯基硫基)甲基)丙基)氨基-3-((三氟甲基)磺酰基)苯磺酰胺,或者称为ABT-263。 该化合物具有974.6
g/mol的分子量,并且具有下式∶
'135公开表明,公开在其中的某些化合物可以以酸加成盐、碱加成盐或两性离子形态存在。这种化合物的酸加成盐包括:乙酸盐,己二酸盐,海藻酸盐,碳酸氢盐,柠檬酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,二葡糖酸盐,甲酸盐,富马酸盐,甘油磷酸盐,谷氨酸盐,半硫酸盐,庚酸盐,己酸盐,盐酸盐,氢溴酸盐,氢碘酸盐,乳糖酸盐,乳酸盐,马来酸盐,均三甲苯磺酸盐,甲磺酸盐,亚萘基磺酸盐,烟酸盐,草酸盐,双羟萘酸盐,果胶酯酸盐,过硫酸盐,磷酸盐,苦味酸盐,丙酸盐,琥珀酸盐,酒石酸盐,硫氰酸盐,三氯乙酸盐,三氟乙酸盐,对甲苯磺酸盐和十一烷酸盐。
需要改进治疗的疾病的具体类型是非霍奇金淋巴瘤(NHL)。在美国,NHL是第六种最普遍类型的新癌症,并且主要出现在60-70岁的患者中。NHL不是单一疾病,其是相关疾病的家族,基于几个特征(包括临床特征和组织学特征)对其进行分类。
一种分类方法基于疾病的自然史将不同的组织亚型归为两种主要类型,即,疾病是否是惰性的(indolent)或攻击性(aggressive)的。通常,惰性亚型生长迟缓,并且通常不能治愈,而攻击性的亚型生长快速,并且可能治愈。滤泡性淋巴瘤是最常见的惰性亚型,并且扩散的大细胞淋巴瘤构成最常见的攻击性亚型。最初在非霍奇金B细胞淋巴瘤中描述了癌蛋白质Bcl-2。
滤泡性淋巴瘤的治疗典型地包括基于生物学的治疗或组合化疗。通常使用美罗华(rituximab)、环磷酰胺、多柔比星、长春花新碱(vincristine)和脱氢可的松(R-CHOP)的组合治疗,如同美罗华、环磷酰胺、长春花新碱和脱氢可的松(prednisone)(RCVP)的组合治疗一样。也使用利用美罗华(靶向CD20,在B细胞的表面上均匀表达的磷蛋白)或氟达拉滨的单一药剂治疗。化疗方案中加入美罗华可以提高响应率,并且可以提高无疾病进展生存期。
放射免疫治疗药剂、高剂量化疗和干细胞移植可用于治疗难治疗的或复发的非霍奇金淋巴瘤。目前,还没有被批准的、可产生治愈效果的治疗方案,并且现行指导方针建议患者在临床试验的背景下进行治疗,甚至在一线环境下。
患有攻击性大B细胞淋巴瘤的患者的一线治疗典型地包括:美罗华,环磷酰胺,多柔比星,长春花新碱和脱氢可的松(R-CHOP),或剂量调节的依托泊苷,脱氢可的松,长春花新碱,环磷酰胺,多柔比星和美罗华(DA-EPOCH-R)。
大部分淋巴瘤最初对这些治疗中的任何一种都有响应,但肿瘤典型地存在复发现象,并且最终变得难以治疗。由于患者接受的方案数量提高,所以,疾病变得更具有化疗耐受性。对一线治疗的平均响应大约为75%,对二线治疗的平均响应为60%,对三线治疗的平均响应为50%,对四线治疗的平均响应大约为35-40%。在多复发环境下,认为对于单一药剂具有接近20%的响应率是积极的,并且可以进一步研究。
现行的化疗剂通过各种机理引起细胞程序死亡,从而引起它们的抗癌响应。然而,许多肿瘤最终变得对这些药剂具有耐受性。在体外短期存活试验和近年来的体内试验中,Bcl-2和Bcl-X L 已经显示赋予了化疗耐性。这表明,如果可以开发针对抑制Bcl-2和Bcl-X L 的功能的改进治疗,则可以成功地克服这种化疗耐性。
本发明概述
当按照'135公开的实施例1制备化合物ABT-263时,可以回收其无定形、玻璃状固体,其不适合作为下游制剂的活性药物组分(API)。本发明人现在已经制备了许多固体结晶形式的新的ABT-263的二酸加成盐,在多种制剂类型中适合于用作API,包括API以颗粒形式与赋形剂一起存在的剂型,例如,口服递送的片剂或胶囊剂。此外,已经发现,包含该新盐的药物组合物显示出至少可与ABT-263游离碱的2 mg/ml溶液(在由PEG-400和DMSO组成的载体中,重量比9:1)相比较的口服生物利用率,并且在某些情况下比后者更高(见'135公开报道)。
在一个实施方案中,本发明提供了N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-环己-1-烯-1-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(吗啉-4-基)-1-((苯基硫基)甲基)丙基)氨基-3-((三氟甲基)磺酰基)苯磺酰胺 二-盐酸盐(ABT-263二-HCl)。
在一个进一步实施方案中,本发明提供了本文所表征的结晶形式I的ABT-263二-HCl。
在一个更进一步实施方案中,本发明提供了本文所表征的结晶形式II的ABT-263二-HCl。
在一个更进一步实施方案中,本发明提供了ABT-263二-HCl的各种溶剂化晶体形式,包括乙醇,1-丙醇,2-丙醇,2-丁醇,叔丁醇,硝基甲烷,乙腈,丙腈,甲酸乙酯,乙酸甲酯,乙酸乙酯,乙酸异丙酯,丙酮,2-丁酮(甲基乙基酮,甲乙酮),甲基异丙酮,1,4二烷,苯,甲苯和丁基醚溶剂化物。
在一个更进一步实施方案中,本发明提供了制备形式I的ABT-263二-HCl的方法,该方法包括:将ABT-263二-HCl的乙醇、1-丙醇、2-丙醇、2-丁醇、叔丁醇、乙腈、丙腈、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、丙酮、甲基异丙酮、1,4-二烷、苯、甲苯或丁基醚溶剂化物形式脱溶剂。
在一个更进一步实施方案中,本发明提供了制备形式II的ABT-263二-HCl的方法,该方法包括:将ABT-263二-HCl的MEK溶剂化形式脱溶剂。
在一个更进一步实施方案中,本发明提供了药物组合物,其包含ABT-263二-HCl和一或多种可药用赋形剂。
在一个更进一步实施方案中,本发明提供了治疗疾病的方法,该疾病以凋亡功能障碍和/或抗凋亡Bcl-2家族蛋白的超表达为特征,该方法包括:给予患有该疾病的患者治疗有效量的ABT
263二-HCl或包含ABT-263二-HCl和一或多种可药用赋形剂的药物组合物。这种疾病的例子包括许多肿瘤疾病,包括癌症。可以按照本方法治疗的具体说明性类型的癌症是非霍奇金淋巴瘤。可以按照本方法治疗的另一种具体说明性类型的癌症是慢性淋巴细胞性白血病。可以按照本方法治疗的又一个具体说明性类型的癌症是急性淋巴细胞性白血病,例如,在儿科患者中。
更进一步提供了维持人癌症患者的血流中ABT-263和/或其一或多种代谢产物的治疗有效血浆浓度的方法,例如,所述患者是患有非霍奇金淋巴瘤、慢性淋巴细胞性白血病或急性淋巴细胞性白血病的患者,包括给予该患者包含ABT-263二-HCl和一或多种可药用赋形剂的药物组合物,剂量相当于每天大约50至大约500 mg ABT-263,平均剂量间隔为大约3小时至大约7天。
本发明的其它实施方案,包括上面所提供那些的更具体方面,可以在随后的详细说明中得到,或可以通过随后的详细说明而变得很明显。
附图的简要说明
图1是结晶形式I的ABT-263二-HCl的PXRD扫描。
图2是结晶形式II的ABT-263二-HCl的PXRD扫描。
详细说明
ABT-263具有至少两个可质子化的氮原子,因此,每当量的化合物能够与一个当量以上(例如,大约1.2至大约2当量,大约1.5至大约2当量或大约1.8至大约2当量)的酸形成酸加成盐。说明性地,可以形成二-盐,包括乙酸盐,己二酸盐,海藻酸盐,碳酸氢盐,柠檬酸盐,天冬氨酸,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,二葡糖酸盐,甲酸盐,富马酸盐,甘油磷酸盐,谷氨酸盐,半硫酸盐,庚酸盐,己酸盐,盐酸盐,氢溴酸盐,氢碘酸盐,乳糖酸盐,乳酸盐,马来酸盐,均三甲苯磺酸盐,甲磺酸盐,亚萘基磺酸盐,烟酸盐,草酸盐,双羟萘酸盐,果胶酯酸盐,过硫酸盐,磷酸盐,苦味酸盐,丙酸盐,琥珀酸盐,酒石酸盐,硫氰酸盐,三氯乙酸盐,三氟乙酸盐,对甲苯磺酸盐和十一烷酸盐二-盐,例如,二-盐酸盐(二-HCl)和二-氢溴酸盐(二-HBr)盐。
ABT-263二-HCl,其具有1047.5 g/mol的分子量,可以由下列结构式代表∶
ABT-263二-HCl可以以固体形式存在,并且可以以这种形式分离,例如下文中的举例说明。作为API使用时,ABT-263二-HCl应该是基本上纯的,例如至少大约90%,至少大约95%,至少大约96%,至少大约97%,至少大约98%,或至少大约99%纯度(按重量计算)。ABT-263二-HCl的固体形式可以是晶体或非晶体。 ABT-263二-HCl还可以以在合适溶解介质(solubilizing medium)中的溶解形式存在,例如下文中的举例说明。在这种介质中,ABT-263二-HCl的浓度(表示为游离碱当量)可以是,例如,至少大约0.1 mg/ml,至少大约0.2 mg/ml,至少大约0.5 mg/ml,至少大约1 mg/ml,至少大约2 mg/ml或至少大约5 mg/ml,至多达到该介质中的溶解度极限,例如至多大约500
mg/ml,至多大约400 mg/ml,至多大约300
mg/ml,至多大约200 mg/ml或至多大约100
mg/ml。
ABT-263二-HCl可以用任何方法制备,包括ABT-263游离碱在合适介质中与2摩尔盐酸(HCl)进行反应。术语“游离碱”是为方便本文使用,指的是ABT-263母体化合物,同时应该了解,严格来说,该母体化合物是两性离子,并由此不能始终起到真正的碱的作用。
ABT-263游离碱可以如上面所引的美国专利申请公开2007/0027135的实施例1所述来制备,本文以引证的方式结合其全部公开内容。
制备ABT-263二-HCl的说明性方法描述如下。
该方法的第一阶段包括制备ABT-263母体化合物的下列反应∶
其中,“步骤1”和“步骤2”产物是分别按照'135公开的实施例1M和1I制备的中间体。“DMAP”是N,N-二甲基氨基-吡啶。“EDCI”是1-(3-二甲基氨基丙基)-3-乙基碳二亚胺。“DMEDA”是N,N-二甲基乙二胺。ABT-263母体化合物不是以固体产物形式从反应混合物中回收的。
更具体地说,将步骤2产物(13.3 kg,20.46 mol)、步骤1产物(9.9 kg,22.5 mol)、DMAP(6.6 kg,53.81
mol)和EDCI盐酸盐(6.12
kg,31.92 mol)加入到反应器中。然后加入二氯甲烷(126
kg),并将得到的反应混合物在30℃加热,直到反应完成为止(大约24小时;步骤2产物剩余<0.3%)。可以通过反相HPLC监测反应。
将反应混合物冷却至室温,并通过加入DMEDA(1.62 kg,18.41 mol)来猝灭过量的活化酸。
将反应混合物蒸馏至大约48升的体积,并加入8.0 kg水和150 kg乙酸乙酯(EtOAc)。将混合物蒸馏至90升的体积,并进一步加入8.0 kg水和150 kg EtOAc。将混合物蒸馏至115升的体积,并加入200 kg 10%乙酸+
0.75%氯化钠溶液和100 kg EtOAc。将反应器的内含物混合,并分离。将有机层用200 kg 10%乙酸+
0.75%氯化钠溶液、267 kg 25% K2HPO4溶液和242 kg pH7的缓冲溶液洗涤。
将有机层浓缩至大约48升,用两份EtOAc( 180 kg,180 kg)旋转-蒸馏(chase - distilled),每次浓缩至大约48升。加入额外的EtOAc(85 kg),用Karl
Fischer滴定来测定水含量。
将得到的EtOAc溶液用乙醇(EtOH,62 kg)稀释,通过聚丙烯0.5μm滤料精制-过滤到清洁反应器中,使用EtOAc(20 kg)作为冲洗液。在独立的便携式反应器中,制备HCl (
4.3 kg)的EtOH ( 80 kg)溶液,通过单独的新滤料和容器精制-过滤到反应器中。EtOH(10
kg)用作冲洗液。精制-过滤有机溶液,从最终提取物中除去残余磷酸盐。必须使用清洁的滤料和容器,以便避免HCl的中和作用。
将得到的溶液浓缩至大约245升,并维持该体积,同时加入额外的EtOH(497
kg)。使用HPLC分析来确定是否需要加入额外的EtOH,以便达到ABT-263二-HCl结晶所需要的大约20体积(vol)。
将产品溶液加热至45℃,加入ABT-263二-HCl晶种(150 g)(在EtOH(1 kg)中的浆液)。在65 rpm下搅拌6小时之后,用1小时将浆液冷却至20℃,并另外混合36小时。进行滤液的分析,以便表明结晶完毕。
使用聚丙烯滤垫,将浆液过滤到过滤-干燥器中。用EtOH(2×80 kg)冲洗固体。在搅拌下(不用真空),以浆液形式施加冲洗液(接触时间每次15-25分钟),而后真空抽滤除去冲洗液。将得到的湿滤饼采集样品,测定杂质,以确定是否需要重结晶。
将固体在真空和氮气氛围中、在50℃下真空干燥8天,同时轻微搅动(对于第一个8小时,每小时轻微搅动5分钟,然后每8小时轮次轻微搅动5分钟)。干燥样品的分析表明何时干燥完成(剩余EtOH<0.05%)。
在上述方法的操作中,白色固体产物产率是17.4 kg(81.0% HPLC峰面积产率,99.72%效能)。
该方法的产物是结晶形式I的ABT-263二-HCl(如下面更充分地描述),通过从乙醇溶剂化物中去溶剂化,可以制备基本上无溶剂的结晶形态。这种产物在各种药物组合物(制剂)的下游制备中已经用作API。
如下所述,由API已经制备ABT-263二-HCl的溶剂化物。
将测定数量(按重量计算)的上面制备的ABT-263二-HCl单独地悬浮在每个0.5 ml溶剂中,如表1所列。将该悬浮液在环境温度下搅拌,避光操作。所得到的溶剂化物的特点在于粉末X射线衍射(PXRD)。
使用配备有弧形位置灵敏探测器和平行束光学装置的G3000衍射器(Inel
Corp., Artenay,France)收集PXRD数据。在40 kV和30 mA条件下,用铜阳极管(1.5 kW细焦)操作衍射器。入射束锗单色仪提供单色辐射。使用衰减的直射光束、以一度间隔校正衍射器。使用硅粉线位置对照准标(
NIST 640c)检查校正。使用Symphonix软件(Inel
Corp., Artenay,France),用计算机控制仪器,并使用Jade软件(version 6.5,Materials
Data,Inc., Livermore,CA)分析数据。将样品装填到铝样品座上,并与载玻片水平。
表1. 制备ABT-263二-HCl晶体溶剂化物使用的溶剂
溶剂 | 化合物的重量(mg) |
乙醇 | 274.5 |
2-丙醇 | 249.8 |
叔丁醇 | 255.8 |
1-丙醇 | 259.6 |
2-丁醇 | 260.1 |
硝基甲烷 | 284.5 |
乙腈 | 290.7 |
丙腈 | 295.5 |
乙酸乙酯 | 300.6 |
乙酸异丙酯 | 301.2 |
甲酸乙酯 | 293.3 |
乙酸甲酯 | 256.5 |
丙酮 | 250.4 |
2-丁酮(MEK) | 252.8 |
甲基异丙酮 | 255.5 |
1,4-二烷 | 262.4 |
苯 | 250.1 |
甲苯 | 290.2 |
丁基醚 | 289.6 |
已经制备某些溶剂化物的单晶体用于结晶分析。
为了制备丙腈溶剂化物的单晶体,在60℃,将上面制备的ABT-263二-HCl悬浮在丙腈中。使用针筒式滤器过滤该悬浮液,并将滤液转移到新管瓶中。将管瓶放置在己烷舱中。一周以后,观察到单晶体。丙腈溶剂化物的晶体学数据提供于表2中。
表2. ABT-263二-HCl丙腈溶剂化物的结晶信息
晶格类型 | 三斜晶 |
空间群 | P 1 |
晶胞棱长a | 13.975 Å |
晶胞棱长b | 16.988 Å |
晶胞棱长c | 17.850 Å |
晶角α | 101.816° |
晶角β | 105.892° |
晶角γ | 112.258° |
晶胞体积 | 3538.28 Å3 |
Z | 2 |
为了制备硝基甲烷溶剂化物的单晶体,在60℃,将上面制备的ABT-263二-HCl悬浮在硝基甲烷中。使用针筒式滤器过滤该悬浮液,并将滤液转移到新管瓶中。将管瓶放置在2-丁酮舱中。一周以后,观察到单晶体。硝基甲烷溶剂化物的晶体学数据提供于表3中。
表3. ABT-263二-HCl硝基甲烷溶剂化物的结晶信息
晶格类型 | 单斜晶 |
空间群 | C2 |
晶胞棱长a | 31.500 Å |
晶胞棱长b | 13.812 Å |
晶胞棱长c | 30.764 Å |
晶角α | 90.000° |
晶角β | 116.205° |
晶角γ | 90.000° |
晶胞体积 | 12009.1 Å3 |
Z | 8 |
为了制备乙腈溶剂化物的单晶体,在高温下,将上面制备的ABT-263二-HCl溶于水/乙腈(1:99,以体积计)中,接近其溶解度极限。然后将得到的澄清溶液自然冷却至环境温度。几天之后,观察到单晶体。乙腈溶剂化物的晶体学数据提供于表4中。
表4. ABT-263二-HCl乙腈溶剂化物的结晶信息
晶格类型 | 三斜晶 |
空间群 | P 1 |
晶胞棱长a | 13.799 Å |
晶胞棱长b | 15.267 Å |
晶胞棱长c | 15.971 Å |
晶角α | 112.862° |
晶角β | 108.978° |
晶角γ | 96.294° |
晶胞体积 | 2822.21 Å3 |
Z | 2 |
各个溶剂化物的PXRD峰列于表5-23中。峰位置典型地是±0.2度2-theta(°2θ)。在丙腈、硝基甲烷和乙腈溶剂化物的情况下,由单晶结构计算PXRD峰。
表5. PXRD峰列表∶ABT-263二-HCl乙醇溶剂化物
峰位置(°2θ) | 相对强度 |
5.7 | 1.3 |
6.8 | 53.3 |
7.1 | 3.3 |
7.9 | 2.5 |
9.6 | 6.5 |
12.3 | 5.6 |
13.6 | 4.5 |
15.8 | 9.3 |
18.4 | 10.2 |
18.6 | 18.6 |
19.5 | 13.7 |
19.8 | 81.5 |
20.0 | 100.0 |
表6. PXRD峰列表∶ABT-263二-HCl 2-丙醇溶剂化物
峰位置(°2θ) | 相对强度 |
6.5 | 11.7 |
7.0 | 56.8 |
8.0 | 2.5 |
12.1 | 5.0 |
16.2 | 7.4 |
17.1 | 4.8 |
17.8 | 4.5 |
18.2 | 100.0 |
18.5 | 96.1 |
18.7 | 38.9 |
19.6 | 6.7 |
表7. PXRD峰列表∶ABT-263二-HCl 叔-丁醇溶剂化物
峰位置(°2θ) | 相对强度 |
6.3 | 8.8 |
6.8 | 69.2 |
7.9 | 3.3 |
11.1 | 6.8 |
11.4 | 6.8 |
12.2 | 5.6 |
13.7 | 5.5 |
15.9 | 14.7 |
17.6 | 10.1 |
18.4 | 100.0 |
表8. PXRD峰列表∶ABT-263二-HCl 1-丙醇溶剂化物
峰位置(°2θ) | 相对强度 |
6.6 | 89.9 |
7.1 | 3.7 |
7.8 | 3.2 |
9.5 | 13.0 |
12.1 | 5.7 |
13.5 | 5.5 |
15.4 | 16.9 |
18.1 | 9.5 |
18.5 | 20.3 |
19.2 | 17.0 |
19.5 | 100.0 |
21.5 | 14.2 |
表9. PXRD峰列表∶ABT-263二-HCl 2-丁醇溶剂化物
峰位置(°2θ) | 相对强度 |
6.8 | 100.0 |
7.9 | 1.2 |
9.8 | 11.1 |
12.2 | 3.2 |
13.6 | 6.0 |
15.8 | 10.0 |
18.2 | 9.1 |
18.5 | 16.6 |
19.8 | 80.1 |
20.0 | 88.4 |
表10. PXRD峰列表∶ABT-263二-HCl硝基甲烷溶剂化物
(由晶体结构计算)
峰位置(°2θ) | 相对强度 |
3.2 | 1.4 |
6.2 | 60.1 |
6.4 | 100.0 |
6.7 | 12.0 |
7.1 | 11.9 |
8.4 | 57.0 |
11.9 | 26.4 |
13.4 | 14.5 |
14.0 | 9.9 |
15.9 | 17.4 |
17.1 | 12.4 |
17.4 | 38.4 |
18.6 | 32.4 |
18.7 | 35.2 |
20.1 | 38.4 |
21.0 | 21.3 |
21.7 | 17.8 |
表11. PXRD峰列表∶ABT-263二-HCl乙腈溶剂化物
(由晶体结构计算)
峰位置(°2θ) | 相对强度 |
6.5 | 92.7 |
6.8 | 59.5 |
7.0 | 29.2 |
7.4 | 2.3 |
8.2 | 50.4 |
9.2 | 6.9 |
11.1 | 12.8 |
12.1 | 12.4 |
13.1 | 17.4 |
14.1 | 16.6 |
15.4 | 25.6 |
15.9 | 26.7 |
17.1 | 46.1 |
17.8 | 100.0 |
18.1 | 81.8 |
18.4 | 56.9 |
19.1 | 13.3 |
20.0 | 19.3 |
20.6 | 23.2 |
21.2 | 75.7 |
21.7 | 17.2 |
表12. PXRD峰列表∶ABT-263二-HCl丙腈溶剂化物
(由晶体结构计算)
峰位置(°2θ) | 相对强度 |
5.5 | 100.0 |
6.0 | 3.0 |
6.6 | 9.3 |
7.1 | 17.0 |
7.3 | 14.1 |
8.4 | 1.0 |
9.4 | 3.4 |
12.7 | 4.9 |
14.2 | 4.8 |
14.6 | 4.5 |
15.7 | 6.3 |
18.0 | 6.6 |
18.3 | 7.8 |
20.6 | 4.6 |
表13. PXRD峰列表∶ABT-263二-HCl乙酸乙酯溶剂化物
峰位置(°2θ) | 相对强度 |
6.7 | 100.0 |
7.2 | 3.2 |
8.0 | 6.4 |
9.6 | 21.9 |
12.4 | 13.2 |
13.5 | 7.3 |
13.7 | 10.3 |
15.1 | 9.2 |
15.8 | 15.0 |
17.3 | 10.9 |
18.5 | 50.1 |
19.8 | 94.3 |
20.0 | 97.5 |
22.1 | 20.0 |
24.5 | 11.2 |
表14. PXRD峰列表∶ABT-263二-HCl乙酸异丙酯溶剂化物
峰位置(°2θ) | 相对强度 |
6.6 | 73.3 |
7.8 | 2.7 |
9.5 | 15.2 |
12.0 | 4.8 |
13.4 | 5.9 |
14.7 | 6.9 |
15.4 | 5.0 |
18.1 | 15.6 |
18.4 | 22.4 |
19.3 | 100.0 |
表15. PXRD峰列表∶ABT-263二-HCl甲酸乙酯溶剂化物
峰位置(°2θ) | 相对强度 |
5.7 | 1.6 |
6.8 | 85.8 |
7.2 | 3.8 |
8.0 | 4.5 |
9.7 | 13.9 |
12.3 | 9.7 |
13.7 | 8.9 |
15.9 | 15.7 |
18.6 | 46.9 |
19.6 | 18.4 |
19.9 | 100.0 |
22.0 | 21.7 |
表16. PXRD峰列表∶ABT-263二-HCl乙酸甲酯溶剂化物
峰位置(°2θ) | 相对强度 |
6.7 | 23.1 |
7.0 | 57.2 |
8.2 | 4.0 |
11.8 | 10.0 |
16.3 | 6.4 |
16.8 | 5.5 |
17.5 | 3.6 |
18.1 | 85 |
18.3 | 100.0 |
18.7 | 19.1 |
21.1 | 19.1 |
表17. PXRD峰列表∶ABT-263二-HCl丙酮溶剂化物
峰位置(°2θ) | 相对强度 |
6.9 | 63.2 |
8.2 | 3.4 |
11.8 | 5.6 |
12.1 | 2.5 |
16.3 | 10.7 |
16.7 | 9.8 |
17.8 | 14.8 |
18.2 | 100.0 |
18.4 | 63.3 |
20.8 | 20.2 |
21.1 | 14.1 |
表18. PXRD峰列表∶ABT-263二-HCl MEK溶剂化物
峰位置(°2θ) | 相对强度 |
6.2 | 100.0 |
8.2 | 4.3 |
10.4 | 6.3 |
13.1 | 8.8 |
17.0 | 39.1 |
17.2 | 38.8 |
18.3 | 14.7 |
18.8 | 9.4 |
表19. PXRD峰列表∶ABT-263二-HCl甲基异丙酮溶剂化物
峰位置(°2θ) | 相对强度 |
6.5 | 100.0 |
7.8 | 1.6 |
9.3 | 15.9 |
12.3 | 6.5 |
13.3 | 4.7 |
14.8 | 5.3 |
15.6 | 5.7 |
18.0 | 26.4 |
18.4 | 8.1 |
19.1 | 50.0 |
19.5 | 64.2 |
峰位置(°2θ) | 相对强度 |
5.7 | 100.0 |
7.0 | 3.1 |
7.5 | 2.9 |
15.3 | 6.8 |
16.0 | 5.0 |
17.0 | 11.4 |
17.8 | 5.8 |
18.4 | 17.7 |
18.6 | 28.6 |
19.5 | 32.4 |
20.4 | 9.1 |
21.3 | 22.1 |
表21. PXRD峰列表∶ABT-263二-HCl苯溶剂化物
峰位置(°2θ) | 相对强度 |
5.3 | 100.0 |
5.7 | 53.9 |
6.5 | 25.9 |
6.8 | 46.5 |
7.2 | 45.6 |
17.9 | 48.1 |
18.2 | 80.4 |
18.6 | 85.7 |
19.3 | 12.2 |
19.6 | 14.9 |
20.2 | 15.3 |
20.7 | 15.3 |
21.0 | 23.6 |
21.3 | 21.4 |
表22. PXRD峰列表∶ABT-263二-HCl甲苯溶剂化物
峰位置(°2θ) | 相对强度 |
5.5 | 100.0 |
6.7 | 14.5 |
7.0 | 5.9 |
7.9 | 4.4 |
9.3 | 3.9 |
10.7 | 7.2 |
14.1 | 13.5 |
14.7 | 8.8 |
17.8 | 41.2 |
18.0 | 42.0 |
18.5 | 17.1 |
19.3 | 36.6 |
19.8 | 16.0 |
表23. PXRD峰列表∶ABT-263二-HCl丁基醚溶剂化物
峰位置(°2θ) | 相对强度 |
6.7 | 28 |
7.0 | 60.6 |
8.4 | 9.8 |
11.8 | 5.9 |
12.2 | 3.5 |
13.5 | 5.3 |
16.5 | 8.0 |
16.7 | 10.8 |
17.9 | 39.7 |
18.4 | 100.0 |
20.7 | 15.4 |
20.8 | 17.1 |
21.2 | 23.1 |
大部分溶剂化物的去溶剂化,包括1-丙醇、2-丙醇、2-丁醇、叔丁醇、乙腈、丙腈、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、丙酮、甲基异丙酮、1,4-二烷、苯、甲苯和丁基醚溶剂化物,提供ABT-263二-HCl的无溶剂的结晶形态,通过PXRD显示,其与乙醇溶剂化物的去溶剂化所制备的API的形态相同。这种结晶形态称为形式I。形式I的ABT-263二-HCl的PXRD扫描示于图1中。形式I的ABT-263二-HCl的PXRD峰列于表24中。具有基本上如其中所表明峰的PXRD图可用于鉴定ABT-263二-HCl,更具体地说,形式I的ABT-263二-HCl。本文中的短语“基本上如所表明的”是指所具有的峰从所表明的位置移动不超过大约0.2°2θ。可以认为,操作与操作之间,峰的相对强度可以多少有点变化,但通常峰强度的排列顺序与表24所示的PXRD图的顺序相似。
表24. PXRD峰列表∶ABT-263二-HCl形式I
峰位置(°2θ) | 相对强度 |
6.8 | 59.0 |
7.2 | 75.9 |
8.5 | 14.3 |
9.3 | 4.3 |
11.2 | 6.5 |
13.8 | 15.8 |
14.0 | 17.7 |
14.9 | 9.5 |
16.7 | 17.5 |
17.5 | 15.7 |
18.2 | 52.2 |
18.5 | 100.0 |
18.7 | 95.4 |
形式I ABT-263二-HCl通常可以与下面的形式II不同,这是由于存在任何一个或多个,例如任何两个或多个,任何三个或更多,任何四个或更多,或所有五个下列PXRD峰∶6.8、7.2、8.5、18.5和18.7°2θ(在每种情况下,±0.2°2θ)。
MEK溶剂化物的去溶剂化可以提供ABT-263二-HCl的无溶剂结晶形态,通过PXRD显示,其与乙醇溶剂化物的去溶剂化所制备的API的形态不同。衍生自MEK溶剂化物的去溶剂化的这种结晶形态称为形式II。形式II的ABT-263二-HCl的PXRD扫描示于图2中。形式II的ABT-263二-HCl的PXRD峰列于表25中。 具有基本上如其中所表明峰的PXRD图可用于鉴定ABT-263二-HCl,更具体地说,形式II的ABT-263二-HCl。本文中的短语“基本上如所表明的”是指所具有的峰从所表明的位置移动不超过大约0.2 °2θ。可以认为,操作与操作之间,峰的相对强度可以多少有点变化,但通常峰强度的排列顺序与表25所示的PXRD图的顺序相似。
表25. PXRD峰列表∶ABT-263二-HCl形式II
峰位置(°2θ) | 相对强度 |
3.7 | 6.0 |
7.4 | 100.0 |
12.1 | 5.3 |
15.6 | 8.6 |
16.1 | 16.2 |
16.6 | 21.6 |
18.3 | 70.2 |
19.0 | 13.4 |
形式II的ABT-263二-HCl通常可以与上面形式I不同,这是由于存在任何一个或两个下列PXRD峰∶3.7和7.4°2θ(在每种情况下,±0.2°2θ)。
ABT-263二-HCl,例如形式I、形式II或其组合,可以用于制备适合于任何给药途径的药物组合物,包括口服,给予需要其的患者。由此,在本发明的某些实施方案中,提供了药物组合物,其包含ABT-263二-HCl和一或多种可药用赋形剂。在一个实施方案中,组合物包含形式I的ABT-263二-HCl。在另一个实施方案中,组合物包含形式II的ABT-263二-HCl。在又一个实施方案中,组合物包含在合适载体系统中的ABT-263二-HCl的溶液。按照任何这些实施方案,可以递送该组合物,例如,通过口服途径。其它给药途径包括但不限于:肠胃外,舌下,口腔,鼻内,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内和关节内途径。
当按照合适方案给予需要其的患者该组合物时,这种组合物包含治疗有效数量的ABT-263二-HCl。本文以游离碱当量数量来表示剂量数量,除非上下文另外要求。典型地,单位剂量(单次给予的数量)大约为10至大约1,000 mg,可以以合适频率给予,例如,每天两次至每周一次。如果给药频率是每天一次(q.d.),则单位剂量和日剂量相同。 举例说明,在本发明的组合物中,ABT-263的单位剂量可以是大约25至大约1,000 mg,更典型地是大约50至大约500 mg,例如大约50 mg,大约100 mg,大约150 mg,大约200 mg,大约250 mg,大约300 mg,大约350 mg,大约400 mg,大约450 mg或大约500 mg。如果以分散剂型形式制备该组合物,例如片剂或胶囊剂,则可以按单个剂型递送单剂型或以小的多个剂型,最典型地是1至大约10个剂型。
单位剂量越高,选择在制剂中能够装填相对高数量API(在这种情况下是ABT-263二-HCl)的赋形剂越合乎需要。典型地,本发明制剂中的ABT-263二-HCl的浓度(表示为游离碱当量)至少为大约1%,例如,大约1%至大约50%(按重量计算),但在特定病例中,可以接受或达到更低和更高浓度。举例说明,在各种实施方案中,ABT-263游离碱当量浓度至少为制剂的大约2%,例如,大约2%至大约40%,按重量计算,例如大约5%,大约10%,大约15%,大约20%,大约25%或大约30%(按重量计算)。
除了API之外,本发明的组合物还包含一或多种可药用赋形剂。如果制备口服固态形式的组合物,例如片剂或胶囊剂,其典型地包括至少一或多种固体稀释剂和一或多种固体崩解剂。任选,赋形剂进一步包括一或多种粘合剂、润湿剂和/或抗摩擦的药剂(润滑剂、防粘剂和/或助流剂)。在药物组合物中,许多赋形剂具有两种或多种功能。本文中,表征具体赋形剂具有某些功能,例如,稀释剂、崩解剂、粘合剂,等等,不应该被解读为为限于该功能。关于赋形剂的详细资料可以在标准参考资料中得到,例如Handbook
of Pharmaceutical Excipients, 3rd ed.(Kibbe, ed.(2000), Washington:
American Pharmaceutical Association)。
举例说明,合适稀释剂包括下列中的单独任何一种或其组合物:乳糖,包括无水乳糖和乳糖一水合物;乳糖醇;麦芽糖醇;甘露糖醇;山梨糖醇;木糖醇;葡萄糖和葡萄糖一水合物;果糖;蔗糖和蔗糖基稀释剂,例如可压缩糖,糖果店的糖和糖球;麦芽糖;肌醇;谷物水解固形物;淀粉(例如,玉米淀粉,麦淀粉,米淀粉,马铃薯淀粉,木薯淀粉,等等),淀粉组分,例如直链淀粉和葡萄糖结合剂,和改性或加工的淀粉,例如预胶凝淀粉;糊精;纤维素,包括粉末纤维素,微晶纤维素,硅化微晶纤维素,食品等级的α-和非晶态纤维素和粉末纤维素,和醋酸纤维素;钙盐,包括碳酸钙,三元磷酸钙,二碱磷酸钙二水合物,一元硫酸钙一水合物,硫酸钙和颗粒状乳酸钙三水合物;碳酸镁;氧化镁;膨润土;高岭土;氯化钠;等等。这种稀释剂(如果存在的话)典型地构成组合物(按重量计算)的总计大约5%至大约95%,例如大约20%至大约90%或大约50%至大约85%。优选,所选择的稀释剂显示出合适的流动特性,如果需要片剂,显示出可压缩性。
微晶纤维素和硅化微晶纤维素是特别有用的稀释剂,并且任选与水溶性的稀释剂例如甘露糖醇组合使用。举例说明,微晶纤维素或硅化微晶纤维素与甘露糖醇的合适重量比为大约10:1至大约1:1,但在特定情况下,可以使用超出该范围的比例。
合适的崩解剂包括(单独一种或组合物):淀粉,包括预胶凝淀粉和羟甲淀粉钠;粘土;硅酸镁铝;纤维素基崩解剂,例如粉末纤维素,微晶纤维素,甲基纤维素,低取代的羟丙基纤维素,羧甲纤维素,羧甲纤维素钙,羧甲纤维素钠和交联羧甲纤维素钠;海藻酸盐;聚维酮;交联聚维酮;聚克利林钾;树胶,例如琼脂,瓜尔胶,角豆荚果,卡拉牙胶,果胶和黄芪胶;胶体二氧化硅;等等。一或多种崩解剂(如果存在的话)典型地构成组合物(按重量计算)的总计大约0.2%至大约30%,例如大约0.5%至大约20%,或大约1%至大约10%。
羟甲淀粉钠是特别有用的崩解剂,并且典型地构成组合物(按重量计算)的总计大约1%至大约20%,例如大约2%至大约15%,或大约5%至大约10%。
粘合剂或粘附剂是有用的赋形剂,特别在组合物是片剂形式的情况下。这种粘合剂和粘附剂应该能够充分粘合制片混合物,以便可以正常加工操作,例如筛选、润滑、挤压和包装,但还应该使片剂崩解,使得在摄入时可以吸收组合物。合适的粘合剂和粘附剂包括(单独一种或组合):阿拉伯胶;黄芪胶;葡萄糖;聚糊精;淀粉,包括预胶凝淀粉;凝胶;改性纤维素,包括甲基纤维素,羧甲纤维素钠,羟丙基甲基纤维素(HPMC),羟丙基纤维素,羟乙基纤维素和乙基纤维素;糊精,包括麦芽糖糊精;玉米蛋白;海藻酸和海藻酸的盐,例如海藻酸钠;硅酸镁铝;膨润土;聚乙二醇(PEG);聚氧化乙烯;胍尔豆胶;多糖酸;聚乙烯吡咯烷酮(聚维酮或PVP),例如聚维酮K-15、K-30和K-29/32;聚丙烯酸(卡波姆);聚甲基丙烯酸酯;等等。一或多种粘合剂和/或粘附剂(如果存在的话)典型地构成组合物(按重量计算)的总计大约0.5%至大约25%,例如大约1%至大约15%,或大约1.5%至大约10%。
聚维酮和羟丙基纤维素(单独一种或组合)是特别有用的片剂制剂的粘合剂,如果存在的话,典型地构成组合物(按重量计算)的大约0.5%至大约15%,例如大约1%至大约10%,或大约2%至大约8%。
通常选择润湿剂(如果存在的话),以便保持药物与水密切结合,这种条件可以提高组合物的生物利用率。可以用作润湿剂的表面活性剂的非限制性例子包括(单独一种或组合):季胺化合物,例如苯扎氯铵、苄索氯铵和氯化十六烷基吡啶;琥珀磺酸二辛钠;聚氧乙烯烷基苯基醚,例如壬苯醇醚9、壬苯醇醚10和辛基酚聚醚9;泊洛沙姆(聚氧乙烯和聚氧化丙烯嵌段共聚物);聚氧乙烯脂肪酸甘油酯和油,例如聚氧乙烯(8)辛酸/癸酸甘油单酯和甘油二酯,聚氧乙烯(35)蓖麻油和聚氧乙烯(40)氢化蓖麻油;聚氧乙烯烷基醚,例如鲸蜡醇聚醚-10、月桂醚-4、月桂醚-23、油醇聚醚-2、油醇聚醚-10、油醇聚醚-20、硬脂醇聚醚-2、硬脂醇聚醚-10、硬脂醇聚醚-20、硬脂醇聚醚-100和聚氧乙烯(20)鲸蜡醇醚;聚氧乙烯脂肪酸酯,例如聚氧乙烯(20)硬脂酸酯,聚氧乙烯(40)硬脂酸酯和聚氧乙烯(100)硬脂酸酯;脱水山梨糖醇酯,例如脱水山梨醇单月桂酸酯,单油酸山梨醇酐酯,脱水山梨糖醇甘油一棕榈酸酯和单硬脂酸山梨糖醇酐酯;聚氧乙烯脱水山梨糖醇酯,例如聚山梨酸酯20和聚山梨酸酯80;丙二醇脂肪酸酯,例如丙二醇月桂酸酯;月桂基磺酸钠;脂肪酸和其盐,例如油酸、油酸钠和油酸三乙醇胺盐;甘油基脂肪酸酯,例如甘油单油酸酯,单硬脂酸甘油酯和硬脂酸棕榈酸甘油酯;四丁酚醛(tyloxapol);等等。一或多种润湿剂(如果存在的话)典型地构成组合物(按重量计算)的总计大约0.1%至大约15%,例如大约0.2%至大约10%,或大约0.5%至大约7%。
非离子型表面活性剂,更尤其是泊洛沙姆,是本文可以使用的润湿剂的例子。举例说明,泊洛沙姆,例如PluronicTM
F127(如果存在的话),典型地构成组合物(按重量计算)的总计大约0.1%至大约10%,例如大约0.2%至大约7%,或大约0.5%至大约5%。
在片剂的压缩期间,润滑剂降低了片剂混合物和制片设备之间的摩擦。合适润滑剂包括(单独一种或组合):甘油基山嵛酸酯;硬脂酸和其盐,包括硬脂酸镁、硬脂酸钙和硬脂酸钠;氢化植物油;硬脂酸棕榈酸甘油酯;滑石粉;石蜡;苯甲酸钠;乙酸钠;富马酸钠;十八烷基富马酸钠;PEGs(例如,PEG 4000和PEG 6000);泊洛沙姆;聚乙烯醇;油酸钠;月桂基磺酸钠;月桂基硫酸镁;等等。一或多种润滑剂(如果存在的话)典型地构成组合物(按重量计算)的总计大约0.05%至大约10%,例如大约0.1%至大约5%,或大约0.2%至大约2%。十八烷基富马酸钠是尤其有用的润滑剂。
防粘剂降低片剂与设备表面的粘附。合适防粘剂包括(单独一种或组合):滑石粉,胶体二氧化硅,淀粉,DL-亮氨酸,月桂基磺酸钠和金属硬脂酸盐。一或多种防粘剂(如果存在的话)典型地构成组合物(按重量计算)的总计大约0.05%至大约10%,例如大约0.1%至大约7%,或大约0.2%至大约5%。胶体二氧化硅是尤其有用的防粘剂。
助流剂提高制片混合物的流动特性,并且降低其中的静电。合适助流剂包括(单独一种或组合):胶体二氧化硅,淀粉,粉末纤维素,月桂基硫酸钠,三硅酸镁和金属硬脂酸盐。一或多种助流剂(如果存在的话)典型地构成组合物(按重量计算)的总计大约0.05%至大约10%,例如大约0.1%至大约7%,或大约0.2%至大约5%。胶体二氧化硅是尤其有用的助流剂。
其它赋形剂,例如缓冲剂、稳定剂、抗氧化剂、抗微生物剂、着色剂、调味剂和甜味剂,在药物领域是已知的,并且可以在本发明的组合物中使用。片剂可以是无包衣的片剂,或可以包含包衣的核,例如,用非功能的膜或改进释放包衣或肠溶包衣。胶囊剂可以具有硬或软壳,其包含例如明胶(硬明胶胶囊或弹性软明胶胶囊形式)、淀粉、卡拉胶和/或HPMC,任选与一或多种增塑剂一起。
本发明的固体口服递送组合物不受制备它所使用的任何方法的限制。可以使用任何合适的药学方法,包括干混合(直接挤压或不直接挤压)和湿或干法成粒。
如果制备液体(包括密封液体)形式的组合物,则可以将API(ABT-263二-HCl)例如溶于合适载体中,典型地是包含API的脂溶剂的载体。单位剂量越高,选择在其溶液中能够容许浓度相对高的药物的载体越合乎需要。典型地,API在载体中的游离碱当量浓度至少为大约10 mg/ml,例如大约10至大约500 mg/ml,但在特定情况中,可以接受或达到更低和更高浓度。举例说明,在各种实施方案中,药物浓度至少为大约10
mg/ml,例如,大约10至大约400
mg/ml,或至少大约20 mg/ml,例如,大约20至大约200 mg/ml,例如大约20、大约25、大约30、大约40、大约50、大约75、大约100、大约125、大约150或大约200 mg/ml。
载体可以是基本上非水的载体,即,不含有水,或具有适量的水,也就是说,实际上对组合物的特性或性能基本上无害的足够少的水。典型地,载体包含零至小于大约5%重量的水。可以理解,本文使用的某些组分可以在它们的分子或超分子结构上或其内部结合少量的水;这种结合水(如果存在的话)不能影响本文所定义载体的“基本上非水的”特征。
在一些实施方案中,载体包括一或多种甘油酯材料。合适的甘油酯材料包括但不限于:中至长链甘油单、二和三酯。本文中的术语“中链”是指单独地具有不少于大约6个和少于大约12个碳原子的烃基链,包括例如C8至C10链。由此,包含辛酰基和癸酰基链的甘油酯材料,例如,辛酸/癸酸甘油单、二和/或三酯,是本文中的“中链”甘油酯材料的例子。本文中的术语“长链”是指单独具有至少大约12个碳原子的烃基链,例如大约12至大约18个碳原子,包括例如月桂基,十四烷基,鲸蜡基,十八烷基,油烯基,亚油酸基和亚麻烯基链。在甘油酯材料中,中至长链烃基可以是饱和的、单或多不饱和的烃基。
在一个实施方案中,载体包含中链和/或长链甘油三酯材料。中链甘油三酯材料的合适例子是辛酸/癸酸甘油三酯产品,例如,Abitec Corp.的Captex
355 EPTM和其中基本上相当的产品。长链甘油三酯的合适例子包括任何可药用植物油,例如芥子(canola)油,椰油,玉米油,棉籽油,亚麻子油,橄榄油,棕榈油,花生油,红花油,芝麻油,大豆油和向日葵油,和这种油的混合物。还可以使用动物来源的油,尤其是海洋动物油,包括例如鱼油。
已经发现尤其有用的载体系统包括两个主要组分∶磷脂和该磷脂的可药用增溶剂。可以理解,本文中以单数形式提及的磷脂、增溶剂或其它制剂组分包括复数;由此,本文明确地包括一种以上的磷脂或一种以上的增溶剂的组合,例如混合物。增溶剂或增溶剂和磷脂的组合也增溶药物,尽管任选存在于载体中的其它载体组分,例如表面活性剂或醇(例如乙醇),可以在一些情况下使药物的溶解性提高。
可以使用任何可药用磷脂或磷脂的混合物。通常,这种磷脂是磷酸、脂肪酸、醇和含氮碱水解时所产生的磷酸酯。可药用磷脂可以包括但不限于:卵磷脂、丝氨酸磷脂和磷脂酰乙醇胺。在一个实施方案中,组合物包括从例如天然卵磷脂得到的卵磷脂。可以使用卵磷脂的任何源,包括动物源,例如蛋黄,但通常优选植物源卵磷脂。大豆尤其富含卵磷脂,其可以提供本发明使用的卵磷脂。
举例说明,磷脂的合适数量为载体的大约15%至大约75%重量,例如大约30%至大约60%重量,不过,在特定情况下,可以使用更大和更小的数量。
对用作增溶剂组成部分的组分没有特别限制,并且在某种程度上取决于所需要的药物和磷脂的浓度。在一个实施方案中中,增溶剂包括一或多种二醇、一或多种乙交酯和/或一或多种甘油酯材料。
合适的二醇包括丙二醇和聚乙二醇(PEGs),具有大约200至大约1,000 g/mol的分子量,例如PEG-400,其具有大约400 g/mol的平均分子量。这种二醇可以提供相对高的药物溶解度;然而,当在包含这种二醇的载体溶液中时,例如,由于二醇倾向于产生超氧化物、过氧化物和/或游离羟基,使得药物氧化降解的可能性提高。载体的二醇含量越高,化学上不稳定药物的降解倾向越大。因此,在一个实施方案中,存在一或多种二醇,总二醇数量至少为载体的大约1%重量但少于大约50%重量,例如少于大约30%重量,少于大约20%重量,少于大约15%重量或少于大约10%重量。在另一个实施方案中,载体基本上不包含二醇。
乙交酯是用一或多种有机酸(例如,中至长链脂肪酸)酯化的二醇,例如丙二醇或PEG。合适实例包括例如丙二醇单辛酸酯、丙二醇单月桂酸酯和丙二醇二月桂酸酯产品,例如Abitec
Corp.的Capmul PG-8TM、Capmul PG-12TM和Capmul
PG-2LTM以及基本上与其相当的产品。
与磷脂一起使用的合适甘油酯材料包括但不限于上述那些甘油酯。在一或多种甘油酯材料作为增溶剂的主要组分存在的情况下,甘油酯的合适总量是有效增溶磷脂的数量,和在与载体的其它组分的组合中,是在溶液中有效保持药物和抗氧化剂的数量。例如,甘油酯材料(例如,中链和/或长链甘油三酯)可以按照载体的大约5%至大约70%重量的总甘油酯数量存在,例如大约15%至大约60%重量或大约25%至大约50%重量。
如果需要的话,可以包括不同于二醇或甘油酯材料的其它增溶剂。这种试剂,例如N-取代的酰胺溶剂,例如二甲基甲酰胺(DMF)和N,N-二甲基乙酰胺(DMA),可以在特定情况下有助于提高药物在载体中的溶解度极限,由此提高药物填充量。然而,本文使用的载体通常不用这种其它试剂就可以提供本文感兴趣的小分子药物的足够的溶解度。
即使当存在足够数量的二醇、乙交酯或甘油酯物质来溶解磷脂材料时,所得到的载体溶液和/或药物载体系统可能相当粘稠,并且很难操作或操作麻烦。在此情况下,合乎需要的是,在载体中包含粘度降低剂,其数量应该有效提供可以接受的低粘度。这种试剂的例子是醇,更尤其是乙醇,优选以基本上无水的形式引入,例如99%乙醇、无水酒精USP或绝对乙醇。然而,通常应该避免极高浓度的乙醇。这尤其在例如以明胶胶囊形式给予药物-载体系统的情况下是正确的,这是因为高乙醇浓度具有导致胶囊机械破损的倾向。通常,乙醇的合适数量是载体的0%至大约25%重量,例如大约1%至大约20%重量,或大约3%至大约15%重量。
任选,载体进一步包含可药用非磷脂表面活性剂。本领域技术人员可以选择合适的本发明组合物所使用的表面活性剂。举例说明,表面活性剂,例如聚山梨酸酯80,其可被包含的量是载体的0%至大约5%重量,例如0%至大约2%重量或0%至大约1%重量。
方便地,预先混合的产品可以包含合适的磷脂+增溶剂组合物方式使用,用于本发明的组合物。预先混合的磷脂+增溶剂产品可以具有以下优点:提高制备本组合物的容易程度。
预先混合的磷脂+增溶剂产品的说明性例子是Phosal 50 PGTM(得自于Phospholipid GmbH,Germany),其包含不小于50%重量的卵磷脂,不超过6%重量的溶血卵磷脂,大约35%重量的丙二醇,大约3%重量的甘油单酯和甘油二酯(得自于向日葵油),大约2%重量的大豆脂肪酸,大约2%重量的乙醇和大约0.2%重量的抗坏血酸棕榈酸酯。
另一个说明性例子是Phosal 53 MCTTM(也得自于Phospholipid
GmbH),其包含不小于53%重量的卵磷脂,不超过6%重量的溶血卵磷脂,大约29%重量的中链甘油三酯,3-6%重量(典型地大约5%)的乙醇,大约3%重量的甘油单酯和甘油二酯(得自于向日葵油),大约2%重量的油酸和大约0.2%重量的抗坏血酸棕榈酸酯(参考组合物)。本文中,含有上述或基本上相当的组分的产品(无论是否以Phosal 53 MCTTM商标销售)一般相当于“卵磷脂+中链甘油三酯53/29”。在本文中,含有“基本上相当的组分”的产品是指在组分列表和组分的相对量方面含有与参考组合物充分相似的组分,从而在相对于本文产品使用的性能方面不会显示出实际差别。
又一个说明性例子是Lipoid S75TM(得自于Lipoid
GmbH),其在增溶系统中包含不小于70%重量的卵磷脂。其可以进一步与中链甘油三酯混合,例如,在30/70重量/重量混合物中,提供包含不小于20%重量的卵磷脂、2-4%重量的磷脂酰乙醇胺、不超过1.5%重量的溶血卵磷脂和67-73%重量的中链甘油三酯的产品(“Lipoid S75TM MCT”)。
又一个说明性例子是Phosal 50 SA+TM(得自于Phospholipid
GmbH),在包含红花油及其它组分的增溶系统中,其包含不小于50%重量的卵磷脂和不超过6%重量的溶血卵磷脂。
这些预先混合产品中每一种的卵磷脂成份源自于大豆卵磷脂。基本上相当的组分的产品可以从其它供应商获得。
在某些实施方案中,预先混合的产品,例如Phosal 50 PGTM、Phosal 53 MCTTM、Lipoid
S75TM MCT或Phosal 50 SA+TM可以基本上构成整个载体系统。在其它实施方案中,存在其它组分,例如乙醇(对于可能存在于预先混合产品中的任何乙醇来说是额外的),非磷脂表面活性剂(例如聚山梨酸酯80),聚乙二醇和/或其它组分。这种额外的组分(如果存在的话)典型地只包含微小数量。举例说明,卵磷脂+中链甘油三酯53/29可以包括在载体中,其数量为载体的大约50%至100%重量,例如大约80%至100%重量。
ABT-263和其二-HCl盐易在氧化环境中降解;由此,在组合物中包含抗氧化剂常常发现是合乎需要的。药物组合物中使用的抗氧化剂是抑制氧化性物种,例如三重态氧或纯态氧、超氧化物、过氧化物和游离羟基产生的最典型的试剂,或清除这种氧化性物种(当它们产生时)的试剂。通常使用的这些类别的抗氧化剂的例子包括丁羟茴醚(BHA),丁羟甲苯(BHT),棕榈酸视黄酯,生育酚,没食子酸丙酯,抗环血酸和抗坏血酸棕榈酸酯。可以使用这种抗氧化剂;或者可以尤其使用更重的硫族抗氧化剂。
硫族是元素周期表的16族(原来被称为VIA族)的元素,包括氧、硫、硒和碲。本文中,“更重硫族”是指具有比氧重的原子量的硫族,具体地说,包括硫和硒。“更重硫族抗氧化剂”或“HCA”是具有抗氧化性能的化合物,其包含一个或多个可氧化的硫或硒原子,最尤其是硫原子。不受理论束缚,认为HCAs主要起竞争性底物的作用,即,作为“损失的”抗氧化剂,其优先被氧化性物种攻击,由此使药物免于过度降解。
在一些实施方案中,HCA包括一或多种式II的抗氧化剂化合物:
其中
n是0、1或2;
Y1是S或Se;
Y2是NHR1、OH或H,其中R1是烷基或烷基羰基;
Y3是COOR2或CH2OH,其中R2是H或烷基;和
R3是H或烷基;
其中烷基独立地任选被独立地选自下列的多个取代基中的一个取代:羧基,烷基羰基,烷氧羰基,氨基和烷基羰基氨基;其可药用盐;或,其中Y1是S,R3是H,其-S-S-二聚体或这种二聚体的可药用盐。
在其它实施方案中,HCA是式III的抗氧化剂化合物:
其中
Y是S、Se或S-S;和
R4和R5独立地选自H,烷基和(CH2)nR6,其中n是0-10,R6是芳基羰基,烷基羰基,烷氧羰基,羧基或CHR7R8-取代的烷基,其中R7和R8独立地是CO2R9,CH2OH,氢或NHR10,其中R9是H,烷基,取代的烷基或芳烷基,R10是氢,烷基,烷基羰基或烷氧羰基。
形成按照式II或式III的取代基的一部分的“烷基”取代基或“烷基”或“烷氧基”是具有1至大约18个碳原子的该基团,并且可以由直链或支链组成。
形成按照式III的取代基的一部分的“芳基”是苯基,其是未取代的或被一个或多个羟基、烷氧基或烷基取代。
在某些实施方案中,R1在式II中是C1-4烷基(例如,甲基或乙基)或(C1-4烷基)羰基(例如,乙酰基)。
在某些实施方案中,R2在式II中是H或C1-18烷基,例如甲基,乙基,丙基(例如,正丙基或异丙基),丁基(例如,正丁基,异丁基或叔丁基),辛基(例如,正辛基或2-乙基己基),十二烷基(例如,月桂基),十三烷基,十四烷基,十六烷基或十八烷基(例如,硬脂基基)。
R3典型地是H或C1-4烷基(例如,甲基或乙基)。
HCA可以是例如天然或合成的氨基酸或其衍生物,例如烷基酯或N-酰基衍生物,或这种氨基酸或衍生物的盐。如果氨基酸或其衍生物衍生自天然源,它典型地是L-构型;然而应当理解,如果需要的话,可以替代D-异构体和D,L-异构体混合物。
本文使用的HCAs的非限制性例子包括β-烷基巯基酮,半胱氨酸,胱氨酸,高半胱氨酸,甲硫氨酸,硫二乙酸,硫代二丙酸,硫代甘油,硒代半胱氨酸,硒代蛋氨酸和其盐、酯、酰胺和硫醚;和其组合物。更具体地说,一或多种HCAs可以选自:N-乙酰半胱氨酸,N-乙酰半胱氨酸丁基酯,N-乙酰半胱氨酸十二烷基酯,N-乙酰基-半胱氨酸乙酯,N-乙酰半胱氨酸甲基酯,N-乙酰半胱氨酸辛基酯,N-乙酰基-半胱氨酸丙基酯,N-乙酰半胱氨酸硬脂基酯,N-乙酰半胱氨酸十四烷基酯,N-乙酰半胱氨酸十三烷基酯,N-乙酰蛋氨酸,N-乙酰蛋氨酸丁基酯,N-乙酰基-甲硫氨酸十二烷基酯,N-乙酰蛋氨酸乙酯,N-乙酰蛋氨酸甲基酯,N-乙酰蛋氨酸辛基酯,N-乙酰蛋氨酸丙基酯,N-乙酰蛋氨酸硬脂基酯,N-乙酰蛋氨酸十四烷基酯,N-乙酰蛋氨酸十三烷基酯,N-乙酰基-硒代半胱氨酸,N-乙酰基硒代半胱氨酸丁基酯,N-乙酰基硒代半胱氨酸十二烷基酯,N-乙酰基硒代半胱氨酸乙酯,N-乙酰基硒代半胱氨酸甲基酯,N-乙酰基-硒代半胱氨酸辛基酯,N-乙酰基硒代半胱氨酸丙基酯,N-乙酰基硒代半胱氨酸硬脂基酯,N-乙酰基硒代半胱氨酸十四烷基酯,N-乙酰基硒代半胱氨酸十三烷基酯,N-乙酰基硒代蛋氨酸,N-乙酰基硒代蛋氨酸丁基酯,N-乙酰基硒代蛋氨酸十二烷基酯,N-乙酰基硒代蛋氨酸乙酯,N-乙酰基硒代蛋氨酸甲基酯,N-乙酰基硒代蛋氨酸辛基酯,N-乙酰基硒代蛋氨酸丙基酯,N-乙酰基-硒代蛋氨酸硬脂基酯,N-乙酰基硒代蛋氨酸十四烷基酯,N-乙酰基-硒代蛋氨酸十三烷基酯,半胱氨酸,半胱氨酸丁基酯,半胱氨酸十二烷基酯,半胱氨酸乙酯,半胱氨酸甲基酯,半胱氨酸辛基酯,半胱氨酸丙基酯,半胱氨酸硬脂基酯,半胱氨酸十四烷基酯,半胱氨酸十三烷基酯,胱氨酸,胱氨酸二丁酯,胱氨酸二(十二烷基)酯,胱氨酸二乙酯,胱氨酸二甲酯,胱氨酸二辛酯,胱氨酸二丙基酯,胱氨酸二硬脂基酯,胱氨酸二(十四烷基)酯,胱氨酸二(十三烷基)酯,N,N-二乙酰基胱氨酸,N,N-二乙酰基胱氨酸二丁酯,N,N-二乙酰基胱氨酸二乙酯,N,N-二乙酰基胱氨酸二(十二烷基)酯,N,N-二乙酰基胱氨酸二甲酯,N,N-二乙酰基胱氨酸二辛酯,N,N-二乙酰基胱氨酸二丙基酯,N,N-二乙酰基胱氨酸二硬脂基酯,N,N-二乙酰基胱氨酸二(十四烷基)酯,N,N-二乙酰基胱氨酸二(十三烷基)酯,硫二乙酸二丁基酯,硫代二丙酸二丁基酯,硫二乙酸二(十二烷基)酯,硫代二丙酸二(十二烷基)酯,硫二乙酸二乙基酯,硫代二丙酸二乙基酯,硫二乙酸二甲基酯,硫代二丙酸二甲基酯,硫二乙酸二辛基酯,硫代二丙酸二辛基酯,硫二乙酸二丙基酯,硫代二丙酸二丙基酯,硫二乙酸二硬脂基酯,硫代二丙酸二硬脂基酯,硫二乙酸二(十四烷基)酯,硫代二丙酸二(十四烷基)酯,高半胱氨酸,高半胱氨酸丁基酯,高半胱氨酸十二烷基酯,高半胱氨酸乙酯,高半胱氨酸甲基酯,高半胱氨酸辛基酯,高半胱氨酸丙基酯,高半胱氨酸硬脂基酯,高半胱氨酸十四烷基酯,高半胱氨酸十三烷基酯,甲硫氨酸,甲硫氨酸丁基酯,甲硫氨酸十二烷基酯,甲硫氨酸乙酯,甲硫氨酸甲基酯,甲硫氨酸辛基酯,甲硫氨酸丙基酯,甲硫氨酸硬脂基酯,甲硫氨酸十四烷基酯,甲硫氨酸十三烷基酯,S-甲基半胱氨酸,S-甲基-半胱氨酸丁基酯,S-甲基半胱氨酸十二烷基酯,S-甲基半胱氨酸乙酯,S-甲基-半胱氨酸甲基酯,S-甲基半胱氨酸辛基酯,S-甲基半胱氨酸丙基酯,S-甲基-半胱氨酸硬脂基酯,S-甲基半胱氨酸十四烷基酯,S-甲基半胱氨酸十三烷基酯,硒代半胱氨酸,硒代半胱氨酸丁基酯,硒代半胱氨酸十二烷基酯,硒代半胱氨酸乙酯,硒代半胱氨酸甲基酯,硒代半胱氨酸辛基酯,硒代半胱氨酸丙基酯,硒代半胱氨酸硬脂基酯,硒代半胱氨酸十四烷基酯,硒代半胱氨酸十三烷基酯,硒代蛋氨酸,硒代蛋氨酸丁基酯,硒代蛋氨酸十二烷基酯,硒代蛋氨酸乙酯,硒代蛋氨酸甲基酯,硒代蛋氨酸辛基酯,硒代蛋氨酸丙基酯,硒代蛋氨酸硬脂基酯,硒代蛋氨酸十四烷基酯,硒代蛋氨酸十三烷基酯,硫二乙酸,硫代二丙酸,硫代甘油,其异构体和异构体的混合物,和其盐。
HCA化合物的盐可以是酸加成盐,例如乙酸盐,己二酸盐,海藻酸盐,碳酸氢盐,柠檬酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,二葡糖酸盐,甲酸盐,富马酸盐,甘油磷酸盐,谷氨酸盐,半硫酸盐,庚酸盐,己酸盐,盐酸盐,氢溴酸盐,氢碘酸盐,乳糖酸盐,乳酸盐,马来酸盐,均三甲苯磺酸盐,甲磺酸盐,亚萘基磺酸盐,烟酸盐,草酸盐,双羟萘酸盐,果胶酯酸盐,过硫酸盐,磷酸盐,苦味酸盐,丙酸盐,琥珀酸盐,酒石酸盐,硫氰酸盐,三氯乙酸盐,三氟乙酸盐,对甲苯磺酸盐和十一烷酸盐。在一个具体实施方案中,一个上面单独叙述化合物的盐酸盐以抗氧化剂有效量存在于组合物中。
不受理论束缚,人们普遍认为,更重硫族抗氧化剂,例如,上面举例说明的那些抗氧化剂,由于本身更容易被氧化(并因此比药物化合物优先氧化),可以保护活性化合物。通常,对于提供药物化合物的可接受的保护度的这种操作方式,抗氧化剂必须存在基本的数量,例如,与药物化合物的摩尔比至少为大约1:10。在某些实施方案中,抗氧化剂与药物化合物的摩尔比大约为1:10至大约2:1,例如大约1:5至大约1.5:1。当该摩尔比是大约1:1(即,大约8:10至大约10:8)时,有时将会获得最好的结果。
利用各种类别的含硫抗氧化剂,也就是亚硫酸盐、亚硫酸氢盐、偏亚硫酸氢盐和硫代硫酸盐类别的无机抗氧化剂,可以提供上述HCAs的替代品。对于复杂物质,这些抗氧化剂的脂溶性差,并且必须以水溶液形式引入到以脂质为基础的载体或药物-载体系统中。水的存在可以促进在ABT-263溶液中形成亚砜,这正是设法减到最小的效果。为了限制所加入水的量,典型地,以大大低于提供与ABT-263成摩尔当量浓度的物质的浓度加入脂溶性差的抗氧化剂。
如果使用脂溶性差的抗氧化剂,例如亚硫酸盐、亚硫酸氢盐、偏亚硫酸氢盐或硫代硫酸盐抗氧化剂,在药物-载体系统中伴随有水,其数量不超过大约1%重量,例如大约0.2%至大约0.8%重量。可以被引进到这种少量水中的这种抗氧化剂的量典型地不超过药物-载体系统的大约0.2%重量,例如,大约0.02%至大约0.2%重量的数量,或大约0.05%至大约0.15%重量。
为了使加入到制剂中的水量减到最小,以相对浓缩的含水储备溶液形式提供抗氧化剂是合乎需要的,例如,含有至少大约10%重量的抗氧化剂。然而,已经发现,如果使用过度浓缩的储备溶液(例如,大约20%或更高),可以在制剂中导致不合需要的的固体沉淀。抗氧化剂在储备溶液中的合适浓度典型地是大约10%至大约18%重量,举例说明,大约15%重量。
按照本实施方案,亚硫酸盐、亚硫酸氢盐、偏亚硫酸氢盐和硫代硫酸盐的钠和钾盐是有用的抗氧化剂;更具体地说,偏亚硫酸氢钠和偏亚硫酸氢钾。
为了进一步使亚砜形成减到最小,任选加入螯合剂,例如EDTA或其盐(例如,乙二胺四醋酸钠或乙二胺四乙酸二钠钙),例如,加入数量为药物-载体系统的大约0.002%至大约0.02%重量。用和抗氧化剂一样的方法,可以以含水储备溶液形式加入EDTA。如果需要的话,抗氧化剂和EDTA可以作为相同储备溶液的组分加入。螯合剂可以螯合能够促进氧化降解的金属离子。
通过选择具有低过氧化值的制剂组分,可以使亚砜形成进一步减到最小。过氧化值是药物赋形剂的沿用已久的性质,并且通常用与每千克赋形剂的过氧化物的毫克当量相当的单位(meq/kg)表示(如本文中)。某些赋形剂固有地具有低过氧化值,但其它的赋形剂,例如具有不饱和脂肪酸(例如油酰部分和/或聚氧乙烯链)的那些赋形剂,可以是过氧化物源。在聚山梨酸酯80的情况下,例如,优选具有不大于大约5的过氧化值的聚山梨酸酯80的源,例如不大于大约2。 合适的源包括Crillet 4HPTM和Super-Refined Tween 80TM,两个都得自于Croda。
不受理论束缚,人们相信,ABT-263的治疗效能至少在某种程度上是由于其具有与Bcl-2家族蛋白(例如Bcl-2、Bcl-X L 或Bcl-w)结合的能力,以抑制该蛋白的抗凋亡作用的方式结合,例如,占据该蛋白的BH3结合沟。
在一个更进一步实施方案中,提供了治疗疾病的方法,该疾病以凋亡功能障碍和/或抗凋亡Bcl-2家族蛋白的超表达为特征,该方法包括:给予患有该疾病的患者治疗有效量的ABT-263二-HCl或包含ABT-263二-HCl和一或多种可药用赋形剂的药物组合物。
患者可以是人或非人(例如,农场、动物园、工作或陪伴动物,或用作模型的实验动物),但在一个重要的实施方案中,患者是需要该药物的人患者,例如,治疗以凋亡功能障碍和/或抗凋亡Bcl-2家族蛋白的超表达为特征的疾病。人患者可以是男性或女性患者,并且可以是任何年龄。患者典型地是成年人,但本发明的方法可以用于治疗儿科患者中的儿童癌症,例如血癌,例如急性淋巴细胞性白血病。
通常以能够提供药物的治疗有效日剂量的数量来给予组合物。本文中,术语“日剂量”是指每天给予的药物数量,与给药频率无关。例如,如果患者接受每天两次的150
mg的单位剂量,则日剂量是300 mg。应该理解,术语“日剂量”的使用并不意味着必须每天给予一次该具体剂量数量。然而,在一个具体实施方案中,给药频率是每天一次(q.d.),并且日剂量和单位剂量在该实施方案中是相同的意思。
构成治疗有效剂量的因素取决于具体制剂的生物利用率,患者(包括患者的物种和体重),所治疗的疾病(例如,癌症的具体类型),疾病的阶段和/或严重程度,个体患者的化合物的耐受性,是否化合物是以单疗法或与一或多种其它药物(例如,治疗癌症的其它化疗药物)组合给予,及其它因素。由此,日剂量可以在很宽的范围内改变,例如,从大约10至大约1,000 mg。在特定情况下,更大或更小的日剂量可以是合适的。可以理解,如果仅仅给予单个这种剂量,则本文讲述的“治疗有效”剂量的叙述未必要求该药物是治疗有效的;典型地,治疗效能取决于按照方案(包括给药的合适频率和持续时间)反复给予的组合物。强烈地优选,尽管所选择的日剂量就治疗癌症而言,足以提供益处,但该日剂量不应该足以引起不利的副作用达到无法接受的或无法忍受的程度。不用过度实验,基于本文公开的内容和本文引用的技术,考虑例如上述那些因素,可以由常规技术的医生选择合适的治疗有效剂量。医生可以例如用相对低的日剂量对癌症患者开始一系列治疗,并在几天或几周期间内逐渐调高剂量,以减少不利的副作用的危险。
举例说明,ABT-263的合适剂量通常是大约25至大约1,000 mg/天,更典型地大约50至大约500 mg/天或大约200至大约400 mg/天,例如大约50、大约100、大约150、大约200、大约250、大约300、大约350、大约400、大约450或大约500 mg/天,以大约3小时至大约7天的平均剂量间隔给药,例如,大约8小时至大约3天,或大约12小时至大约2天。在大多数情况下,每天一次(q.d.)的给药方案是合适的。
本文的“平均剂量间隔”定义为:时间跨度(例如一天或一周)除以该时间跨度内所给予的单位剂量数目。例如,如果一天给予药物三次,大约8 am、大约中午和大约6 pm,则平均剂量间隔是8小时(24小时时间跨度除以3)。如果将药物配制为分散剂型,例如片剂或胶囊剂,为了定义平均剂量间隔,认为一次给予的许多(例如,2至大约10)剂型是单位剂量。
在某些实施方案中,可以选择日剂量数量和剂量间隔,以便保持ABT-263的血浆浓度在大约0.5至大约10μg/ml范围。由此,在按照这种实施方案的ABT-263治疗的疗程期间,稳定的血浆峰浓度(Cmax)通常应该不超过大约10μg/ml,稳定的血浆谷浓度(Cmin)通常应该不低于大约0.5μg/ml。进一步发现,合乎需要的是,在上面提供的范围之内,选择有效日剂量数量和平均剂量间隔,以便提供Cmax/Cmin比例不大于大约5,例如不大于大约3(在稳态下)。可以理解,更长的剂量间隔倾向于导致更大的Cmax/Cmin比例。举例说明,在稳态下,可以利用本方法达到ABT-263的大约3至大约8μg/ml的Cmax和大约1至大约5μg/ml的Cmin。在人PK研究中,可以建立Cmax和Cmin的稳态值,例如,按照标准规程进行,包括但不局限于管理机构(例如美国食品与药物管理局(FDA))可接受的那些规程。
由于认为本发明的组合物只显示出微小的食品效果,所以,按照本实施方案,可以与食品一起或不与食品一起给药,即,在非禁食或禁食条件下给药。通常优选给予非禁食患者本组合物。
本发明的组合物适合于在单疗法或在组合治疗中使用,例如,与其它化疗药物或电离辐射一起使用。本发明的一个特别优点是:可以每天口服一次,这种方案便于用其它口服给予药物(基于每天一次的方案)进行治疗的患者。患者自己或由护理者在患者家庭中容易完成口服给药;对于在医院或居所护理环境中的患者来说,也是方便的给药途径。
举例说明,组合治疗包括:伴随给予本发明组合物(包含ABT-263二-HCl)与下列中的一或多种:硼替佐米,卡铂,顺铂,环磷酰胺,达卡巴嗪,地塞米松,多西他赛,多柔比星,依托泊苷,氟达拉滨,羟基多柔比星,依立替康,太平洋紫杉醇,雷帕霉素,美罗华,长春花新碱等等,例如,用多药疗法,例如CHOP(环磷酰胺+羟基多柔比星+长春花新碱+脱氢可的松),RCVP(美罗华+环磷酰胺+长春花新碱+脱氢可的松),R-CHOP(美罗华+CHOP)或DA-EPOCH-R(剂量调节的依托泊苷,脱氢可的松,长春花新碱,环磷酰胺,多柔比星和美罗华)。
包含ABT-263二-HCl的本发明组合物可以在组合治疗中与一或多种治疗剂一起给予,这种治疗剂包括但不局限于:血管生成抑制剂,抗增殖药剂,其它细胞程序死亡启动子(例如,Bcl-xL,Bcl-w和Bfl-1抑制剂),死亡受体途径的活化剂,BiTE(双-特异性T细胞衔接物)抗体,双重变量区域结合蛋白(DVDs),细胞程序死亡蛋白的抑制剂(IAPs),microRNAs,丝裂原-活化的胞外信号调节激酶抑制剂,多价结合蛋白,聚ADP(腺苷二磷酸)-核糖聚合酶(PARP)抑制剂,小抑制性核醣核酸(siRNAs),激酶抑制剂,受体酪氨酸激酶抑制剂,极光激酶抑制剂,polo样激酶抑制剂,bcr-abl激酶抑制剂,生长因子抑制剂,COX-2抑制剂,非甾体抗炎症的药物(NSAIDs),抗有丝分裂剂,烷基化剂,代谢拮抗剂,插入性抗生素,包含铂的化疗剂,生长因子抑制剂,电离辐射,细胞周期抑制剂,酶,拓扑异构酶抑制剂,生物反应调节剂,免疫,抗体,激素治疗,类视黄醇,三角肌(deltoids),植物生物碱,蛋白酶体抑制剂,HSP-90抑制剂,组蛋白脱乙酰基酶(HDAC)抑制剂,嘌呤类似物,嘧啶类似物,MEK抑制剂,CDK抑制剂,ErbB2受体抑制剂,mTOR抑制剂以及其它抗肿瘤剂。
血管生成抑制剂包括但不局限于:EGFR抑制剂,PDGFR抑制剂,VEGFR抑制剂,TIE2抑制剂,IGF1R抑制剂,基质金属蛋白酶2(MMP-2)抑制剂,基质金属蛋白酶9(MMP-9)抑制剂和凝血栓蛋白类似物。
EGFR抑制剂的例子包括但不局限于:吉非替尼,埃洛替尼,西妥昔单抗,EMD-7200,ABX-EGF,HR3,IgA抗体,TP-38(IVAX),EGFR融合蛋白,EGF-疫苗,抗EGFR免疫脂质体和拉帕替尼。
PDGFR抑制剂的例子包括但不局限于:CP-673451和CP-868596。
VEGFR抑制剂的例子包括但不局限于:贝伐单抗,舒尼替尼,索拉非尼,CP-547632,阿西替尼(axitinib),凡德他尼(vandetanib),AEE788,AZD-2171,VEGF trap,瓦他拉尼,哌加他尼(pegaptanib),IM862,帕唑帕尼,ABT-869和angiozyme。
不同于本文中的ABT-263或式I化合物的Bcl-2家族蛋白抑制剂包括但不局限于:AT-101((-)棉子酚),Genasense Bcl-2-靶向反义寡核苷酸(G3139或oblimersen),IPI-194,IPI-565,ABT-737,GX-070(obatoclax)等等。
死亡受体途径的活化剂包括但不局限于:TRAIL,靶向死亡受体(例如,DR4和DR5)的抗体或其它药剂,例如apomab,conatumumab,ETR2-ST01,GDC0145(lexatumumab),HGS-1029,LBY-135,PRO-1762和曲妥珠单抗。
凝血栓蛋白类似物的例子包括但不局限于:TSP-1,ABT-510,ABT-567和ABT-898。
极光激酶抑制剂的例子包括但不局限于:VX-680,AZD-1152和MLN-8054。
polo样激酶抑制剂的例子包括但不局限于:BI-2536。
bcr-abl激酶抑制剂的例子包括但不局限于:伊马替尼和达沙替尼。
包含铂的药剂的例子包括但不局限于:顺铂,卡铂,依他铂,乐铂,奈达铂,奥沙利铂和沙铂(satraplatin)。
mTOR抑制剂的例子包括但不局限于:CCI-779,雷帕霉素,temsirolimus,依维莫司,RAD001和AP-23573。
HSP-90抑制剂的例子包括但不局限于:格尔德霉素,根赤壳菌素,17-AAG,KOS-953,17-DMAG,CNF-101,CNF-1010,17-AAG-nab,NCS-683664,efungumab,CNF-2024,PU3,PU24FCl,VER-49009,IPI-504,SNX-2112和STA-9090。
HDAC抑制剂的例子包括但不局限于:辛二酰苯胺异羟肟酸(SAHA),MS-275,丙戊酸,TSA,LAQ-824,trapoxin和缩酚酸肽。
MEK抑制剂的例子包括但不局限于:PD-325901,ARRY-142886,ARRY-438162和PD-98059。
CDK抑制剂的例子包括但不局限于:夫拉平度(flavopyridol),MCS-5A,CVT-2584,seliciclib ZK-304709,PHA-690509,BMI-1040,GPC-286199,BMS-387032,PD-332991和AZD-5438。
COX-2抑制剂的例子包括但不局限于:西乐葆,帕瑞考营,德拉昔布(deracoxib),ABT-963,默沙东,罗美昔布(lumiracoxib),BMS-347070,RS
57067,NS-398,伐地考昔,罗非考昔,SD-8381,4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰基苯基)-1H-吡咯,T-614,JTE-522,S-2474,SVT-2016,CT-3和SC-58125。
NSAIDs的例子包括但不局限于:双水杨酯,二氟尼柳,布洛芬,酮洛芬,萘丁美酮,吡罗昔康,萘普生,双氯芬酸,消炎痛,舒林酸,甲苯酰吡酸,依托度酸,酮咯酸和奥沙普秦。
ErbB2受体抑制剂的例子包括但不局限于:CP-724714,卡拉替尼(canertinib),曲妥珠单抗,petuzumab,TAK-165,ionafamib,GW-282974,EKB-569,PI-166,dHER2,APC-8024,抗HER/2neu双特异性抗体B7.her2IgG3和HER2三官能双特异性抗体mAB AR-209和mAB 2B-1。
烷基化剂的例子包括但不局限于:氮芥N-氧化物,环磷酰胺,异环磷酰胺,氯乙环磷酰胺,苯丁酸氮芥,苯丙氨酸氮芥,白消安,二溴甘露醇,卡波醌,硫替派,雷莫司汀(Ranimustine),嘧啶亚硝脲,Cloretazine(拉莫司汀(laromustine)),AMD-473,六甲蜜胺,AP-5280,apaziquone,brostallicin,苯达莫司汀,卡莫司汀,雌莫司汀,福莫司汀,葡膦酰胺,KW-2170,马磷酰胺(mafosfamide),二溴卫矛醇,环己亚硝脲,曲奥舒凡(treosulfan),达卡巴嗪和替莫唑胺。
代谢拮抗剂的例子包括但不局限于:氨甲喋呤,6-巯基嘌呤核糖核苷,巯基嘌呤,5-氟尿嘧啶(5-FU)(单独或与亚叶酸组合),替加氟,UFT,去氧氟尿苷,卡莫氟,阿糖胞苷,阿糖胞苷十八烷基磷酸钠,依诺他滨,S-1,培美曲唑(Pemetrexed),吉西他滨,氟达拉滨,5-阿扎胞苷,卡培他滨,克拉屈滨,氯法拉滨(clofarabine),地西他滨,依氟鸟氨酸,ethenylcytidine,阿糖胞苷,羟基脲,TS-1,苯丙氨酸氮芥,奈拉滨(nelarabine),诺拉曲特(nolatrexed),培美曲唑二钠(Pemetrexed),喷司他丁,pelitrexol,雷替曲塞(raltitrexed),triapine,三甲曲沙,阿糖腺苷,霉酚酸,十八烷基磷酸钠,喷司他丁,噻唑呋啉,利巴韦林,EICAR,羟基脲和去铁胺。
抗生素的例子包括:插入式抗生素,阿柔比星,放线菌素D,氨柔比星,annamycin,多柔比星,博来霉素,柔红霉素,多柔比星(包括脂质体多柔比星),依沙芦星,表柔比星,glarubicin,伊达比星,丝裂霉素C,奈莫柔比星,新制癌菌素,硫酸培洛霉素,吡柔比星,蝴蝶霉素(rebeccamycin),stimalamer,链脲霉素,戊柔比星(Valrubicin),新制癌菌素和其组合。
拓扑异构酶抑制剂的例子包括但不局限于:阿柔比星,氨萘非特,贝洛替康(belotecan),喜树碱,10-羟基喜树碱,9-氨基-喜树碱,安吖啶,右雷佐生,二氟替康(diflomotecan),依立替康HCl,伊朵堤卡林(edotecarin),表柔比星,依托泊苷,依沙替康(exatecan),becatecarin,吉马替康,勒托替康,orathecin,BN-80915,米托蒽醌,吡柔比星(pirarbucin),pixantrone,鲁比替康,索布佐生,SN-38,tafluposide和托泊替康。
抗体的例子包括但不局限于:美罗华,西妥昔单抗,贝伐单抗,曲妥珠单抗,CD40-特异性抗体和IGF1R-特异性抗体,chTNT-1/B,denosumab,依决洛单抗,WX G250,zanolimumab,林妥珠单抗和ticilimumab。
激素治疗的例子包括但不局限于:碳酸司维拉姆(sevelamer),rilostane,促黄体素释放激素,modrastane,依西美坦,亮丙瑞林乙酸酯,布舍瑞林,西曲瑞克,地洛瑞林,组氨瑞林(Histrelin),阿那曲唑,fosrelin,戈舍瑞林,地盖瑞利(degarelix),度骨化醇(doxercalciferol),法屈唑,福美坦,三苯氧胺,阿佐昔芬(arzoxifene),比卡鲁胺,阿倍瑞克(Abarelix),曲普瑞林,非那雄胺,氟维司群,枸橼酸托瑞米芬,雷诺昔酚,曲洛司坦,拉索昔芬,来曲唑,氟他胺,甲地孕酮,美服培酮,尼鲁米特,地塞米松,脱氢可的松及其它糖皮质激素。
类视黄醇或三角肌(deltoids)的例子包括但不局限于:西奥骨化醇(seocalcitol),来沙骨化醇(lexacalcitol),芬维A胺,aliretinoin,维甲酸,贝沙罗汀(Bexarotene)和LGD-1550。
植物生物碱的例子包括但不局限于:长春花新碱,长春花碱,去乙酰长春酰胺和长春瑞宾。
蛋白酶体抑制剂的例子包括但不局限于:硼替佐米(Bortezomib),MG-132,NPI-0052和PR-171。
免疫的例子包括但不局限于:干扰素和许多其它免疫提高药剂。干扰素包括干扰素α,干扰素α-2a,干扰素α-2b,干扰素β,干扰素γ-1a,干扰素γ-1b,干扰素γ-n1和其组合物。其它药剂包括非格司亭,蘑菇多糖,sizofilan,注射卡介苗,乌苯美司,WF-10(四氯十氧化物(tetrachlorodecaoxide)或TCDO),阿地白介素,阿仑单抗(Alemtuzumab),BAM-002,达卡巴嗪,达(克)珠单抗,地尼白介素(denileukin),吉妥珠单抗奥唑米星(gemtuzumab
ozogamicin),ibritumomab,咪喹莫特,来格司亭,黑素瘤疫苗,莫拉司亭,sargaramostim,他索纳明(tasonermin),tecleukin,thymalasin,托西莫单抗(tositumomab),Lorus Pharmaceuticals的VirulizinTM免疫治疗剂,Z-100(Maruyama的特异物质或SSM),ZevalinTM(90Y-替伊莫单抗(ibritumomab
tiuxetan)),依帕珠单抗,米妥莫单抗(mitumomab),oregovomab,pemtumomab,ProvengeTM (sipuleucel-T),替西白介素(teceleukin),TherocysTM(Bacillus
Calmette-Guerin),细胞毒素淋巴细胞抗原4(CTLA4)抗体和能够阻断CTLA4的药剂,例如MDX-010。
生物反应调节剂的例子是调节生物机体的防卫机制或生物反应(例如,组织细胞的存活、生长或分化)、从而使它们具有抗肿瘤活性的药剂。这种药剂包括但不局限于:云芝多糖K(krestin),蘑菇多糖,西佐喃(sizofuran),溶链菌制剂(picibanil),PF-3512676和乌苯美司。
嘧啶类似物的例子包括但不局限于:5-氟尿嘧啶,氮尿苷,去氧氟尿苷,雷替曲塞(raltitrexed),阿糖胞苷,阿糖胞苷,氟达拉滨,三乙酰尿苷,曲沙他滨(Troxacitabine)和吉西他滨。
嘌呤类似物的例子包括但不局限于:巯基嘌呤和硫鸟嘌呤。
抗有丝分裂剂的例子包括但不局限于:N-(2-((4-羟基苯基)氨基)吡啶-3-基)-4-甲氧基苯磺酰胺,太平洋紫杉醇,多西他赛,larotaxel,埃坡霉素D,PNU-100940,巴他布林(batabulin),伊沙匹隆,patupilone,XRP-9881,长春氟宁和ZK-EPO(合成的埃坡霉素)。
放射治疗的例子包括但不局限于:外束放射治疗(XBRT),远距离治疗,近距疗法,密封源放射治疗和未密封源放射治疗。
BiTE抗体是引导T细胞攻击癌细胞、同时使两个细胞结合的双-特异性抗体。然后T细胞攻击靶向癌细胞。BiTE抗体的例子包括但不局限于:阿德木单抗(adecatumumab)(Micromet MT201),blinatumomab(Micromet MT103)等等。不受理论限制,T细胞引起靶向癌细胞的细胞程序死亡的一个机理是通过溶细胞的颗粒组分(包括穿孔素和粒酶B)的胞吐作用。在这方面,已经显示Bcl-2可以通过穿孔素和粒酶B来减弱细胞程序死亡的诱导。这些数据说明,当靶向癌细胞时,抑制Bcl-2可以增加由T细胞引起的细胞毒素效果(Sutton等人(1997)J. Immunol. 158:5783-5790)。
SiRNAs是具有内源RNA碱基或化学上调节的核苷酸的分子。该修饰不能消除细胞活性,但可以提高稳定性和/或提高细胞效能。化学修饰的例子包括硫代磷酯基团,2'-脱氧核苷酸,包含2'-OCH3-的核糖核苷酸,2'-F-核糖核苷酸,2'-甲氧基乙基核糖核苷酸,其组合物等等。siRNA可以具有变化长度(例如,10-200 bps)和结构(例如,发夹形,单/双链,凸形,凹形/缺口,不重合),并且在细胞中被加工,提供活性基因沉默。双链siRNA(dsRNA)在每个链(钝端)上或非对称端(突出端)可以具有相同数目的核苷酸。1-2个核苷酸的突出端可以存在于有义链和/或反义链上,以及存在于所得到链的5'-和/或3'-端。例如,靶向Mcl-1的siRNA已经显示其可提高ABT-263的活性(Tse等人(2008)Cancer
Res. 68:3421-3428和其中的参考文献)。
多价结合蛋白是包含两个或多个抗原结合位点的结合蛋白。可以设计多价结合蛋白,使其具有三个或更多个抗原结合位点,并且通常不是天然存在的抗体。术语“多特异性结合蛋白”是指能够结合两个或多个相关或无关靶向的结合蛋白。双重变量区域(DVD)结合蛋白是包含两个或多个抗原结合位点的四价或多价结合蛋白。这种DVD可以是单特异性的(即,能够结合一个抗原)或多特异性的(即,能够结合两个或多个抗原)。包含两个重链DVD多肽和两个轻链DVD多肽的DVD结合蛋白被称为DVD Ig's。DVD Ig的每一半包含重链DVD多肽、轻链DVD多肽和两个抗原结合位点。每个结合位点包含重链可变域和轻链可变域,每个抗原结合位点具有总共6个涉及抗原结合的CDR。
PARP抑制剂包括但不局限于:ABT-888,olaparib,KU-59436,AZD-2281,AG-014699,BSI-201,BGP-15,INO-1001,ONO-2231等等。
另外或或者,本发明的组合物可以在组合治疗中与一或多种选自下列的抗肿瘤剂一起给予:ABT-100,N-乙酰基秋水仙醇-O-磷酸盐,阿维A,AE-941,糖苷配基原人参萜二醇,arglabin,三氧化二砷,AS04佐剂-吸附的HPV疫苗,L-门冬酰胺酶,阿他美坦,阿曲生坦(atrasentan),AVE-8062,波生坦,canfosfamide,CanvaxinTM,catumaxomab,CeaVacTM,西莫白介素,combrestatin
A4P,contusugene ladenovec,CotaraTM,环丙孕酮,脱氧柯福霉素,右雷佐生,N,N-二乙基-2-(4-(苯基甲基)苯氧基)乙胺,5,6-二甲基吨酮-4-乙酸,二十二碳六烯酸/太平洋紫杉醇,discodermolide,乙丙昔罗(efaproxiral),enzastaurin,埃坡霉素B,乙炔尿嘧啶(ethynyluracil),依昔舒林(exisulind),falimarev,GastrimmuneTM,GMK疫苗,GVAXTM,卤夫酮(halofuginone),组胺,羟基脲,依班膦酸,替伊莫单抗(ibritumomab tiuxetan),IL-13-PE38,inalimarev,白介素4,KSB-311,兰瑞肽,来那度胺(lenalidomide),洛那法尼(lonafarnib),洛伐他汀,5,10-亚甲基四氢叶酸,米伐木肽(mifamurtide),米特福辛,莫特沙芬(motexafin),奥利默森(oblimersen),OncoVAXTM,OsidemTM,太平洋紫杉醇白蛋白-稳定化纳米颗粒,聚谷氨酸紫杉醇(paclitaxel
poliglumex),帕米膦酸盐,帕尼单抗(panitumumab),聚乙二醇化干扰素alfa,培加帕酶,苯妥帝尔(phenoxodiol),聚(I)-聚(C12U),普鲁苄肼,豹蛙酶(ranpirnase),rebimastat,重组体四价HPV疫苗,角鲨胺(squalamine),星孢菌素,STn-KLH疫苗,T4 endonuclase V,维生素A酸(tazarotene),6,6',7,12-四甲氧基-2,2'-二甲基-1β-berbaman,反应停,TNFeradeTM,131I-托西莫单抗(tositumomab),曲贝替定(trabectedin),三嗪酮,肿瘤坏死因子,UkrainTM,牛痘-MUC-1疫苗,L-缬氨酸-L-boroproline,VitaxinTM,维特斯朋(vitespen),唑来膦酸和佐柔比星。
在一个实施方案中,给予需要的患者治疗有效量的包含ABT-263二-HCl的本发明组合物,以便治疗疾病,在该疾病期间,抗凋亡Bcl-2蛋白、抗凋亡Bcl-X L 蛋白和抗凋亡Bcl-w蛋白中的一或多种过度表达。
在另一个实施方案中,给予需要的患者治疗有效量的包含ABT-263二-HCl的本发明组合物,以便治疗异常的细胞生长和/或失调的细胞程序死亡的疾病。
这种疾病的例子包括但不局限于:癌症,间皮瘤,膀胱癌,胰腺癌,皮肤癌,头或颈癌,皮肤或眼内的黑素瘤,卵巢癌,乳腺癌,子宫癌,输卵管癌,子宫内膜癌,宫颈癌,阴道癌,外阴癌,骨癌,结肠癌,直肠癌,肛区癌,胃癌,胃肠(胃、结肠直肠和/或十二指肠)癌,慢性淋巴细胞性白血病,急性淋巴细胞性白血病,食道癌,小肠癌,内分泌系统癌,甲状腺癌,甲状旁腺癌,肾上腺癌,软组织肉瘤,尿道癌,阴茎癌,睾丸癌,肝细胞(肝脏和/或胆管)癌,原发性或继发性中枢神经系统肿瘤,原发性或继发性脑肿瘤,淋巴肉芽肿病,慢性或急性白血病,慢性粒细胞性白血病,淋巴细胞性淋巴瘤,淋巴细胞性白血病,滤泡性淋巴瘤,T细胞或B细胞源的淋巴恶性肿瘤,黑素瘤,多发性骨髓瘤,口腔癌,非小-细胞肺癌,前列腺癌,小细胞肺癌,肾和/或输尿管癌,肾细胞癌,肾盂癌,中枢神经系统的瘤,原发性中枢神经系统淋巴瘤,非霍奇金淋巴瘤,脊椎轴肿瘤,脑干神经胶质瘤,垂体腺瘤,肾上腺皮质癌,胆囊癌,脾癌,肝胆管型肝癌,纤维肉瘤,神经母细胞瘤,成视网膜细胞瘤或其组合。
在一个更具体实施方案中,给予需要其的患者治疗有效量的包含ABT-263二-HCl的本发明组合物,以便治疗膀胱癌,脑癌,乳腺癌,骨髓癌,子宫颈癌,慢性淋巴细胞性白血病,急性淋巴细胞性白血病,结肠直肠癌,食道癌,肝细胞癌,淋巴细胞性白血病,滤泡性淋巴瘤,T细胞或B细胞源的淋巴恶性肿瘤,黑素瘤,粒细胞性白血病,骨髓瘤,口腔癌,卵巢癌,非小细胞肺癌,前列腺癌,小细胞肺癌或脾癌。
按照这些实施方案中的任一项,在单疗法或在组合治疗中与一或多种额外的治疗剂一起给予该组合物。
例如,治疗患者下列疾病的方法:间皮瘤,膀胱癌,胰腺癌,皮肤癌,头或颈癌,皮肤或眼内的黑素瘤,卵巢癌,乳腺癌,子宫癌,输卵管癌,子宫内膜癌,宫颈癌,阴道癌,外阴癌,骨癌,结肠癌,直肠癌,肛区癌,胃癌,胃肠(胃,结肠直肠和/或十二指肠)癌,慢性淋巴细胞性白血病,急性淋巴细胞性白血病,食道癌,小肠癌,内分泌系统癌,甲状腺癌,甲状旁腺癌,肾上腺癌,软组织肉瘤,尿道癌,阴茎癌,睾丸癌,肝细胞(肝脏和/或胆管)癌,原发性或继发性中枢神经系统肿瘤,原发性或继发性脑肿瘤,淋巴肉芽肿病,慢性或急性白血病,慢性粒细胞性白血病,淋巴细胞性淋巴瘤,淋巴细胞性白血病,滤泡性淋巴瘤,T细胞或B细胞源的淋巴恶性肿瘤,黑素瘤,多发性骨髓瘤,口腔癌,非小细胞肺癌,前列腺癌,小细胞肺癌,肾和/或输尿管癌,肾细胞癌,肾盂癌,中枢神经系统瘤,原发性中枢神经系统淋巴瘤,非霍奇金淋巴瘤,脊椎轴肿瘤,脑干神经胶质瘤,垂体腺瘤,肾上腺皮质癌,胆囊癌,脾癌,肝胆管型肝癌,纤维肉瘤,神经母细胞瘤,成视网膜细胞瘤或其组合,包括给予该患者治疗有效量的:(a)包含ABT-263二-HCl的本发明组合物,和(b)下列中的一或多种:依托泊苷,长春花新碱,CHOP,美罗华,雷帕霉素,R-CHOP,RCVP,
DA-EPOCH-R或硼替佐米(Bortezomib)。
在具体实施方案中,在单疗法中给予需要其的患者治疗有效量的包含ABT-263二-HCl的本发明组合物或在组合治疗中将其与下列一起给予:治疗有效量的依托泊苷,长春花新碱,CHOP,美罗华,雷帕霉素,R-CHOP,RCVP,DA-EPOCH-R或硼替佐米(Bortezomib),用于治疗淋巴恶性肿瘤,例如B细胞淋巴瘤或非霍奇金淋巴瘤。
在其它具体实施方案中,在单疗法中给予需要其的患者治疗有效量的包含ABT-263二-HCl的本发明组合物或在组合治疗中将其与下列一起给予:治疗有效量的依托泊苷,长春花新碱,CHOP,美罗华,雷帕霉素,R-CHOP,RCVP,DA-EPOCH-R或硼替佐米(Bortezomib),用于治疗慢性淋巴细胞性白血病或急性淋巴细胞性白血病。
本发明还提供了在人癌症患者的血流中维持ABT-263和/或其一或多种代谢产物的治疗有效血浆浓度的方法,包括给予该患者本文所描述的药物组合物,剂量数量相当于每天大约50至大约500 mg ABT-263,平均剂量间隔为大约3小时至大约7天。
构成治疗有效血浆浓度尤其取决于存在于患者之中的具体癌症、癌症的阶段、严重程度和攻击性和寻求的结果(例如,稳定性,肿瘤生长减小,肿瘤收缩,转移病变的危险降低,等等)。就治疗癌症而言,尽管该血浆浓度足以提供益处,但强烈地优选,该血浆浓度不应该足以引起不利的副作用达到无法接受的或无法忍受的程度。
通常,对于治疗癌症和淋巴恶性肿瘤,例如,尤其是非霍奇金淋巴瘤,ABT-263的血浆浓度在大多数情况下应该维持在大约0.5至大约10μg/ml的范围。由此,在ABT-263治疗的疗程期间,稳定的Cmax通常应该不超过大约10μg/ml,稳定的Cmin通常应该不低于大约0.5μg/ml。进一步发现,在上面提供的范围之内选择日剂量数量和平均剂量间隔是合乎需要的,从而有效提供在稳态下Cmax/Cmin比例不大于大约5,例如不大于大约3。可以理解,更长的剂量间隔将会倾向于导致更大的Cmax/Cmin比例。举例说明,在稳态下,可以利用本方法达到大约3至大约8μg/ml的ABT-263的Cmax和大约1至大约5μg/ml的Cmin。
按照本实施方案,保持治疗有效ABT-263血浆水平的有效日剂量数量是大约50至大约500 mg。在大多数情况下,合适的日剂量数量为大约200至大约400 mg。举例说明,日剂量数量可以是例如大约50、大约100、大约150、大约200、大约250、大约300、大约350、大约400、大约450或大约500 mg。
按照本实施方案,保持治疗有效ABT-263血浆水平的有效平均剂量间隔是大约3小时至大约7天。在大多数情况下,合适的平均剂量间隔是大约8小时至大约3天,或大约12小时至大约2天。每天一次(q.d.)的给药方案常常是合适的。
在其它实施方案中,按照本实施方案的给药可以与食品一起或不与食品一起给予,即,在非禁食或禁食条件下给药。通常优选给予非禁食患者本组合物。
与本发明相关的其它信息可以在最近公开的文章(Tse等人(2008)Cancer
Res. 68:3421-3428)和其中的补充数据(可在Cancer Research Online(cancerres.aacrjournals.org/)中获得)中得到。本文以引证的方式结合该文章和其补充数据的全部内容。
Claims (26)
1.化合物N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-环己-1-烯-1-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(吗啉-4-基)-1-((苯基硫基)甲基)丙基)氨基-3-((三氟甲基)磺酰基)苯磺酰胺二-盐酸盐(ABT-263二-HCl)。
2.权利要求1的化合物,为固体形式。
3.权利要求1的化合物,其以溶解形式在增溶介质中,浓度至少为每ml介质大约1 mg ABT-263游离碱当量。
4.权利要求1的化合物,其是晶体多晶型物形式I,其特征至少为:在任何一个或多个下列位置具有粉末X射线衍射峰:6.8、7.2、8.5、18.5和18.7°2θ,±0.2°2θ。
5.权利要求4的晶体多晶型物,其特征至少为:在所述位置中的每一个位置具有粉末X射线衍射峰。
6.权利要求4的晶体多晶型物,其特征为:具有基本上如下表所表明的粉末X射线衍射图:
。
7.权利要求1的化合物,其是晶体多晶型物形式II,其特征至少为:在3.7或7.4°2θ±0.2°2θ处具有粉末X射线衍射峰。
8.权利要求7的晶体多晶型物,其特征至少为:在3.7和7.4°2θ±0.2°2θ二者处具有粉末X射线衍射峰。
9.权利要求7的晶体多晶型物,其特征为:具有基本上如下表所表明的粉末X射线衍射图:
。
10.权利要求1的化合物,其是晶体溶剂化物形式,包含用有机溶剂溶剂化的ABT-263二-HCl。
12.制备权利要求4的晶体多晶型物的方法,该方法包括:将ABT-263二-HCl的乙醇、1-丙醇、2-丙醇、2-丁醇、叔丁醇、乙腈、丙腈、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、丙酮、甲基异丙酮、1,4-二烷、苯、甲苯或丁基醚溶剂化物脱溶剂。
13.制备权利要求7的晶体多晶型物的方法,该方法包括:将ABT-263二-HCl的甲基乙基酮溶剂化物脱溶剂。
14.药物组合物,其包含ABT-263二-HCl和一或多种可药用赋形剂。
15.权利要求14的组合物,其包含ABT-263二-HCl的晶体多晶型物形式I。
16.权利要求14的组合物,其包含ABT-263二-HCl的晶体多晶型物形式II。
17.权利要求14的组合物,其包含在包含脂溶剂的载体的溶液中的ABT-263二-HCl。
18.ABT-263二-HCl或包含ABT-263二-HCl和一或多种可药用赋形剂的药物组合物用于治疗以凋亡功能障碍和/或抗凋亡Bcl-2家族蛋白的超表达为特征的疾病的用途,其是通过给予患有该疾病的患者治疗有效量的ABT-263二-HCl或所述药物组合物使用的。
19.权利要求18的用途,其中ABT-263二-HCl或药物组合物是通过下列途径给予的:口服,肠胃外,舌下,口腔,鼻内,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内或关节内途径。
20.权利要求18或权利要求19的用途,其中疾病是肿瘤病。
21.权利要求20的用途,其中肿瘤病选自:癌症,间皮瘤,膀胱癌,胰腺癌,皮肤癌,头或颈癌,皮肤或眼内的黑素瘤,卵巢癌,乳腺癌,子宫癌,输卵管癌,子宫内膜癌,宫颈癌,阴道癌,外阴癌,骨癌,结肠癌,直肠癌,肛区癌,胃癌,胃肠(胃、结肠直肠和/或十二指肠)癌,慢性淋巴细胞性白血病,急性淋巴细胞性白血病,食道癌,小肠癌,内分泌系统癌,甲状腺癌,甲状旁腺癌,肾上腺癌,软组织肉瘤,尿道癌,阴茎癌,睾丸癌,肝细胞(肝脏和/或胆管)癌,原发性或继发性中枢神经系统肿瘤,原发性或继发性脑肿瘤,淋巴肉芽肿病,慢性或急性白血病,慢性粒细胞性白血病,淋巴细胞性淋巴瘤,淋巴细胞性白血病,滤泡性淋巴瘤,T细胞或B细胞源的淋巴恶性肿瘤,黑素瘤,多发性骨髓瘤,口腔癌,非小-细胞肺癌,前列腺癌,小细胞肺癌,肾和/或输尿管癌,肾细胞癌,肾盂癌,中枢神经系统的瘤,原发性中枢神经系统淋巴瘤,非霍奇金淋巴瘤,脊椎轴肿瘤,脑干神经胶质瘤,垂体腺瘤,肾上腺皮质癌,胆囊癌,脾癌,肝胆管型肝癌,纤维肉瘤,神经母细胞瘤,成视网膜细胞瘤和其组合。
22.权利要求20的用途,其中肿瘤病是淋巴恶性肿瘤。
23.权利要求22的用途,其中淋巴恶性肿瘤是非霍奇金淋巴瘤。
24.权利要求20的用途,其中肿瘤病是慢性淋巴细胞性白血病或急性淋巴细胞性白血病。
25.权利要求18-24的任一项的用途,其中口服给予组合物,剂量为每天大约50至大约500 mg ABT-263游离碱当量,平均治疗间隔为大约3小时至大约7天。
26.权利要求18-24的任一项的用途,其中每天一次口服给予组合物,剂量为每天大约200至大约400 mg ABT-263游离碱当量。
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AR076509A1 (es) | 2011-06-15 |
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KR20120005538A (ko) | 2012-01-16 |
US20100305125A1 (en) | 2010-12-02 |
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WO2010127190A1 (en) | 2010-11-04 |
RU2011148521A (ru) | 2013-06-10 |
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JP2012525433A (ja) | 2012-10-22 |
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