CN113853374A - 具有增强的生物利用度的化合物形式及其制剂 - Google Patents
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Abstract
本发明总体涉及具有增强的水溶性和溶解速率的化合物的非晶态形式及其非晶态固体分散体和口服药物制剂,以及制备它们的方法。本发明具体涉及5‑氟‑2‑(6‑氟‑2‑甲基‑1H‑苯并咪唑‑1‑基)‑N‑[4‑(三氟甲基)苯基]嘧啶‑4,6‑二胺的非晶态形式及其非晶态固体分散体和口服药物制剂,以及制备它们的方法。
Description
相关申请的交叉引用
本申请要求于2019年3月11日提交的临时专利申请号62/816,402的权益,其全部内容通过引入并入本文。
技术领域
本发明总体涉及在结晶形式(BCS II类物质)时具有低水溶性和溶出速率的化合物的非晶态形式、其非晶态固体分散体、其口服药物制剂、以及制备非晶态分散体和制剂的方法。本发明具体涉及5-氟-2-(6-氟-2-甲基-1H-苯并咪唑-1-基)-N-[4-(三氟甲基)苯基]嘧啶-4,6-二胺的非晶态形式和非晶态固体分散体及其口服药物制剂,以及制备它们的方法。
背景技术
口服施用治疗剂的生物利用度是该药剂被人体吸收并在靶位点(例如,细胞内或细胞上等等)变得可用于体内靶标(例如,用于相互作用或复合等)的程度。为了使生物可利用,治疗剂通常需要相对于所施用的剂量具有一定的水溶性。
生物药剂学分类系统(BCS)是由美国食品和药物管理局(FDA)开发的系统,用于根据活性药物成分(API)的溶解度和肠道通透性来区分活性药物成分(API)的形式,如下:I类:高溶解度、高渗透性;II类:低溶解性、高渗透性;III类:高溶解性、低渗透性;IV类:低溶解性、低渗透性。配制BCS II类API的组合物以提高溶解度并因此提高生物利用度会是一个挑战。
使某些化合物更易溶解的方法之一是制备化合物的非晶态形式。然而,制备一些化合物的非晶态形式会很困难的,并且制备足够稳定的非晶态形式以用于药物制剂尤其困难。在某些情况下,非晶态固体分散体(ASD)可用于增加某些物质的溶解度和生物利用度。然而,确定稳定的且不干扰活性药物成分(API)生物利用度的ASD制剂很困难的。
因此,对于具有改善的溶解度和生物利用度,从而提供给药便利和增加API载量的药物组合物,在本领域仍有持续的需要和在市场仍有持续的需求。
发明内容
在本文所述的一个方面,5-氟-2-(6-氟-2-甲基-1H-苯并咪唑-1-基)-N-[4-(三氟甲基)苯基]嘧啶-4,6-二胺的非晶态形式,其具有化合物A的分子式:
在本文所述的另一方面,化合物A的非晶态形式至少90%是非晶态的。
在本文所述的另一方面,化合物A的非晶态形式是基本上纯的非晶态形式。
在本文所述的一方面,非晶态固体分散体(ASD)包含化合物A的非晶态形式和稳定聚合物。
在本文所述的另一方面,稳定聚合物选自聚乙烯吡咯烷酮或乙酸琥珀酸羟丙基甲基纤维素。
在本文所述的另一方面,稳定聚合物是乙酸琥珀酸羟丙基甲基纤维素。
在本文所述的另一方面,化合物A的重量与稳定聚合物的重量的比为约5:95至约60:40。
在本文所述的另一方面,化合物A的重量与稳定聚合物的重量的比为约10:90至约40:60。
在本文所述的一方面,ASD通过溶剂浇铸包含化合物A和稳定聚合物的溶液获得。
在本文所述的一方面,ASD通过喷雾干燥包含化合物A和稳定聚合物的溶液获得。
在本文所述的一方面,制备ASD的方法包括:(a)将化合物A和一种或多种稳定聚合物溶解在溶剂中形成溶液;和(b)干燥溶液以形成ASD,其中化合物A以非晶态形式存在。
在本文所述的另一方面,溶剂选自丙酮、甲乙酮、二氯甲烷或甲醇。
在本文所述的另一方面,通过溶剂浇铸将溶液干燥形成化合物A的ASD。
在本文所述的另一方面,通过喷雾干燥将溶液干燥形成化合物A的ASD。
在本文所述的一方面,药物组合物包含化合物A的ASD和一种或多种药学上可接受的辅料的混合物。
在本文所述的另一方面,一种或多种药学上可接受的辅料选自稀释剂、崩解剂、润滑剂或表面活性剂。
在本文所述的另一方面,表面活性剂选自十二烷基硫酸钠或泊洛沙姆407(Poloxamer407)。
在本文所述的一方面,制备药物组合物的方法包括:(a)研磨化合物A的ASD形成固体分散体粉末;(b)将粉末与一种或多种药学上可接受的辅料混合形成混合物;(c)将混合物造粒形成颗粒;和(d)分别将颗粒压片或包囊形成片剂或胶囊。
附图说明
图1显示了由化合物A的喷雾干燥分散体(SDD)和稳定聚合物制备本文所述片剂的方法流程图;
图2显示了原始化合物A(I型)的粉末X射线衍射图;
图3显示了化合物A的I型和结晶多晶A型和B型的粉末X射线衍射图的叠加;
图4显示了化合物A的I型、A型和B型的差示扫描量热法(DSC)曲线的叠加;
图5显示了HPMC-AS L和与具有A型的化合物A一起研磨的HPMC-AS L的DSC热谱图;
图6显示了PVP CL和与具有A型的化合物A一起研磨的PVP CL的DSC热谱图;
图7显示了PVP VA和与具有A型的化合物A一起研磨的PVP VA的DSC热谱图;
图8显示了PVP K30和与具有A型的化合物A一起研磨的PVP K30的DSC热谱图;
图9显示了HPMC邻苯二甲酸酯和与具有A型的化合物A一起研磨的HPMC邻苯二甲酸酯的DSC热谱图;
图10显示了具有A型的化合物A、具有A型的化合物A和聚合物的物理混合物以及不含表面活性剂的基于HPMCAS-LG的化合物A的ASD的X射线粉末衍射图;
图11显示了具有A型的化合物A、具有A型的化合物A和聚合物的物理混合物以及含有泊洛沙姆407的基于HPMCAS-LG的化合物A的ASD的X射线粉末衍射图;
图12显示了具有A型的化合物A、具有A型的化合物A和聚合物的物理混合物以及含有十二烷基硫酸钠(SLS)基于HPMCAS-LG的化合物A的ASD的X射线粉末衍射图;
图13A显示了具有A型的化合物A和不含表面活性剂的聚合物的物理混合物的DSC热谱图;
图13B显示不含表面活性剂的化合物A的ASD的DSC热谱图;
图14A显示了化合物A、聚合物和泊洛沙姆407的物理混合物的DSC热谱图;
图14B显示了含有泊洛沙姆407的化合物A的ASD的DSC热谱图;
图15A显示了化合物A、聚合物和SLS的物理混合物的DSC热谱图;
图15B显示了含有SLS的化合物A的ASD的DSC热谱图;
图16显示了含有不同量的化合物A的ASD的DSC热谱图;
图17显示了含有不同量的化合物A的ASD的X射线粉末衍射图;
图18显示了化合物A和两种不同SDD的X射线粉末衍射图,一种含有PVP-VA-64,另一种含有HPMC-AS-L;
图19显示了化合物A与HPMC-AS-LG和与PVP-VA-64的SDD溶出曲线图;
图20显示了具有A型的化合物A、化合物A与HPMC-AS的SDD、用于活性片剂制剂的化合物A与HPMC-AS的混合物以及用于安慰剂制剂的HPMC-AS的X射线粉末衍射图;
图21显示了在开放条件下在40℃/75%RH下储存6个月后,具有不同浓度泊洛沙姆407的活性制剂片剂在1分钟时的崩解。
具体实施方式
在本文所述的一个方面,5-氟-2-(6-氟-2-甲基-1H-苯并咪唑-1-基)-N-[4-(三氟甲基)苯基]嘧啶-4,6-二胺的非晶态形式,其具有化合物A的分子式:
在本文所述的另一方面,化合物A的非晶态形式至少90%是非晶态的。
在本文所述的另一方面,化合物A的非晶态形式是基本上纯的非晶态形式。
在本文所述的一方面,非晶态固体分散体(ASD)包含化合物A的非晶态形式和稳定聚合物。
在本文所述的另一方面,稳定聚合物选自聚乙烯吡咯烷酮或乙酸琥珀酸羟丙基甲基纤维素。
在本文所述的另一方面,稳定聚合物是乙酸琥珀酸羟丙基甲基纤维素。
在本文所述的另一方面,化合物A的重量与稳定聚合物的重量的比为约5:95至约60:40。
在本文所述的另一方面,化合物A的重量与稳定聚合物的重量的比为约10:90至约40:60。
在本文所述的一方面,ASD通过溶剂浇铸包含化合物A和稳定聚合物的溶液获得。
在本文所述的另一方面,ASD通过喷雾干燥包含化合物A和稳定聚合物的溶液获得。
在本文所述的一方面,制备ASD的方法包括:(a)将化合物A和一种或多种稳定聚合物溶解在溶剂中形成溶液;和(b)干燥溶液形成ASD,其中化合物A以非晶态形式存在。
在本文所述的另一方面,溶剂选自丙酮、甲乙酮、二氯甲烷或甲醇。
在本文所述的另一方面,通过溶剂浇铸将溶液干燥形成化合物A的ASD。
在本文所述的另一方面,通过喷雾干燥将溶液干燥形成化合物A的ASD。
在本文所述的一方面,药物组合物包含化合物A的ASD和一种或多种药学上可接受的辅料的混合物。
在本文所述的另一方面,一种或多种药学上可接受的辅料选自稀释剂、崩解剂、润滑剂或表面活性剂。
在本文所述的另一方面,表面活性剂选自十二烷基硫酸钠或泊洛沙姆407。
在本文所述的一方面,制备药物组合物的方法包括:(a)研磨化合物A的ASD形成固体分散体粉末;(b)将粉末与一种或多种药学上可接受的辅料混合形成混合物;(c)将混合物造粒形成颗粒;和(d)分别将颗粒压片或包囊形成片剂或胶囊。
定义
本文所用的术语“非晶态”是指缺乏规则晶体结构的固态化合物的形式。不受理论的束缚,据信非晶态化合物A比结晶化合物A需要更少的溶解能量,并且这种降低的溶解能量需求至少部分地有助于增加溶解速率和/或潜在地减少由化合物A的非晶态形式及其组合物表现出的治疗起效时间。
术语“I型”是指如国际公开文件号WO2014/081906中所述的化合物A的形式。其中公开了化合物A和制备其晶体(非-非晶态)形式的方法。当根据WO2014/081906中描述的方法合成时,得到化合物A为结晶粉末,其熔点为240至242℃。其中公开的化合物可用于治疗癌症,包括实体瘤和血液癌症,例如但不限于弥漫性内源性脑桥胶质瘤(DIPG)、卵巢癌、胰腺癌、肉瘤和血液癌症等。
术语“A型”和“B型”是指化合物A的形式,其是纯化的无水结晶多晶型形式。下文实施例1中描述的化合物A的进一步研究表明,A型是该化合物最稳定的无水晶型,和B型转化为A型。在稳定的A型晶型中,化合物A是BCS II物质。
虽然可以制备呈A型晶型的化合物A的口服剂型,但是已经使用了多种方法来增加化合物在此类制剂中的溶解度和/或溶出速率,包括在制剂之前将化合物A微粉化,以及添加药物辅料,例如崩解剂和表面活性剂。此类口服剂型的实例在以下实施例2中提供。
可溶胶囊口服剂型可由化合物A的结晶形式制备。此类胶囊可通过将具有A型的化合物A溶解于水溶性有机溶剂中来制备,例如聚乙二醇300或400、乙醇、丙二醇、甘油、N-甲基-2-吡咯烷酮、二甲基乙酰胺和/或二甲基亚砜以及非离子表面活性剂,例如聚山梨醇酯20、聚山梨醇酯80、Solutol HS 15、脱水山梨糖醇单油酸酯、泊洛沙姆407、月桂酸聚乙二醇甘油酯(Gelucire 44/14)或其他合适的表面活性剂。此类胶囊制剂的实例在以下实施例3和4中提供。由于添加溶解形式的辅料,胶囊尺寸限制了标准胶囊中API的装载量。例如,下面实施例4中使用的胶囊含有10或50mg的化合物A。为了向人类受试者施用更高剂量的化合物A,如实施例11中讨论的临床试验中所做的那样,必须服用更多的胶囊以提供所需的剂量。
化合物A的非晶态形式
本文公开的化合物A的非晶态形式比上述化合物的结晶形式明显的更易溶解。当与聚合物一起配制为非晶态固体分散体(ASD)时,化合物A的非晶态形式是稳定的。如下所述,所得化合物-聚合物基质导致化合物A的非晶态形式在ASD中有更大溶解度和API在ASD中有更高的负载能力。因此,可以装载在片剂或胶囊中的API的量显著增加,从而将为了单一治疗有效剂量而施用大量片剂或胶囊的需要降到最低。
一方面,本文公开的ASD中化合物A的非晶态形式是至少90%非晶态,更优选至少95%非晶态,甚至更优选至少99%非晶态。在另一方面,化合物A的非晶态形式是基本上纯的非晶态形式。在另一方面,化合物A基本上纯的非晶态形式不包含可检测量的化合物A的晶体形式。
固体分散体
当在ASD中与稳定聚合物组合时,可以以稳定形式制备化合物A的非晶态形式。本文所用的术语“固体分散体”是指非晶态固体分散体(ASD),其中API以基本上非晶态的形式存在于稳定聚合物基质中。为了有效果,稳定聚合物优选与化合物是相容的,并且能够在施用于受试者时从与其形成的稳定聚合物基质中释放所述化合物。
已经开发了几种技术来制备固体分散体,包括热熔挤出、共沉淀、喷雾干燥、热熔凝固或溶剂浇铸。因此,基于由分散聚合物形成的基质,由这些不同方法制备的固体分散体可能在性质上不同,例如孔隙率、表面积、密度、稳定性、吸湿性、溶解性以及因此生物利用度。
在本文所述的一方面,化合物A的ASD是通过溶剂浇铸制备。在本文所述的另一方面,ASD是通过喷雾干燥制备,在这种情况下,ASD呈喷雾干燥分散体(SDD)形式。
术语“稳定聚合物”和“稳定聚合物基质”是指本文描述的用于制备ASD的聚合物,当与化合物A的非晶态形式混合时,形成有效稳定化合物A非晶态形式的基质,因此当包含在其中时减少非晶态化合物A向晶体化合物A的转化。一方面,稳定聚合物选自羟丙基甲基纤维素(“羟甲基纤维素”或HPMC)、乙酸琥珀酸酯(HPMCAS)、聚乙烯吡咯烷酮(“聚维酮”或PVP)或乙烯基吡咯烷酮-乙酸乙烯酯共聚物(“共聚维酮”或PVP VA 64)。稳定聚合物优选是当向受试者口服给药时,化合物A可以很容易地被受试者生物利用的一种。在另一方面,稳定聚合物选自HPMCAS,L型HPMCAS或M型HPMCAS。L型是指聚合物中琥珀酰基与乙酰基取代的比具有高比例,而M型具有中等比例,每种类型在不同的pH水平下溶解。在另一方面,稳定聚合物是L型HPMCAS。
在本文所述的一方面,ASD任选地包括表面活性剂,进一步提高化合物A在ASD中的溶解度。在另一方面,表面活性剂选自十二烷基硫酸钠和泊洛沙姆407。在另一方面,表面活性剂是泊洛沙姆407。
在本文所述的一方面,ASD中化合物A与稳定聚合物的比例稳定了基质中化合物A的非晶态形式。在本文所述的另一方面,化合物:聚合物的比例选自按重量计约5:95至约60:40的范围,或按重量计约10:90至约40:60的范围。在本文所述的另一方面,化合物:聚合物的比例按重量计为约40:60。在本文所述的一方面,在ASD中不存在辅料的情况下,化合物A加载的量选自按重量计约30%至约50%的范围,或按重量计约30%至约50%的范围。在本文所述的另一方面,化合物A的加载量按重量计为约40%。
在本文所述的一方面,制备化合物A的ASD的方法包括将化合物A溶解在溶剂液体中的一种或多种稳定聚合物中以形成溶液,然后干燥溶液形成固体分散体,其中化合物A是以非晶态形式存在于化合物-聚合物基质中。在本文所述的另一方面,干燥步骤通过溶剂浇铸进行。在本文所述的另一方面,干燥步骤通过喷雾干燥进行。在本文所述的另一方面,所使用的溶剂是基于化合物A在溶剂中的溶解度来选择的。
在本文所述的另一方面,所选择的溶剂符合由国际人用药物注册技术要求协调会议(ICH指南)制定的残留溶剂杂质指南中规定的绿色化学要求和标准。在本文所述的另一方面,也可以使用机械方式例如加热和搅拌来促进化合物A在溶剂液体中的溶解。溶剂液体还可包含非有机部分,例如水。可以使用的合适溶剂的非限制性实例包括例如水-醇混合物、甲醇、乙醇、异丙醇、丙酮和甲乙酮。一方面,所用溶剂为丙酮、乙醇、异丙醇或甲乙酮。在另一方面,溶剂是丙酮。
在本文所述的一个方面,喷雾干燥可用于制备化合物A的ASD。通常,喷雾干燥是将包含溶解的物质和稳定聚合物的溶液快速喷洒在暖空气气流上的过程,从而形成干粉。在本文所述的另一方面,ASD可以任选地被研磨或粉碎以提供ASD的细粉或微粉化粉末形式。得到的ASD或其粉末可以直接装入胶囊内口服。在本文所述的另一方面,药物组合物可包含与一种或多种额外辅料混合的ASD或其粉末。在本文提供的一方面,该药物组合物包含的ASD的量选自按重量计约5%至约90%的范围、按重量计约20%至约80%的范围、按重量计约30%至约70%的范围、或按重量计约40%至约60%的范围。在本文提供的另一方面,药物组合物包含ASD的量选自按重量计40%至约60%的范围。
在本文提供的一方面,ASD或其药物组合物包含用于口服给药的水性悬浮液。在另一方面,水性混悬液可以通过将ASD或其药物组合物(例如,一种或多种片剂或胶囊)溶解在水中来制备。在另一方面,可将水性混悬液的治疗有效剂量施用于吞咽片剂或胶囊有困难的患者,例如小孩。
药物组合物
本文所使用的术语“辅料”是指任何物质,其本身不是治疗剂,用作载体或媒介以将治疗剂递送至受试者,或添加至药物组合物以改善其处理或储存特性或以允许或促进将组合物的剂量单位形成为离散制品,例如适合口服给药的胶囊或片剂。辅料包括但不限于稀释剂、崩解剂、粘合剂、胶粘剂、表面活性剂、润滑剂、助流剂、表面改性剂、添加以掩盖或抵消令人不快的味道或气味的物质、调味剂、染料、香料和添加以改善组合物外观的物质。
在本文所述的一个方面,含有与一种或多种药学上可接受的辅料混合的化合物A的ASD和稳定聚合物的药物组合物可包含每剂量单位化合物A所需量,并且如果打算用于口服给药,药物组合物的剂量单位形式可以是选自片剂、囊片、丸剂、硬或软胶囊、锭剂、扁囊剂、粉剂、颗粒剂或混悬剂。在本文所述的一方面,药物组合物为包含预定量的化合物A的离散剂量单位的形式,例如片剂或胶囊。在一个优选的方面,离散剂量单位是片剂。
辅料
在本文所述的另一方面,本文所述的药物组合物任选地包含一种或多种药学上可接受的稀释剂作为辅料。合适的稀释剂单独或组合的任选自乳糖,包括无水乳糖或乳糖一水合物;淀粉,包括可直接压缩的和水解的淀粉;甘露醇;山梨糖醇;木糖醇;葡萄糖和葡萄糖一水合物;基于蔗糖的稀释剂,包括糖果糖;钙基稀释剂,包括一水硫酸氢钙、二水磷酸氢钙;硫酸钙二水合物或颗粒状乳酸钙三水合物;葡聚糖;肌醇;水解谷物固体;直链淀粉;纤维素,包括食品级来源的非晶态纤维素和粉末状纤维素;微晶纤维素、改性或共同加工的微晶纤维素、颗粒外微晶纤维素或硅化微晶纤维素;碳酸钙;甘氨酸;膨润土;聚乙烯吡咯烷酮,等等。在本文所述的另一方面,此类稀释剂可作为组合物总重量的一部分,其范围选自约5%至约90%、约10%至约60%,或约30%至约50%。所选的稀释剂优选表现出合适的流动性,并且在需要片剂的情况下提高可压缩性。
在本文所述的另一方面,药学上可接受的稀释剂单独或组合的任选自微晶纤维素、改性或共同加工的微晶纤维素、颗粒外微晶纤维素或硅化微晶纤维素,或乳糖一水合物。在本文所述的另一方面,此类稀释剂可以以约30%至约50%的范围作为组合物总重量的一部分存在。在本文所述的另一方面,此类稀释剂可以组合物总重量的约40%存在。
在一方面,无论是单独的还是组合的乳糖和微晶纤维素,在与其他稀释剂比较后,已发现与化合物A化学相容。在另一方面,颗粒外微晶纤维素,即在制粒步骤之后添加到组合物中的微晶纤维素,可用于提高硬度(对于片剂)。在另一方面,乳糖一水合物提供具有合适的化合物A释放速率、稳定性和预压缩流动性的药物组合物。
在另一方面,本文所述的药物组合物任选地包含一种或多种药学上可接受的崩解剂作为辅料,特别是对于片剂制剂。合适的崩解剂单独或组合的包括淀粉,包括羟基乙酸淀粉钠和预胶化玉米淀粉、粘土、纤维素(例如纯化纤维素)、微晶纤维素、甲基纤维素、羧甲基纤维素和羧甲基纤维素钠、交联羧甲基纤维素钠、藻酸盐、交聚维酮和树胶,例如琼脂、瓜尔豆、刺槐豆、刺梧桐、果胶和黄蓍胶。交联羧甲基纤维素钠是优选的用于片剂或胶囊崩解的崩解剂。交联羧甲基纤维素钠赋予本文所述的颗粒状组合物优异的颗粒内崩解能力。
崩解剂可以在组合物制备期间的任何合适的步骤中加入,特别是在造粒之前或在压缩之前的润滑步骤期间。如果存在,此类崩解剂总共占组合物总重量的约0.2%至约30%,优选约0.2%至约10%,更优选约1%至约6%。
本文所述的组合物任选地包含一种或多种药学上可接受的粘合剂或胶粘剂作为辅料,特别是对于片剂制剂。此类粘合剂和胶粘剂优选的赋予被压片的粉末足够的内聚力,以允许正常加工操作,例如施胶(sizing)、润滑、压缩和包装,但仍允许片剂在摄入时崩解并且组合物被吸收。合适的粘合剂和胶粘剂单独或组合的包括金合欢、黄芪、蔗糖、明胶、葡萄糖、淀粉,例如但不限于预胶化淀粉、纤维素,例如但不限于甲基纤维素和羧甲基纤维素钠、海藻酸和海藻酸盐、硅酸铝镁、聚乙二醇、瓜尔豆胶、多糖酸、膨润土、聚维酮,例如聚维酮K-15、K-30和K-29/32、聚甲基丙烯酸酯、HPMC、羟丙基纤维素、醋酸琥珀酸羟丙基纤维素(HPMC-AS)和乙基纤维素。如果存在的话,此类粘合剂和/或胶粘剂总共构成组合物总重量的约0.5%至约60%,优选约0.75%至约40%,更优选约1%至约30%。
在本文所述的一方面,组合物任选地包含一种或多种药学上可接受的表面活性剂作为辅料以提高化合物A的生物利用度。可以使用的表面活性剂的非限制性实例包括季铵化合物,例如二辛基磺基琥珀酸钠、聚氧乙烯烷基苯基醚,例如壬苯醇9、壬苯醇10和辛苯醇9、泊洛沙姆(聚氧乙烯和聚丙烯嵌段共聚物,例如泊洛沙姆407)、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、聚乙烯烷基醚,例如聚氧乙烯(20)鲸蜡硬脂醚、聚氧乙烯脂肪酸酯,例如聚氧乙烯(40)硬脂酸酯、聚氧乙烯脱水山梨糖醇酯,例如聚山梨醇酯20和聚山梨醇酯80(例如吐温80),丙二醇脂肪酸酯,例如月桂酸丙二醇酯、十二烷基硫酸钠、脂肪酸及其盐,例如油酸、油酸钠和油酸三乙醇胺、甘油脂肪酸酯,例如脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯和脱水山梨糖醇单硬脂酸酯、泰洛沙泊及它们的混合物。在本文所述的另一方面,阴离子表面活性剂例如泊洛沙姆407是特别优选的。如果存在的话,此类表面活性剂总共构成组合物总重量的约0.25%至约20%,优选约0.4%至约10%,更优选约0.5%至约5%。
在本文所述的一方面,组合物任选地包含一种或多种药学上可接受的润滑剂(包括抗粘剂和/或助流剂)作为辅料。合适的润滑剂单独或组合地包括甘油二酯、硬脂酸及其盐(包括硬脂酸镁、硬脂酸钙和硬脂酸钠)、氢化植物油、胶体二氧化硅、滑石、蜡、硼酸、苯甲酸钠、醋酸钠、富马酸钠、氯化钠、DL-亮氨酸、聚乙二醇、油酸钠、十二烷基硫酸钠和月桂基硫酸镁。在本文所述的另一方面,硬脂酸镁是优选的润滑剂,用于例如在压片期间减少设备和粒状混合物之间的摩擦。如果存在的话,此类润滑剂占组合物总重量的约0.1%至约10%,优选约0.25%至约5%,更优选约0.5%至约3%。
合适的抗粘剂包括滑石、玉米淀粉、DL-亮氨酸、十二烷基硫酸钠和金属硬脂酸盐。滑石是优选的抗粘剂或助流剂,用于例如减少制剂对设备表面的粘附和减少组合物混合时的静电。如果存在的话,滑石占组合物总重量的约0.1%至约10%,更优选约0.25%至约5%,再更优选约0.5%至约2%。
助流剂可用于促进固体制剂的粉末流动。合适的助流剂包括胶态二氧化硅、淀粉、滑石、磷酸三钙、粉末状纤维素和三硅酸镁。特别优选胶体二氧化硅。如果存在的话,这种助流剂占组合物总重量的约0.1%至约5%,更优选约0.25%至约5%,更优选约0.5%至约3%。
其他辅料例如着色剂、调味剂和甜味剂是制药领域已知的并且可用于本文所述的组合物中。片剂可以被包衣,例如用肠溶包衣、非功能性化妆品包衣、干粉压缩包衣或不包衣。本文所述的组合物还可包含例如缓冲剂。
在本文所述的一方面,药物组合物包含按重量计约40%至约60%的化合物A和HPMC-AS的ASD,优选SDD,其中化合物A与HPMC-AS的比例为约10:90到约40:60。在另一方面,药物组合物还包含约30%至约50%的微晶纤维素和乳糖一水合物、按重量计约1%至约6%范围的交联羧甲基纤维素钠、按重量计约0.5%至约5%范围的泊洛沙姆407和按重量计约0.5%至约3%范围的硬脂酸镁。在另一方面,药物组合物还包含约0.5%至约2%范围的胶体二氧化硅。
在本文所述的一方面,制备药物组合物的方法包括将化合物A混合物的ASD与一种或多种辅料混合形成混合物,然后分别将混合物压片或包囊形成片剂或胶囊。
在本文所述的另一方面,如图1所示,制备药物组合物的方法包括:(a)将化合物A的ASD与一种或多种辅料混合形成混合物,(b)将混合物制粒以形成颗粒,和(c)分别将颗粒压片或包囊制成胶囊片剂。颗粒最初可制备为干法制粒。干法制粒可以通过压实来完成,例如通过碾压和碾磨,然后是一过程,例如在筛子中压碎或在搅拌机或磨机中剪切,以形成颗粒物质。优选在压片前加入润滑剂。颗粒的制备可以在低剪切或高剪切下独立进行。优选的工艺形成的颗粒具有可接受的含量均匀性、易于崩解、流动充分,从而在胶囊填充或压片过程中可以可靠地控制重量变化,并且在散装时密度足够大,因此可以在所选设备中加工一批,以显示可接受的剂型特征。
在标准的崩解试验,本文所述的片剂组合物优选的辅料提供小于约30分钟、优选约20分钟或更短、更优选约10分钟或更短、还更优选约5分钟或更短的崩解时间。
化合物A的治疗剂量
在本文所述的一个方面,药物组合物包括作为剂量单位施用的化合物A的ASD的单位剂型。本文中的术语“剂量单位”是指药物组合物的一部分,其含有一定量的治疗剂或预防剂,在本例中为化合物A,适合于单次口服给药以提供治疗效果。通常,每次给药需要一个剂量单位以提供包含足够量的药剂以产生所需效果的剂量。可以根据需要重复施用此类剂量。
本文所使用的术语“有效量”、“预防有效量”或“治疗有效量”是指ASD形式的化合物A的量,其在有需要的患者的癌症中有效地产生所需的预防、治疗、改善、抑制或预防作用。
在向患者施用包含呈ASD形式的化合物A的药物组合物的上下文中,本文所使用的术语“有效量”是指呈ASD形式的化合物A的量,其为足以在患者或患者细胞中实现至少一种或多种以下效果(如适用):(i)抑制肿瘤增殖;(ii)肿瘤大小或数量的减少;(iii)减轻或改善癌症或其相关症状的严重程度;(iv)预防癌症或与之相关的症状的进展;(v)癌症或与之相关的症状的消退;(vi)预防癌症或与之相关的症状的发展或发作;(vii)预防癌症或与癌症相关的症状的复发;(viii)减少与癌症相关的症状的持续时间;(ix)减少或消除癌症干细胞或肿瘤干细胞群;(x)减少或消除肿瘤或赘生物的生长;(xi)减少或消除癌细胞或肿瘤细胞的增殖;(xii)减少或消除过表达的肿瘤或赘生物的形成;(xiii)根除或控制原发性、区域性和/或转移性癌症;(xiv)降低患者死亡率;(xv)延缓患者数量增加;(xvi)延长患者的缓解时间;(xvii)维持或控制肿瘤或赘生物的大小,使得通过本领域技术人员可用的常规方法诸如MRI、X射线和CAT扫描所测量的,在施用标准疗法后,其大小不增加或增加小于肿瘤的大小;(xviii)疾病进展延迟增加;(xix)提高患者存活率;(xx)减少患者住院率;(xxi)缩短患者住院时间;(xxii)增强或改善另一种疗法的预防或治疗效果;(xxiii)与癌症相关的症状数量减少;(xxiv)提高患者的无癌生存率;和/或(xxv)增加癌症患者的无症状存活率。
一般而言,术语“有效量”还包括给予患者呈ASD形式的化合物A的量,其范围为约0.001mg/Kg/天至约500mg/Kg/天、或约0.01mg/Kg/天至约500mg/Kg/天、或约0.1mg至约500mg/Kg/天、或约1.0mg/天至约500mg/Kg/天,以单次、分次或连续剂量给予体重在约40至约200Kg范围内的患者或受试者(对于高于或低于此范围的患者或受试者,尤其是40Kg以下的儿童,可以调整其剂量)。预计普通的成年受试者具有约60至约100Kg范围内的中间体重。对象的有效量也将取决于各种因素,包括对象的体重、大小和健康。可以根据临床医生的技能和判断来确定给定患者的有效量。
在另一方面,当基于受试者或患者的体重来调整每日剂量时,ASD形式的化合物A可以以约2、5、10、20、50、80、100、150、200、250、300或500mg/Kg/天配制用于递送。根据受试者或患者的体重调整的日剂量可以作为单次、分次或连续剂量给药。在另一方面,当ASD形式的化合物A的剂量每天给予超过一次时,该剂量可以每天给予一次、两次、三次或更多次。在另一方面,向受试者施用一个或多个ASD形式化合物A的有效量的剂量,其中每个剂量的有效量可能不同。本文所述的另一方面包括ASD形式化合物A的有效量在约0.001mg/Kg/天至约500mg/Kg/天范围内。
在本文所述的范围内,用于制造药物或用于治疗有需要受试者的癌症的方法的ASD形式化合物A的“有效量”旨在包括剂量范围每天给药约0.1ng至约3500mg、每天给药约0.1μg至约3500mg、每天给药约0.1mg至约3500mg、每天给药约1mg至约3500mg、每天给药约1mg至约3000mg、每天给药约0.05mg至约1500mg、每天给药约0.5mg至约1500mg、每天给药约1mg至约1500mg、每天给药约5mg至约1500mg、每天给药约10mg至约600mg、每天给药约0.5mg至约2000mg,或者每天给药约5.0mg至约1500mg范围内的量。
本文所述的另一方面包括ASD形式化合物A的有效量在约0.1ng至约3500mg范围内。
在本文所述的一方面,所述药物组合物是以约10mg至约1000mg、或约50mg至约400mg、或约50mg至约200mg范围的治疗有效剂量施用的片剂或胶囊剂。在本文所述的另一方面,典型的剂量单位包含约10、20、25、50、75、100、125、150、175、200、250、300、350或400mg呈ASD的化合物A。一方面,对于成年人,本文所述组合物中每剂量单位的ASD形式化合物A的治疗有效量通常为约50mg至约400mg。在另一方面,本文所述组合物中每剂量单位的ASD形式化合物A的治疗有效量为约100mg至约200mg,例如约100mg或约200mg。在另一方面,如本文所述的每剂量单位的ASD形式化合物A的治疗有效量是约50mg或约200mg。可任选包含ASD形式化合物A治疗有效量的剂量单位来适应用于实现所需日剂量的所需给药频率。
在本文所述的一个或多个方面,施用于任何类型癌症的ASD形式的化合物A组合物的有效量可通过体外或体内结果初步估计,体外结果来自使用患者细胞或本领域技术人员已知的细胞系的细胞培养测定,体内结果来自相关动物模型,例如小鼠、黑猩猩、狨猴或绢毛猴动物模型。相关动物模型也可用于确定合适的浓度范围和给药途径。然后可以使用此类信息来确定用于人体的有用剂量和给药途径。治疗功效和毒性可以通过细胞培养物或实验动物中的标准药物程序确定,例如ED50(对50%的群体治疗有效的剂量)和LD50(对50%的群体致死的剂量)。毒性和治疗作用之间的剂量比称为治疗指数,可以表示为比值,LD50/ED50。在一些方面,有效量使得达到大的治疗指数。在进一步的方面,剂量在包括具有很少或没有毒性的ED50的血浆浓度范围内。剂量可在此范围内变化,这取决于所采用的剂型、患者的敏感性和给药途径。
在本文所述的一个方面,就ASD形式的化合物A观察到的浓度-生物学效应(药效学)关系表明目标血浆浓度范围为约0.001μg/mL至约50μg/mL,约0.01μg/mL至约20μg/mL、约0.05μg/mL至约10μg/mL、或约0.1μg/mL至约5μg/mL。在本文所述的另一方面,目标血浆浓度可以在范围约3hr·μg/mL至约70hr·μg/mL、约3hr·μg/mL至约60hr·μg/mL、约3hr·μg/mL至约50hr·μg/mL、约3hr·μg/mL至约40hr·μg/mL、约3hr·μg/mL至约30hr·μg/mL、约3hr·μg/mL至约20hr·μg/mL、约3hr·μg/mL至约10hr·μg/mL等,或介于两者之间的任何范围。
为了达到这样的血浆浓度,ASD形式的化合物A可以以0.001μg至100,000mg不等的剂量给药,这取决于对体重约40至约100kg的患者以单一、分开或连续剂量的给药途径(对于高于或低于此体重范围的患者,尤其是40kg以下的儿童,可调整其剂量)。
确切的剂量将由执业者根据与受试者相关的因素确定。可以调整剂量和给药以提供足够水平的活性剂或维持所需的效果。可考虑的给药因素包括疾病状态的严重程度、受试者的总体健康状况、受试者的种族、年龄、体重和性别、饮食、给药时间和频率、药物组合、反应敏感性、对与药物代谢物相关的毒性的耐受性、其他癌症疗法和方案的经验以及对此类疗法和方案的耐受性/反应。根据特定制剂的半衰期和清除率,可以每2、3或4天、每周一次或每两周一次施用长效药物组合物。
ASD形式的化合物A可以通过口服、眼部、直肠、口腔、外用、鼻、眼、皮下、肌内、静脉内(推注和输注)、脑内、透皮和肺的途径给予受试者。
本文中的术语“口服给药”包括将治疗剂或其组合物递送至受试者的任何形式,其中将所述药剂或组合物置于受试者的口中,无论所述药剂或组合物是否被立即吞咽。药剂的吸收可发生在胃肠道的任何部分或多个部分,包括口腔、食道、胃、十二指肠、回肠和结肠。术语“可口服递送”在本文中是指适合于口服给药。
ASD组合物的使用
呈非晶态固体分散体(ASD)形式的化合物A的药物组合物,包括本文公开的任何剂型,可用于治疗各种类型的癌症,包括实体瘤和血液学癌症,通过向有需要的受试者施用组合物的口服剂型的治疗有效量。给药的剂型优选包含如本文所公开的化合物A的固体分散体。
本文所述的一方面包括可以用本文公开的非晶态固体分散体形式的化合物A的药物组合物治疗的癌症类型的非限制性实例,例如:白血病,例如但不限于急性白血病、急性淋巴细胞白血病、急性粒细胞白血病,例如成髓细胞白血病、早幼粒细胞白血病、粒单核细胞白血病、单核细胞白血病和红白血病白血病以及骨髓增生异常综合征;慢性白血病,例如但不限于慢性粒细胞(粒细胞)白血病、慢性淋巴细胞白血病、毛细胞白血病;真性红细胞增多症;淋巴瘤,例如但不限于霍奇金(Hodgkin’s)淋巴瘤、非霍奇金淋巴瘤;多发性骨髓瘤,例如但不限于冒烟型多发性骨髓瘤(smoldering multiple myeloma)、非分泌性骨髓瘤、骨硬化性骨髓瘤、浆细胞白血病、孤立性白细胞瘤和髓外白细胞瘤;瓦尔登斯特伦巨球蛋白血症;意义不明的单克隆丙种球蛋白病;良性单克隆丙种球蛋白病;重链病;骨和结缔组织肉瘤,例如但不限于骨肉瘤(bone sarcoma)、骨肉瘤(osteosarcoma)、软骨肉瘤、尤文氏(Ewing’s)肉瘤、恶性巨细胞瘤、骨纤维肉瘤、脊索瘤、骨膜肉瘤、软组织肉瘤、血管肉瘤(血管肉瘤)、纤维肉瘤、卡波西(Kaposi’s)肉瘤、平滑肌肉瘤、脂肪肉瘤、淋巴管肉瘤、神经鞘瘤、横纹肌肉瘤、滑膜肉瘤;神经胶质脑肿瘤(即神经胶质瘤)例如但不限于星形细胞瘤、室管膜瘤、少突神经胶质瘤、脑干神经胶质瘤、视神经胶质瘤、弥漫性内源性脑桥神经胶质瘤、混合性神经胶质瘤(即少突星形细胞瘤)、胶质母细胞瘤、多形性胶质母细胞瘤、非神经胶质瘤、声学神经瘤、颅咽管瘤、髓母细胞瘤、脑膜瘤、松果体细胞瘤、松果体母细胞瘤、原发性脑淋巴瘤;乳腺癌,包括但不限于导管癌、腺癌、小叶(癌细胞)癌、导管内癌、髓质乳腺癌、粘液性乳腺癌、管状乳腺癌、乳头状乳腺癌、佩吉特氏(Paget’s)病和炎性乳腺癌;肾上腺癌,例如但不限于嗜铬细胞瘤和肾上腺皮质癌;甲状腺癌,例如但不限于乳头状或滤泡状甲状腺癌、髓样甲状腺癌和未分化甲状腺癌;胰腺癌,例如但不限于胰岛素瘤、胃泌素瘤、胰高血糖素瘤、舒血管肠肽瘤(VIPoma)、分泌生长抑素的肿瘤和类癌或胰岛细胞瘤;垂体癌,例如但不限于库欣(Cushing’s)病、泌乳素分泌肿瘤、肢端肥大症和尿崩症;眼癌,例如但不限于眼部黑色素瘤,例如虹膜黑色素瘤、脉络膜黑色素瘤和睫状体黑色素瘤、以及视网膜母细胞瘤;阴道癌,例如鳞状细胞癌、腺癌和黑色素瘤;外阴癌,例如鳞状细胞癌、黑色素瘤、腺癌、基底细胞癌、肉瘤和佩吉特病;宫颈癌,例如但不限于鳞状细胞癌和腺癌;子宫癌,例如但不限于子宫内膜癌和子宫肉瘤;卵巢癌,例如但不限于卵巢上皮癌、交界性肿瘤;生殖细胞肿瘤和间质瘤;食道癌例如但不限于鳞状癌、腺癌、腺样囊性癌、粘液表皮样癌、腺鳞癌、肉瘤、黑色素瘤、乳癌、疣状癌和燕麦细胞(癌细胞)癌;胃癌,例如但不限于腺癌、真菌性(息肉状)、溃疡性、浅表扩散、弥漫性扩散、恶性淋巴瘤、脂肪肉瘤、纤维肉瘤和癌肉瘤;结肠癌;直肠癌;肝癌,例如但不限于肝细胞癌和肝母细胞瘤;胆囊癌,例如腺癌;胆管癌,例如但不限于乳头状、结节状和弥漫性;肺癌,例如非小细胞肺癌、鳞状细胞癌(表皮样癌)、腺癌、大细胞癌、小细胞肺癌;睾丸癌例如但不限于生殖肿瘤、精原细胞瘤、间变性、经典(典型)、精母细胞非精原细胞瘤、胚胎癌、畸胎瘤癌、绒毛膜癌(卵黄囊瘤);前列腺癌,例如但不限于前列腺上皮内瘤变、腺癌、平滑肌肉瘤和横纹肌肉瘤;肾脏癌(penal cancer);口腔癌,例如但不限于鳞状细胞癌;基底癌(basal cancer);唾液腺癌,例如但不限于腺癌、粘液表皮样癌和腺样囊性癌;咽癌,例如但不限于鳞状细胞癌和疣状癌;皮肤癌例如但不限于基底细胞癌、鳞状细胞癌和黑色素瘤、浅表扩散性黑色素瘤、结节性黑色素瘤、黑色素瘤恶性黑色素瘤、肢端黑色素瘤;肾癌,例如但不限于肾细胞癌、腺癌、肾肥大瘤、纤维肉瘤、移行细胞癌(肾盂和/或输尿管);维尔姆斯瘤(Wilms’tumor)、膀胱癌例如但不限于移行细胞癌、鳞状细胞癌、腺癌、癌肉瘤。此外,癌症包括粘液肉瘤、骨源性肉瘤、内皮肉瘤、淋巴管内皮瘤、间皮瘤、滑膜瘤、血管母细胞瘤、上皮癌、囊腺癌、支气管癌、汗腺癌、皮脂腺癌、乳头状癌和乳头状腺癌(对此类疾病的综述,参见Fishman et al.,1985,Medicine,2d Ed.,J.B.Lippincott Co.,费城和Murphy et al.,1997,InformedDecisions:The Complete Book of Cancer Diagnosis,Treatment,and Recovery,VikingPenguin,Penguin Books U.S.A.,Inc.,美国)。
本文所述的另一方面包括可以用本文公开的ASD形式的化合物A的药物组合物治疗的癌症类型的其他实例,例如:癌,包括膀胱癌、乳腺癌、结肠癌、肾、肝、肺、卵巢、胰腺、胃、子宫颈、甲状腺和皮肤;包括鳞状细胞癌;淋巴系造血肿瘤,包括白血病、急性淋巴细胞白血病、急性淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、伯基特(Burkitt’s)淋巴瘤;髓系造血肿瘤,包括急性和慢性髓性白血病和早幼粒细胞白血病;间叶源性肿瘤,包括纤维肉瘤和横纹肌肉瘤;其他肿瘤,包括黑色素瘤、精原细胞瘤、畸胎癌、神经母细胞瘤;中枢和外周神经系统肿瘤,包括星形细胞瘤、神经母细胞瘤、神经胶质瘤和神经鞘瘤;间叶源性肿瘤,包括纤维肉瘤、横纹肌肉瘤和骨肉瘤;和其他肿瘤,包括黑色素瘤、色素性干皮病、角化棘皮瘤、精原细胞瘤、甲状腺滤泡癌和畸胎癌。
本文描述的另一方面包括可以用本文公开的ASD形式的化合物A的药物组合物治疗的癌症类型的其他实例,例如:与细胞凋亡异常相关的癌症,包括但不限于滤泡性淋巴瘤、具有p53突变的癌、乳腺、前列腺和卵巢的激素依赖性肿瘤、以及癌前病变,例如家族性腺瘤性息肉病和骨髓增生异常综合征。本文所述的另一方面包括可用本文公开的ASD形式的化合物A的药物组合物治疗的癌症类型的其他实例,例如:恶性肿瘤或增殖异常变化(例如化生和异常增殖),或过度增殖性疾病在皮肤、肺、肝、骨、脑、胃、结肠、乳房、前列腺、膀胱、肾、胰腺、卵巢和/或子宫的任何部位按照本文所述的方法进行治疗。本文所述的另一方面包括可用本文公开的ASD形式的化合物A的药物组合物治疗的癌症类型的其他实例,例如:肉瘤或黑素瘤。
在一个具体方面,如本文所述治疗的癌症是白血病、淋巴瘤或骨髓瘤(例如,多发性骨髓瘤)。可用本文所述方法治疗的白血病和其他血源性癌症的非限制性实例包括急性淋巴细胞白血病(ALL)、急性淋巴细胞B细胞白血病、急性淋巴细胞T细胞白血病、急性成髓细胞白血病(AML)、急性早幼粒细胞白血病(APL)、急性单核细胞白血病、急性红白血病、急性巨核细胞白血病、急性粒单核细胞白血病、急性非淋巴细胞白血病、急性未分化白血病、慢性粒细胞白血病(CML)、慢性淋巴细胞白血病(CLL)和毛细胞白血病。
可根据本文所述方法治疗的淋巴瘤的非限制性实例包括霍奇金淋巴瘤、非霍奇金淋巴瘤、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症、重链病和真性红细胞增多症。
在另一方面,如本文所述治疗的癌症是实体瘤。可根据本文所述方法治疗的实体瘤的实例包括但不限于纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、结直肠癌、肾癌、胰腺癌、骨癌、乳腺癌、卵巢癌、前列腺癌、食道癌、胃癌、口腔癌、鼻癌、咽喉癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、维尔姆斯瘤、宫颈癌、子宫癌症、睾丸癌、小细胞肺癌、膀胱癌癌、肺癌、上皮癌、胶质瘤、多形性胶质母细胞瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、皮肤癌、黑色素瘤、神经母细胞瘤和视网膜母细胞瘤。
在另一方面,如本文所述治疗的癌症包括但不限于脑癌、胃癌、血液学癌症、肺癌、非小细胞肺癌、胰腺癌、前列腺癌、唾液腺癌、结直肠癌、肝细胞癌、肝癌、乳腺癌或肉瘤、食道癌或肉瘤、胃癌或肉瘤、纤维肉瘤、胶质母细胞瘤、弥漫性固有脑桥胶质瘤、髓母细胞瘤、神经母细胞瘤、弥漫性大B细胞淋巴瘤、B细胞非霍奇金淋巴瘤、霍奇金淋巴瘤或慢性或急性髓系白血病。
在另一方面,如本文所述治疗的癌症包括但不限于尽管改进的手术和辐射技术治疗后复发的肿瘤。肿瘤复发的原因有很多,其中一种合理的解释是肿瘤群体中存在癌症干细胞(CSC)或肿瘤干细胞(肿瘤起始细胞)。CSC定义为与任何类型的血癌、实体瘤癌或转移癌相关的干细胞群。肿瘤干细胞是那些在肿瘤内特异性发现的细胞。两者都具有与正常干细胞相似的特征。与正常干细胞一样,CSC和肿瘤干细胞具有自我更新的潜力。然而,与正常干细胞不同的是,CSC和肿瘤干细胞无法在不受控制的情况下进行终末分化和增殖。它们增强的DNA修复能力也使它们能够对旨在杀死癌细胞和肿瘤细胞的细胞毒性化学治疗药物产生抗药性。因此,靶向CSC和肿瘤干细胞可能是一种有效的癌症治疗方法。另一种方法是靶向各种负责维持CSC和肿瘤干细胞自我更新能力的转录因子。
本文所使用的术语“治疗(treat)”、“治疗(treatment)”或“治疗(treating)”是指:(i)预防疾病、紊乱和/或病症在可能易患该疾病、紊乱和/或病症但尚未被诊断为患有所述疾病、紊乱和/或病症的受试者中发生;(ii)抑制疾病、紊乱和/或病症,即阻止其发展;和/或(iii)缓解疾病、紊乱和/或病症,即引起疾病、紊乱和/或病症的消退。
本文所使用的术语“受试者”是指人、马、猪、牛、鼠、大鼠、犬和猫物种的成员。在一些方面,受试者是哺乳动物或温血脊椎动物。在其他方面,受试者是人。本文所使用的术语“患者”可与“受试者”和“人”交替使用。
在某些方面,受试者是0至6个月大、6至12个月大、6至18个月大、18至36个月大、1至5岁、5至10岁、10至15岁、15至20岁、20至25岁、25至30岁、30至35岁、35至40岁、40至45岁、45至50岁、50至55岁、55至60岁、60至65岁、65至70岁、70至75岁、75至80岁、80至85岁、85至90岁、90至95岁或95至100岁的人。在一些方面,受试者是人类婴儿。在其他方面,受试者是人类蹒跚学步的幼儿。在其他方面,受试者是人类儿童。在其他方面,受试者是成人。在其他方面,受试者是老年人。
本文所使用的术语“老年人”是指65岁或65岁以上的人;术语“成人”是指年满18岁的人;术语“人类儿童”是指1岁至18岁的人类;术语“人类婴儿”是指新生儿至一岁的人;并且,术语“人类幼儿”是指1岁至3岁的人类。
在某些方面,受试者处于免疫受损状态或免疫抑制状态或处于变得免疫受损或免疫抑制的风险中。在某些方面,受试者正在接受免疫抑制治疗或正在从免疫抑制治疗中恢复。在某些方面,受试者患有或有患癌症、艾滋病或细菌感染的风险。在某些方面,受试者正在、将要或已经接受手术、化学疗法和/或放射疗法。在某些方面,受试者患有囊性纤维化、肺纤维化或其他影响肺部的病症。在某些方面,受试者已经、将要或已经进行了组织移植。
在一些方面,癌症可能变得难以通过常规“护理标准”疗法进行治疗,使得患者已经停止常规疗法。一方面,不受理论的限制,术语“难治性”是指癌细胞、肿瘤细胞、癌症干细胞或肿瘤干细胞的至少一些显著部分尽管进行治疗仍继续增殖。可以在体内或体外通过本领域已知的用于分析疗法对癌细胞、肿瘤细胞、癌症干细胞或肿瘤干细胞的影响的任何方法确定癌症是否对特定疗法难治,在这种情况下使用“难治性”的本领域公认的含义。在某些方面,患有难治性癌症的患者是其癌症对常规或“护理标准”疗法无反应或抗性的患者。在某些方面,患有难治性癌症的患者患有恶化的癌症。当肿瘤或赘生物未显著根除和/或症状未显著减轻时,证明疾病恶化,即对治疗缺乏临床反应。可以在体内或体外通过本领域已知的用于测定治疗癌症的疗法的有效性的任何方法确定患者是否患有难治性癌症,在这种情况下使用“难治性”的本领域公认的含义。
在某些方面,根据本文描述的方法待治疗的患者是已经用抗生素、抗病毒药、抗真菌药或其他生物疗法、免疫疗法或抗癌疗法治疗的患者。这些患者中包括患有难治性癌症的患者或对于常规疗法来说太年轻的患者。在一些方面,接受治疗的患者是未接受过治疗的,没有接受过任何先前的治疗。在任何前述方面中,待治疗的患者科能接受小分子疗法。
在一些方面,可将化合物A的ASD形式预防性地施用于患者以防止有患癌症风险的患者发生癌症。在一些方面,化合物A的ASD形式可以治疗性地施用于对常规疗法的不良反应敏感的患者。在一些方面,被给予化合物A的ASD形式的受试者没有接受过先前的治疗。在其他方面,将化合物A的ASD形式施用于已接受先前治疗的受试者。在一些方面,由于缺乏从治疗中获益、治疗的副作用或不可接受的毒性水平,施用化合物A的ASD形式的受试者已经停止先前的治疗。
在一些方面,被施用化合物A的ASD形式的受试者将经历或已经经历手术、化学疗法、抗体疗法、激素疗法和/或放射疗法。在某些方面,患者已接受手术以去除肿瘤或赘生物。在某些方面,受试者将进行或已经进行过或正在接受组织或器官移植。
对于化合物A的任何组合物,对于任何类型的癌症要施用的有效量可以通过体外或体内结果初步估计,体外结果来自使用患者细胞或本领域技术人员已知的细胞系的细胞培养测定,体内结果来自相关动物模型,例如小鼠、黑猩猩、狨猴或绢毛猴动物模型。相关动物模型也可用于确定合适的浓度范围和给药途径。然后可以使用此类信息来确定用于人体的有用剂量和给药途径。治疗功效和毒性可以通过细胞培养物或实验动物中的标准药物程序确定,例如ED50(对50%的群体治疗有效的剂量)和LD50(对50%的群体致死的剂量)。毒性和治疗作用之间的剂量比称为治疗指数,可以表示为比值,LD50/ED50。在一些方面,有效量使得达到大的治疗指数。在进一步的方面,剂量在包括具有很少或没有毒性的ED50的血浆浓度范围内。剂量可在此范围内变化,这取决于所采用的剂型、患者的敏感性和给药途径。
更具体地,关于化合物A观察到的浓度-生物学效应(药效学)关系表明目标血浆浓度范围为约3hr·μg/mL至约70hr·μg/mL、约3hr·μg/mL至约60hr·μg/mL、约3hr·μg/mL至约50hr·μg/mL、约3hr·μg/mL至约40hr·μg/mL、约3hr·μg/mL至约30hr·μg/mL、约3hr·μg/mL至约20hr·μg/mL、约3hr·μg/mL至约10hr·μg/mL等,或介于两者之间的任何范围。为了达到这样的血浆浓度,本文所述的化合物A或其形式可以以0.001μg至100,000mg不等的剂量给药,这取决于对体重约40至约100kg的患者以单一、分开或连续剂量的给药途径(对于高于或低于此体重范围的患者,尤其是40kg以下的儿童,可调整其剂量)。
确切的剂量将由执业者根据与受试者相关的因素确定。可以调整剂量和给药以提供足够水平的活性剂或维持所需的效果。可考虑的给药因素包括疾病状态的严重程度、受试者的总体健康状况、受试者的种族、年龄、体重和性别、饮食、给药时间和频率、药物组合、反应敏感性、对与药物代谢物相关的毒性的耐受性、其他癌症疗法和方案的经验以及对此类疗法和方案的耐受性/反应。
组合疗法
通过施用上文公开的化合物A的ASD形式或其药物组合物与一种或多种另外的试剂组合来治疗癌症的方法可以进一步包括向有需要的受试者施用有效量的化合物A的ASD形式或其药物组合物,所述试剂选自抗癌剂、抗增殖剂、化学治疗剂、免疫调节剂、抗血管生成剂、抗炎剂、烷化剂、甾体和非甾体抗炎剂、镇痛剂、白三烯拮抗剂、b2-激动剂、抗胆碱能剂、激素剂、生物剂、微管蛋白结合剂、糖皮质激素、皮质类固醇剂、抗菌剂、抗组胺剂、抗疟疾剂、抗病毒剂、抗生素等等,并且,任选地进行放射治疗。
根据本文所述的方法,组合产品可以包括活性成分的组合,其可以是:(1)在组合制剂中共同配制和同时给药或递送;(2)作为单独的制剂顺序递送或并行递送;(3)通过本领域已知的任何其他组合方案。当在交替疗法中作为单独的制剂递送时,本文所述的方法可以包括例如但不限于以单独的溶液、乳剂、悬浮液、片剂、丸剂或胶囊剂或通过单独注射器中的不同注射给药或递送。通常,当交替给药时,连续给予每种活性成分有效剂量,一个剂量接着另一个。相反,在平行给药或同时给药时,两种或更多种活性成分的有效剂量一起给药。也可以使用间歇性顺序或平行组合给药的各种替代组合。
此类药剂的具体实例包括但不限于免疫调节剂(例如干扰素、青霉胺等)、抗血管生成剂、抗炎剂(例如肾上腺皮质激素、皮质类固醇(例如倍氯米松、布地奈德)、氟尼缩松、氟替卡松、曲安西龙(triamcinolone)、甲基泼尼松龙(methylprednisolone)、泼尼松龙、泼尼松、氢化可的松)、糖皮质激素、甾体和非甾体抗炎药(例如阿司匹林、布洛芬、双氯芬酸和COX-2抑制剂))、止痛药、白三烯拮抗剂(例如孟鲁司特(montelukast)、甲基黄嘌呤、扎鲁司特(zafirlukast)和齐留通(zileuton))、β2-激动剂(例如沙丁胺醇、比特罗(biterol)、非诺特罗、异他林(isoetharine)、奥西那林(metaproterenol)、吡布特罗、沙丁胺醇、特布他林、福莫特罗、沙美特罗和沙丁胺醇特布他林)、抗胆碱能药(例如异丙托溴铵和氧托溴铵)、抗菌药(例如柳氮磺吡啶、氨苯砜等)、抗组胺药、抗疟疾药(例如羟氯喹)、抗病毒药(例如核苷类似物(例如齐多夫定、阿昔洛韦、更昔洛韦、阿糖腺苷、碘苷、三氟尿苷、利巴韦林(ribavirin)、膦甲酸、金刚烷胺、金刚乙胺、沙奎那韦、茚地那韦、利托那韦和AZT)和抗生素(例如更生霉素(以前称为放线菌素)、博来霉素、红霉素、青霉素、光神霉素和氨茴霉素(anthramycin)(AMC))。
可与化合物A的ASD形式组合使用的额外药剂的具体实例包括但不限于:阿西维辛(acivicin)、阿柔比星、盐酸阿考达唑(acodazole hydrochloride)、阿克罗宁、阿多来新(adozelesin)、阿地白介素、六甲蜜胺、氨霉素、醋酸阿美蒽醌(ametantrone acetate)、氨鲁米特、安吖啶、阿那曲唑、蒽环霉素、氨茴霉素、天冬酰胺酶、曲林菌素(asperlin)、阿扎胞苷、阿扎替派(azetepa)、含氮霉素(azotomycin)、巴马司他、苯佐替哌(benzodepa)、比卡鲁胺、比生群盐酸盐(bisantrene hydrochloride)、双奈法德二甲磺酸盐(bisnafidedimesylate)、双膦酸盐(例如帕米膦酸盐(pamidronate)氯膦酸钠(sodiumclondronate)唑来膦酸阿仑膦酸盐依替膦酸盐、伊班膦酸盐(ibandornate)、英卡膦酸盐(cimadronate)、利塞膦酸盐(risedromate)和替鲁膦酸盐(tiludromate))、比折来新(bizelesin)、硫酸博来霉素、布喹那钠、溴匹立明(bropirimine)、白消安、放线菌素(cactinomycin)、卡鲁睾酮(calusterone)、卡拉酰胺(caracemide)、卡贝替姆(carbetimer)、卡铂、卡莫司汀、盐酸卡柔比星、卡折来新(carzelesin)、西地芬戈(cedefingol)、苯丁酸氮芥、西罗霉素(cirolemycin)、顺铂、克拉屈滨、甲磺酸克立那托(crisnatol mesylate)、环磷酰胺、阿糖胞苷、达卡巴嗪、更生霉素(dactinomycin)、道诺霉素盐酸盐、地西他滨、去甲基化剂、右奥马铂(dexormaplatin)、地扎胍宁(dezaguanine)、地扎胍宁甲磺酸盐、地吖醌(diaziquone)、多西紫杉醇、阿霉素、盐酸多柔比星、屈洛昔芬、屈洛昔芬柠檬酸盐、丙酸屈他雄酮(dromostanolone propionate)、达佐霉素(duazomycin)、依达曲沙、依氟鸟氨酸盐酸盐、EphA2抑制剂、依沙芦星、恩洛铂(enloplatin)、恩普氨酯、依匹哌啶(epipropidine)、表柔比星盐酸盐、厄布洛唑(erbulozole)、依索比星盐酸盐、雌莫司汀、雌莫司汀磷酸钠、依他硝唑、依托泊苷、依托泊苷磷酸盐、艾托卜宁(etoprine)、法倔唑盐酸盐、法扎拉滨、芬维A胺、氟尿苷、氟达拉滨磷酸盐、5-氟尿嘧啶、氟西他滨、磷喹酮、福司曲星钠(fostriecin sodium)、吉西他滨、盐酸吉西他滨、组蛋白脱乙酰酶抑制剂、羟基脲、盐酸伊达比星、异环磷酰胺、伊莫福新、甲磺酸伊马替尼、白介素II(包括重组白介素II或rIL2),干扰素α2a、干扰素α2b、干扰素αn1、干扰素αn3、干扰素βIa、干扰素γIb、异丙铂、伊立替康盐酸盐、醋酸兰瑞肽、来那度胺、来曲唑、醋酸亮丙瑞林、利阿唑盐酸盐(liarozole hydrochloride)、洛美曲索钠、洛莫司汀、盐酸洛氧蒽醌、马索罗酚(masoprocol)、美登素、二氯甲基二乙胺盐酸盐、抗CD2抗体、甲地孕酮醋酸盐、美仑孕酮醋酸盐、美法兰(melphalan)、美诺立尔(menogaril)、巯嘌呤、甲氨蝶呤、甲氨蝶呤钠、氯苯氨啶(metoprine)、美妥替哌、米丁度胺(mitindomide)、米托卡星(mitocarcin)、丝裂红素(mitocromin)、丝裂菌褶素(mitogillin)、丝裂马菌素(mitomalcin)、丝裂霉素、丝裂帕菌素(mitosper)、米托坦、米托蒽醌盐酸盐、霉酚酸、诺考达唑、诺加霉素、奥马铂、奥昔舒仑(oxisuran)、紫杉醇、培门冬酶(pegaspargase)、佩里霉素(peliomycin)、戊氮芥(pentamustine)、培洛霉素硫酸盐、过磷酰胺、哌泊溴烷、哌泊舒凡、盐酸吡咯蒽酮、普卡霉素、普罗美坦(plomestane)、卟吩姆钠、紫菜霉素、泼尼莫司汀、甲苄肼盐酸盐、嘌呤霉素、盐酸嘌呤霉素、吡唑呋喃菌素、利波腺苷(riboprine)、罗谷亚胺、沙芬戈、沙芬戈盐酸盐、司莫司汀(semustine)、辛曲秦、磷乙酰天冬氨酸钠(sparfosate sodium)、稀疏霉素、锗螺胺盐酸盐、螺莫司汀、螺铂、链霉黑素、链脲佐菌素、磺氯苯脲、他利霉素、替可加兰钠(tecogalansodium)、替加氟(tegafur)、盐酸替洛蒽醌、替莫泊芬、替尼泊苷、特洛昔酮、睾内酯、硫咪嘌呤(thiamiprine)、硫鸟嘌呤、噻替哌、噻唑呋林(tiazofurin)、替拉扎明、托瑞米芬柠檬酸盐、醋酸曲托龙、磷酸曲西瑞滨、三甲曲沙(trimetrexate)、葡萄糖醛酸三甲曲沙、曲普瑞林、盐酸妥布氯唑、尿嘧啶芥末、乌瑞替派、伐普肽、维替泊芬、硫酸长春花碱、硫酸长春新碱、长春地辛、硫酸长春地辛、硫酸长春匹定、硫酸长春甘酯、硫酸长春罗新、酒石酸长春瑞滨、硫酸长春罗定、硫酸长春利定、沃利替尼、伏氯唑、折尼铂、净司他丁(zinostatin)、盐酸佐柔比星等等。
根据本方法治疗介导的癌症的其他实例包括用抗癌剂或抗增殖剂治疗,其中抗癌剂或抗增殖剂选自但不限于:20-Epi-1,25-二羟基维生素D3(MC 1288、MC 1301、KH 1060)、5-乙炔尿嘧啶、阿比特龙、阿柔比星、酰基富烯(acylfulvene)、腺环戊醇(adecypenol)、阿多来新、阿地白介素、ALL-TK拮抗剂、六甲蜜胺、氨莫司汀(ambamustine)、胺肟(amidox)、氨磷汀、氨基乙酰丙酸、氨柔比星、安吖啶、阿那格雷、阿那曲唑、穿心莲内酯、血管生成抑制剂、拮抗剂D、拮抗剂G、安雷利克斯(antarelix)、抗背侧化形态发生蛋白-1(antidorsalizing morphogenetic protein-1)、抗雄激素、抗雌激素、抗瘤酮(antineoplaston)、反义寡核苷酸、阿非迪霉素甘氨酸盐、凋亡基因调节剂、细胞凋亡调节剂、脱嘌呤核酸(apurinic acid)、ara-CDP-DL-PTBA(0-棕榈酰-1-硫代甘油)、精氨酸脱氨酶、阿苏拉克(asulacrine)、阿他美坦、阿莫司汀、阿西他汀1(axinastatin 1)、阿西他汀2、阿西他汀3、阿扎西隆(azasetron)、阿扎毒素(azatoxin)、重氮酪氨酸(azatyrosine)、浆果赤霉素III衍生物、巴拉诺(balanol)、巴马司他、BCR/ABL拮抗剂、苯并氯(benzochlorins)、苯甲酰星形孢菌素(benzoylstaurosporine)、β内酰胺衍生物、β-阿勒辛(alethine)、β克拉霉素B(betaclamycin B)、桦木酸、bFGF抑制剂、比卡鲁胺、比生群、双氮丙啶精胺(bisaziridinylspermine)、双萘法德、双扎汀A(bistratene A)、比折来新、布雷弗莱特(breflate)、溴匹立明(bropirimine)、布朵替坦(budotitane)、丁硫氨酸亚砜亚胺、卡泊三醇、钙磷酸蛋白C、喜树碱衍生物、金丝雀痘IL-2、卡培他滨、甲酰胺-氨基-三唑(CaRestM3)、CARN700、软骨衍生抑制剂、卡折来新、酪蛋白激酶抑制剂(ICOS)、栗精胺、天蚕抗菌肽B(cecropin B)、西曲瑞克、氯林斯(chlorlns)、氯代喹喔啉磺酰胺、西卡前列素(cicaprost)、顺式卟啉、克拉屈滨、氯米芬类似物(clomifene analogues)、克霉唑、柯利霉素A(collismycin A)、柯利霉素B、康普瑞汀A4(combretastatin A4)、康普瑞汀类似物、措那格林(conagenin)、海甘蓝西丁816(crambescidin816)、克里斯那托尔(crisnatol)、念珠藻素8、念珠藻素A衍生物、箭毒素A(curacin A)、环戊蒽醌、环铂(cycloplatam)、卷曲霉素(cypemycin)、阿糖胞苷烷磷酯(cytarabine ocfosfate)(YNK01或)、溶细胞因子、细胞抑制素(cytostatin)、达昔单抗(dacliximab)、地西他滨、脱氢膜海鞘素B(dehydrodidemnin B)、地洛瑞林、地塞米松、右异环磷酰胺(dexifosfamide)、右雷佐生、右维拉帕米、亚丝醌(diaziquone)、膜海鞘素B、二羟基苯并氧肟酸(didox)、二乙基去甲精胺(diethylnorspermine)、二氢-5-氮杂胞苷、二氢紫杉醇、二氧霉素(dioxamycin)、二苯基螺莫司汀、多西紫杉醇、二十二烷醇、多拉司琼、去氧氟尿苷、屈洛昔芬、屈大麻酚、倍癌霉素SA(duocarmycin SA)、依布硒啉、依考莫司汀、依地福新、依决洛单抗、依氟鸟氨酸、榄香烯、乙嘧替氟、表柔比星、依立雄胺(epristeride)、雌莫司汀类似物、雌激素激动剂、雌激素拮抗剂、依他硝唑、磷酸依托泊苷、依西美坦、法倔唑、法扎拉滨、芬维A胺、非格司亭、非那雄胺、黄酮吡醇(flavopiridol)、氟卓斯汀(flezelastine)、氟甾酮(fluasterone)、氟达拉滨、氟道红霉素盐酸盐(fluorodaunorunicin hydrochloride)、福酚美克、福美司坦、福司曲星、福莫司汀、钆特沙弗林(gadolinium texaphyrin)、硝酸镓、加洛他滨、加尼瑞克、白明胶酶抑制剂、吉西他滨、谷胱甘肽抑制剂、HMG CoA还原酶抑制剂(例如阿托伐他汀、西立伐他汀、氟伐他汀、氟伐他汀、卢普妥(lupitor)、洛伐他汀、瑞舒伐他汀和辛伐他汀)、磺胺(hepsulfam)、调节蛋白、六亚甲基双乙酰胺、金丝桃素、伊班膦酸、伊达比星、艾多昔芬、伊决孟酮、伊莫福新、伊洛马司他、咪唑吖啶酮、咪喹莫特、免疫刺激肽、胰岛素样生长因子-1受体抑制剂、干扰素激动剂、干扰素、白细胞介素、碘苄胍、碘阿霉素、甘薯黑斑霉醇(ipomeanol)、4伊罗普拉、伊索格列定(irsogladine)、异苯唑(isobengazole)、异高卤虫蛋白B(isohomohalicondrin B)、伊他司琼、大环肽天然产物(jasplakinolide)、卡哈拉利特F(kahalalide F)、片螺素N三乙酸盐(lamellarin N triacetate)、兰瑞肽、莱那霉素(leinamycin)、来格司亭、香菇多糖硫酸盐、瘦素(leptolstatin)、来曲唑、白血病抑制因子、白细胞α干扰素、亮丙瑞林/雌激素/黄体酮组合物、亮丙瑞林、左旋咪唑、LFA-3TIP)、利阿唑、线性多胺类似物、亲脂性二糖肽、亲油性铂化合物、利索林酰胺7(lissoclinamide7)、洛铂、蚯蚓磷脂(lombricine)、洛美曲索、氯尼达明(lonidamine)、洛氧蒽醌、洛伐他汀、洛索立宾、勒托替康、泰克萨菲瑞镥(lutetium texaphyrin)、溶豆茶碱(lysofylline)、裂解肽、美坦辛、制甘糖酶素A(mannostatin A)、马马司他、马索罗酚、乳腺丝抑蛋白(maspin)、基质溶素抑制剂、基质金属蛋白酶抑制剂、美诺立尔、美巴龙(merbarone)、美替瑞林(meterelin)、蛋氨酸酶、甲氧氯普胺(metoclopramide)、MIF互变异构酶抑制剂、米非司酮、米替福新、米立司亭、错配的双链RNA、米托胍腙、二溴卫矛醇、丝裂霉素类似物、米托萘胺、丝裂毒素成纤维细胞生长因子-皂草素、米托蒽醌、莫法罗汀、莫格司亭(molgramostim)、单克隆抗体,人绒毛膜促性腺激素、单磷酰脂质A/分枝杆菌细胞壁骨架(CWS/MPL)、莫哌达醇、多重耐药基因抑制剂、基于多种肿瘤抑制基因1的治疗、芥末抗癌剂、印度洋海绵B(mycaperoxide B)、分枝杆菌细胞壁提取物、米瑞波酮(myriaporone)、N-乙酰地那林(N-acetyldinaline)、N-取代的苯甲酰胺、那法瑞林、那瑞替喷(nagrestip)、纳洛酮/镇痛新(pentazocine)组合物、纳帕文(napavin)、萘萜(naphterpin)、那托司亭、奈达铂、奈莫柔比星、奈立膦酸、中性内肽酶、尼鲁米特、尼沙霉素(nisamycin)、一氧化氮调节剂、氮氧化物抗氧化剂、硝胺、06-苄基鸟嘌呤、奥曲肽、芥子酮(okicenone)、寡核苷酸、奥那司酮、甲氧嘧啶(oracin)、口服细胞因子诱导剂、奥马铂、奥沙特隆、奥沙利铂、黄霉素(oxaunomycin)、紫杉醇、紫杉醇类似物、紫杉醇衍生物、帕劳胺、棕榈酰根霉素(palmitoylrhizoxin)、帕米膦酸、人参三醇、帕诺米芬、副乳杆菌素(parabactin)、帕泽利汀(pazelliptine)、培门冬酶、培得星(peldesine)(BCX 340)、戊聚糖多硫酸钠、喷司他丁、喷曲唑(pentrozole)、全氟溴铵、过磷酰胺、紫苏醇脱氢酶、吩嗪霉素(phenazinomycin)、乙酸苯酯、磷酸酶抑制剂、溶链菌制剂(picibanil)、毛果芸香碱盐酸盐、吡柔比星、吡曲克辛、胎素(placetin)A、胎素B、血纤维蛋白溶酶原激活剂抑制剂、铂络合物、铂化合物、铂-三胺络合物、卟吩姆钠、紫菜霉素(porfiromycin)、强的松、丙基双吖啶酮、前列腺素J2、蛋白酶体抑制剂、基于蛋白A的免疫调节剂、蛋白激酶C抑制剂、微藻(microalgal)、蛋白酪氨酸磷酸酶抑制剂、嘌呤核苷磷酸化酶抑制剂、红紫素、吡唑吖啶、吡啶氧化血红蛋白聚氧乙烯缀合物、raf拮抗剂、雷替曲塞、雷莫司琼、ras法呢基蛋白转移酶抑制剂、ras抑制剂、ras-GAP抑制剂、去甲基化的瑞替立汀、铼Re 186依替膦酸盐、根霉素、核酶、RII维甲酰酚胺(RIIretinamide)、罗谷亚胺、罗希吐碱、罗莫肽、罗喹美克、红豆杉酮B1(rubiginone B1)、鲁博氧(ruboxyl)、沙芬戈(safingol)、圣托品(saintopin)、SarCNU、肌肉叶绿醇A、沙格司亭、Sdi 1模拟物、司莫司汀、衰老衍生抑制剂1、有义寡核苷酸、信号转导抑制剂、信号转导调节剂、单链抗原结合蛋白、西佐喃、索布佐生(sobuzoxane)、硼卡钠(sodium borocaptate)、苯乙酸钠、索伏若(solverol)、生长调节素结合蛋白、索纳明(sonermin)、斯帕叶酸(sparfosic acid)、穗霉素D(spicamycin D)、螺莫司汀、斯耐潘定(splenopentin)、海绵抑素1(spongistatin1)、角鲨胺、干细胞抑制剂、干细胞分裂抑制剂、香豆酰胺(stipiamide)、溶基质素抑制剂、亚磺酸、超活性血管活性肠肽拮抗剂、苏拉迪斯塔(suradista)、苏拉明、苦马豆素、合成糖胺聚糖、他莫司汀、5-氟尿嘧啶、亚叶酸、它莫昔芬甲碘化物、牛磺莫司汀、他扎罗汀、替可加兰钠、替加氟、吡喃碲(tellurapyrylium)、端粒酶抑制剂、替莫泊芬、替莫唑胺、替尼泊苷、四氯十氧化物(tetrachlorodecaoxide)、四唑胺、菌体胚素(thaliblastine)、噻可拉林(thiocoraline)、促血小板生成素、促血小板生成素模拟物、胸腺法新、促胸腺生成素受体激动剂、胸腺曲南(thymotrinan)、促甲状腺激素、锡乙基乙紫红素(tin ethyl etiopurpurin)、替拉扎明、二氯环戊二烯钛(titanocene bichloride)、托普森丁(topsentin)、托瑞米芬、全能干细胞因子、翻译抑制剂、维甲酸、三乙酰尿苷、曲西瑞滨、三甲曲沙、曲普瑞林、托烷司琼、妥罗雄脲、酪氨酸激酶抑制剂、酪氨酸磷酸化抑制剂(tyrphostins)、UBC抑制剂、乌苯美司、泌尿生殖窦衍生生长抑制因子、尿激酶受体拮抗剂、伐普肽、维若林B(variolin B)、载体系统、红细胞基因治疗、沙利度胺、维拉雷琐(velaresol)、维拉明(veramine)、维尔丁(verdins)、维替泊芬、长春瑞滨、长春碱(vinxaltine)、沃利替尼、伏率唑、扎诺特隆、折尼铂、亚苄维C(zilascorb)、净司他丁斯酯(zinostatin stimalamer)等等。
在一些方面,额外的药剂是与ASD形式的化合物A组合使用的一种或多种免疫调节剂。免疫调节剂的非限制性实例包括蛋白质类药剂,例如细胞因子、肽模拟物和抗体(例如,人源、人源化、嵌合、单克隆、多克隆、Fvs、ScFvs、Fab或F(ab)2片段或表位结合片段)、核酸分子(例如反义核酸分子和三螺旋)、癌症分子、有机化合物和无机化合物。
特别地,可与化合物A的ASD形式组合使用的一种或多种免疫调节剂包括但不限于甲氨蝶呤、来氟米特、环磷酰胺、癌得星(cytoxan)、环孢菌素A、米诺环素、硫唑嘌呤抗生素(例如FK506(他克莫司)),甲基强的松龙(MP)、皮质类固醇、类固醇、霉酚酸酯(mycophenolate mofetil)、雷帕霉素(西罗莫司)、咪唑立宾、脱氧精胍菌素、布喹那、丙二腈胺(malononitriloamindes)(例如,来氟酰胺(leflunamide))、T细胞受体调节剂、细胞因子受体调节剂和调节肥大细胞调节剂。
在一方面,免疫调节剂是化学治疗剂。在另一个方面,免疫调节剂是除化疗剂之外的免疫调节剂。在一些方面,本文所述使用的额外药剂不是免疫调节剂。
在一些方面,额外的药剂是一种或多种可以与化合物A的ASD形式组合使用的抗血管生成剂。抗血管生成剂的非限制性实例包括蛋白质、多肽、肽、融合蛋白、抗体(例如人的、人源化的、嵌合的、单克隆的、多克隆的、Fvs、ScFvs、Fab片段、F(ab)2片段及其抗原结合片段),例如免疫特异性结合TNF-α的抗体、核酸分子(例如反义分子或三螺旋)、有机分子、无机分子和减少或抑制血管生成的癌症分子。在其他方面,本文所述的额外药剂不是抗血管生成剂。
在一些方面,可以与化合物A的ASD形式组合使用的额外的药剂是一种或多种抗炎剂。抗炎剂的非限制性实例包括可用于治疗炎性疾病的任何抗炎剂。抗炎剂的非限制性实例包括非甾体抗炎药(NSAID)、甾体抗炎药、抗胆碱能药(例如硫酸阿托品、硝酸阿托品和溴化异丙托铵2-激动剂(例如沙丁胺醇(和)、比托特罗左旋沙丁胺醇间羟喘息定(metaproterenol)吡布特罗特布他林(terbutlaine)(和)、沙丁胺醇(和)、福莫特罗(FORADIL)、沙美特罗(和SEREVENT))、甲基黄嘌呤(例如茶碱(和))等等。NSAID的例子包括但不限于阿司匹林、布洛芬、塞来昔布双氯芬酸依托度酸非诺洛芬吲哚美辛酮咯酸奥沙普秦萘丁美酮(nabumentone)舒林酸(sulindac)托美丁(tolmentin)罗非昔布萘普生 酮洛芬萘丁美酮等等。此类NSAID通过抑制环氧化酶(例如COX-1和/或COX-2)发挥作用。甾体抗炎药的实例包括但不限于糖皮质激素、地塞米松皮质类固醇(例如甲泼尼龙)、可的松、氢化可的松、泼尼松(和)、泼尼松龙(和)、曲安西龙、氮磺吡啶、类二十烷酸抑制剂(例如前列腺素、血栓烷和白三烯)等。
在某些方面,可以与化合物A的ASD形式组合使用的额外药剂是烷化剂、亚硝基脲、抗代谢物、蒽环霉素、拓扑异构酶II抑制剂、有丝分裂抑制剂等。烷化剂包括但不限于白消安、顺铂、卡铂、苯丁酸氮芥、环磷酰胺、异环磷酰胺、脱卡巴肼、甲氯乙胺、甲氨苯蝶啶、噻唑啉胺等。亚硝基脲包括但不限于卡莫司汀洛莫司汀等。抗代谢物包括但不限于5-氟尿嘧啶、卡培他滨、甲氨蝶呤、吉西他滨、阿糖胞苷、氟达拉滨等。蒽环霉素包括但不限于道诺霉素、多柔比星、表柔比星、伊达比星、米托蒽醌等。拓扑异构酶II抑制剂包括但不限于拓扑替康、伊立替康、依托泊苷(VP-16)、替尼泊苷等。有丝分裂抑制剂包括但不限于紫杉烷类(紫杉醇、多西他赛)和长春花生物碱(长春碱、长春新碱和长春瑞滨)等。
在更具体的方面,可以与化合物A的ASD形式组合使用的额外的抗癌剂、抗增殖剂或化疗剂包括但不限于阿柏西普、安吖啶、博来霉素、白消安、卡培他滨、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、克拉屈滨、氯法拉滨、克瑞他酶(crisantaspase)、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素、道诺霉素(IV和脂质体)、多西紫杉醇、多柔比星(IV和脂质体)、恩扎司他林(enzastaurin)、表柔比星、依托泊苷、氟达拉滨、5-氟尿嘧啶(5-FU)、吉西他滨、卡莫司汀植入物、羟基脲、伊达比星、异环磷酰胺、甲磺酸伊马替尼、伊立替康、兰瑞肽、来那度胺、亚叶酸、环己亚硝脲、美法仑、巯嘌呤、美司钠、甲氨蝶呤、丝裂霉素、米托蒽醌、奥曲肽、奥沙利铂、紫杉醇、培美曲塞、喷司他丁、甲苄肼、雷替曲塞、沙铂(satraplatin,)、索拉非尼、链脲佐菌素、舒尼替尼、替加氟尿嘧啶(tegafur uracil)、替莫唑胺、替尼泊苷、沙利度胺、硫替哌、硫鸟嘌呤、拓扑替康、曲奥舒凡(treosulfan)、瓦他拉尼(vatalanib)、长春花碱、长春新碱、长春地辛、长春瑞滨、沃利替尼、ZD6474、单克隆抗体(例如贝伐单抗、西妥昔单抗、IMC-A12、IMC-1121B、medi-522、利妥昔单抗等)、激素类药物(例如阿那曲唑、比卡鲁胺、布舍瑞林、环丙孕酮、己烯雌酚、依西美坦、氟他胺、戈舍瑞林(乳房和前列腺)、来曲唑、亮丙瑞林、甲羟孕酮、醋酸甲地孕酮、它莫昔芬、托瑞米芬、曲普瑞林等等)、生物制剂(例如干扰素、白细胞介素-12等等)、血管生成受体酪氨酸激酶(RTK)抑制剂(例如AE-941、血管抑制素、羧胺三唑、西仑吉肽、内皮抑素、氢溴酸卤夫酮、2甲氧基雌二醇、乳酸角鲨胺、SU6668等等)、微管蛋白结合剂(例如康普瑞汀(combretastatin)A4磷酸盐等等)、基质金属蛋白酶抑制剂(例如BMS-275291等等)和/或丝氨酸/苏氨酸/酪氨酸激酶抑制剂和任选的非甾体或COX-2抗炎剂(例如塞来昔布等等)或皮质类固醇(例如强的松等等)。
在更具体的方面,可以与化合物A的ASD形式组合使用的一种或多种额外的抗癌剂、抗增殖剂或化疗剂选自贝伐单抗、卡铂、顺铂、多西紫杉醇、多柔比星、依西美坦、吉西他滨、5-氟尿嘧啶、伊马替尼、伊立替康、索拉非尼、舒尼替尼、替莫唑胺、沃利替尼或其组合。
在一些方面,化合物A的ASD形式与一种或多种额外的抗癌剂、抗增殖剂或化学治疗剂与放射疗法组合使用,放射疗法包括使用X射线、伽马射线和其他放射源以破坏癌细胞或肿瘤细胞。在具体方面,放射疗法以外部束放射或远距疗法施用,其中放射来自远程源。在其他方面,放射疗法以内部疗法或近距离放射疗法施用,其中放射源放置于靠近癌细胞、肿瘤细胞和/或肿瘤块。
目前可用的抗癌剂、抗增殖剂或化学治疗剂、它们的给药方案、给药途径和推荐的以单独或组合使用是在本领域已知的,并且已经在例如医师案头参考(Physician’s DeskReference)的文献中进行了描述。
任何已知有用的、或已用于或目前正用于治疗癌症的抗癌、抗增殖或化学治疗剂或抗癌疗法可与包含如本文所述施用的化合物A的ASD形式的药物组合物组合使用。参见,例如,Gilman et al.,Goodman and Gilman's:The Pharmacological Basis ofTherapeutics,10th ed.,McGraw-Hill,New York,2001;The Merck Manual of Diagnosisand Therapy,Berkow,M.D.et al.(eds.),17th Ed.,Merck Sharp&Dohme ResearchLaboratories,Rahway,NJ,1999;Cecil Textbook of Medicine,20th Ed.,Bennett andPlum(eds.),W.B.Saunders,Philadelphia,1996,和医师案头参考关于癌症疗法(例如,使用预防或治疗剂)的信息,这些疗法已经或正在用于预防、治疗和/或管理各种类型的癌症。
实施例
以下实施例说明本文所述的化合物A的ASD形式的方面,以及说明化合物A的比较形式及其组合物。这些示例不应被解释为限制。
实施例1
根据WO2014/081906中描述的方法制备的化合物A,在下文中称为“I型”或“原始”形式,被发现是结晶的白色至灰白色固体。根据动态蒸汽吸附(DVS)的结果,发现原始形式有些吸湿,在95%RH下吸水率约为1.3%,在pH 6.5的磷酸盐缓冲液中几乎不溶,溶解度<1μg/mL,在pH 6.5的禁食状态肠液(FaSSIF)中,溶解度约为18μg/mL。化合物A的I型的cLogP为5.2,表明该化合物具有高度亲脂性并具有弱碱性芳族氨基(pKa<3)。
化合物A的X-射线衍射分析表明I型本质上是结晶的,如图2所示。多晶型筛选研究表明化合物A有两种溶剂化形式,本文称为A型和B型。A型是通过将化合物A的I型溶解在乙醇中,在25℃下振摇72小时,将所得到的混合物离心以从上清液中分离固体物质,然后在50℃下真空干燥样品过夜。所得样品在本文中通过XRPD、DSC和TGA表征。
通过将I型溶解在异丙醇中形成饱和溶液,然后加入水作为反溶剂同时搅拌直至形成沉淀,从而得到B型。通过离心将固体物质与上清液分离,在50℃下真空干燥过夜,并在此通过XRPD、DSC和TGA表征。
I型、A型和B型的XRPD谱的叠加显示在图3中。化合物A的I型、A型和B型的DSC扫描的叠加显示在图4中。两种结晶多晶型的多晶型稳定性研究表明,A型比B型更稳定。
实施例2
已发现表面活性剂的存在增加了化合物A的A型形式的水溶性。因此,制备了化合物A的两种固体剂型,A型片剂1和A型片剂2,如下表1所示。
表1-两种固体剂型的组成
如下制备两种片剂剂型。将化合物A的晶型A、十二烷基硫酸钠和微晶纤维素预混合,然后加入甘露醇、交聚维酮和二氧化硅并混合。使用干法制粒工艺将混合物制粒,随后使用压片机获得片剂。将片剂压碎并连续通过12和18目筛分以得到颗粒。根据剂量,将颗粒装入0号或00号白色不透明明胶胶囊中。
如下实施例11所述,还在食蟹猴中评估了上述两种原型片剂制剂。A型片剂1和2的绝对口服生物利用度分别为9%和34%,和AUC0-无穷大(AUC0-inf)暴露分别为1.77和6.98hr·μg/mL。任一制剂在10mg/kg的剂量下均未达到目标暴露量(AUC0-无穷大)。
实施例3
使用聚乙二醇4000、吐温80和两种不同的溶剂月桂酸聚乙二醇甘油酯和SolutolHS15开发了化合物A溶解的晶型A的两种胶囊剂型,如下表2所示。
表2-两种胶囊制剂的组成
评价了两种胶囊剂型在0.01N HCl和FaSSIF,pH 6.5中的体外溶出行为。两者均显示在0.01N HCl和FaSSIF,pH 6.5中在45分钟内完全溶解。在猴PK研究中进一步评估了两种原型剂型,在下面的实施例11中所述。
实施例4
还研发了两种另外的胶囊剂型,分别含有10mg和50mg剂量的化合物A的晶型A,溶解在聚乙二醇4000和月桂酸聚乙二醇甘油酯的混合物中,用于人体测试。这两种剂型的组成在下表3中提供:
表3-溶解的胶囊制剂的组成
尽管该制剂在临床试验中表现良好,但活性药物成分(API)的装载量和所施用的胶囊量对于治疗癌症患者不是最佳的。
实施例5
测试了化合物A的ASD形式作为提高溶解速率、溶解度并由此提高口服生物利用度的可能方法。为了探索化合物A的这种方法,评估了以下用于制备非晶态SDD的聚合物:聚乙烯吡咯烷酮K30(PVP K30)、聚乙烯吡咯烷酮醋酸乙烯酯64(PVP-VA-64)、聚乙烯吡咯烷酮标准精细CL(PVP CL)、醋酸琥珀酸羟丙甲纤维素(HPMCAS-L)和羟丙甲纤维素邻苯二甲酸酯。单独的聚合物与化合物A以1:1的比例研磨,并通过DSC进行分析以检查化合物A-聚合物基质的热行为,然后选择用于制备非晶态喷雾干燥分散体(SDD)的聚合物。
为了确认在熔融条件下聚合物中化合物A的非晶态形式的固态,使用DSC进行热表征。为了确认在熔融条件下聚合物中化合物A的晶型A的存在或不存在,使用DSC进行热表征。得到的热谱图提供在图5-9中,图5为含HPMCAS-AS-L的热谱图,图6为含PVP CL的热谱图,图7为含PVP-VA的热谱图,图8为含PVP K30的热谱图,图9为含HPMC邻苯二甲酸酯的热谱图。在每幅图中,提供了含有和不含化合物A聚合物的热谱图。基于DSC热谱图,其中化合物A晶型A的吸热峰不存在被筛选为两种聚合物,特别的是HPMC-AS-L和PVP-VA-64,用于进一步研究。
实施例6
使用计算和实验技术评估了不同聚合物和化合物A-聚合物比率的非晶态物理状态。评估的聚合物是PVP VA 64、PVP K30、HPMC-AS、丙烯酸树脂L100-55、HPMC E3和HPMCE15。筛选和配方研发结合了某些评估工具的使用。混溶性测定是一种计算机模拟,用于评估不同稳定载体的相分离倾向。在各种负载下评估用各种工艺溶剂制备的ASD化合物A的量。使用不同稳定载体和化合物A负载量的溶剂浇注试验的结果用于进一步缩小配方变量和过饱和度研究。还使用溶剂转移法评估了不同稳定载体的沉淀抑制。基于聚合物的混溶性、理化特性和水溶性测量,三种原型喷雾干燥中间体,[化合物A:HPMC-AS L]和[化合物A:HPMC-AS M]和[化合物A:PVP VA 64]以选择的比例[40:60%w/w]进行进一步评估。然而,与基于HPMCAS L和基于HPMCAS M的制剂相比,发现基于PVP VA 64的SDI更具吸湿性。
实施例7
使用溶剂浇铸技术获得化合物A的ASD。将化合物A和聚合物溶解在甲乙酮(MEK)和表面活性剂(十二烷基硫酸钠(SLS0或泊洛沙姆407)和水中。将表面活性剂溶液缓慢加入到化合物A和聚合物(羟丙基甲基纤维素乙酸琥珀酸酯(HPMC-AS-L))的溶液中,得到均匀溶液。溶剂在约80-85℃下蒸发三天,得到化合物A的ASD,如表4所示:
表4:ASD制剂组合物
ASD-1、ASD-2和ASD-3的XRPD分析结果分别显示在图10、11和12中。在溶剂浇铸之前从ASD-1、ASD-2和ASD-3的混合物获得的DSC结果分别显示在图13A、14A和15A,而由相同的三种混合物制备的ASD分别显示在图13B、14B和15B。XRPD和DSC结果均证实所有三种混合物在溶剂浇铸之前都是结晶的,发现由此制备所得的分散体在每种情况下都是非晶态的。
对如上所述制备的三种固体分散体中的每一种进行了稳定性研究。在40℃和75%相对湿度(RH)下两周后,用DSC和XRPD测试每种固体分散体的样品。ASD-1分散体(无表面活性剂)和ASD-3分散体(含泊洛沙姆407)均保持非晶态,而在ASD-2(含SLS)的XRPD中出现一些峰,表明在ASD-2中存在可检测量的结晶化合物A。结果表明化合物A的固体分散体在分散体中不存在SLS作为表面活性剂的情况下可以是稳定的。
评估了化合物A在具有两种不同等级的HPMC-AS(L和M等级)的固体非晶态分散体中的溶解度。与使用HPMC-AS M级聚合物的那些相比,化合物A发现在由HPMC-AS L制成的非晶态分散体中更容易溶解。
实施例8
为了优化API的负载,通过溶剂浇铸在固体分散体中不同百分比(10、50、70和90)的API来制备化合物A的非晶态分散体。10%和90%是仅用于评估目的的阳性对照。四种分散体的DSC和XRPD扫描分别示于图16和17中。如其中所示,由于图16的DSC显示的熔融吸热,固体分散体中API的50%负载是不可行的。因此,固体分散体中API的负载量保持在40%。
实施例9
喷雾干燥分散体(SDD)用上文实例5中确定用于进一步研究的两种稳定聚合物HPMC-AS-LG和PVP-VA-64中的每一种制备,方法是将每种聚合物和化合物A完全溶解在丙酮中,然后喷雾干燥。从每个SDD和单独从化合物A获得的粉末X射线衍射结果显示在图18中。XRPD结果显示两种分散体中的化合物A都是非晶态的。
实施例10
根据下表5制备化合物A和HPMC-AS-L(SDD1)或PVP-VA-64(SDD2)的SDD制剂:
表5-喷雾干燥分散体制剂
以与上述实例8中所述相同的方式制备两种SDD。将化合物A、SDD、SLS和微晶纤维素在低剪切混合器中预混合。加入甘露醇、交聚维酮和二氧化硅并在低剪切混合器中混合。通过在压片机上制备粒块的干法制粒工艺将干混合物制粒。将粒块压碎并连续通过12和18目筛分以得到颗粒,并将最终API负载量为17%w/w的颗粒装入0号白色不透明明胶胶囊(50mg强度)中。
使用下表6中所示的溶出参数评估了两种制剂SDDl和SDD2在生物相关介质、禁食状态模拟肠液(FaSSIF)、pH 6.5中的溶出行为。
表6-溶出参数
溶出度仪 | USP装置II(Paddles) |
温度 | 37℃±0.5℃ |
旋转速度 | 50rpm |
溶出缓冲液/体积<sup>1</sup> | 600mL;FaSSIF,pH 6.5 |
胶囊号 | 一粒0号明胶胶囊 |
强度 | 50mg |
采样量<sup>2</sup> | 5mL |
采样时间点(T<sub>min</sub>) | (T<sub>0</sub>,T<sub>5</sub>,T<sub>15</sub>,T<sub>30</sub>,T<sub>45</sub>,T<sub>60</sub>,T<sub>120</sub>) |
两种SDD制剂所得溶出曲线示于图19。由HPMC-AS-L制成的SDD的溶出曲线显示在45分钟内完全溶解。
实施例11
进行药代动力学猴研究,比较了实例2中制备的结晶化合物A的两种片剂、实例3中制备的胶囊剂型、和实例8中制备的SDD2胶囊和具有如下表7所示的组成的喷雾干燥中间体(SDI)的原型制剂。
表7-用于猴子PK研究的SDI片剂组合物
研究的结果总结在下表8中
表8-猴子PK研究结果
从表8可以看出,在约50mg/动物(约10mg/kg)的剂量下,当以胶囊2(7%API负载)的溶解制剂给药时,化合物A的平均系统暴露量(AUC0-无穷大)提供了最高的相对生物利用度和暴露。非晶态SDD1制剂显示出相对良好的暴露(AUC:14433ng·hr/mL)和约70%的绝对生物利用度。
研发了具有化合物A和具有40%负载量的HPMC-AS LG SDD的制剂。辅料相容性研究确定了某些辅料与ASD形式化合物A一起稳定的。选自微晶纤维素、乳糖一水合物、交联羧甲基纤维素钠、泊洛沙姆407、胶体二氧化硅和化合物A的SDD中间体(SDI)形式的辅料预先混合并过筛。随后将硬脂酸镁作为润滑剂加入到预混合物中。使用干法造粒工艺增加预混物的密度。随后将润滑剂硬脂酸镁和颗粒外辅料微晶纤维素、乳糖一水合物和交联羧甲基纤维素钠加入颗粒混合物中。将具有下表9所示组成的混合物压制成不同强度的片剂。
表9-混合物组分
成分名称 | %w/w | g/批 |
化合物A/HPMC-AS(40%)SDD | 50 | 2000 |
微晶纤维素 | 22.6 | 903 |
乳糖一水合物 | 15.9 | 635 |
交联羧甲基纤维素钠 | 4.7 | 188 |
泊洛沙姆407 | 5.0 | 200 |
胶体二氧化硅 | 0.90 | 36 |
硬脂酸镁 | 0.95 | 38 |
总计: | 100.0 | 4000 |
出于比较的目的,制备了具有与混合物相同辅料的安慰剂片剂,但不含SDD。
具有化合物A的A型、化合物A/HPMC-AS(40%)SDD和安慰剂的混合物各自通过X-射线粉末衍射法进行分析。所得的XRPD显示在图20。结果表明SDD和SDD混合物是非晶态的。与安慰剂XRPD相比可以看出,混合物的XRPD中唯一的峰来自辅料。
实施例12
具有50mg和200mg化合物A的SDD形式的片剂由单个颗粒批次制备,对于两种剂量强度中的每一种使用不同颗粒的量。两种片剂剂量中的每一种的颗粒组成示于下表10中:
表10-50mg和200mg强度化合物A SDD片剂的组成
通过干法制粒、研磨和混合过程获得颗粒。通过将微晶纤维素、乳糖一水合物、交联羧甲基纤维素钠、泊洛沙姆407、胶体二氧化硅和SDD的混合物一起过筛,从而获得干颗粒,然后加入硬脂酸镁并混合得到第一混合物。通过干法制粒增加第一混合物的密度以提供第一部分颗粒。将第二份硬脂酸镁用30目筛过筛,然后与第一份颗粒混合并在V型混合器中混合2分钟以得到第二混合物。然后使用辊压机并研磨获得第二部分颗粒。将研磨好的颗粒加入V型混合器中,并与颗粒外辅料的微晶纤维素、乳糖一水合物和交联羧甲基纤维素钠混合。将颗粒外辅料通过30目筛进行筛分,然后加入V型混合器并与颗粒混合2分钟以提供第三种混合物。使用提供符合片剂尺寸的模具将第三种混合物压制成不同的片剂强度。在12个月的稳定性研究中,发现两种片剂剂型在25℃和60%的相对湿度下都是稳定的。
本实例所述制备的50mg和200mg片剂具有改善的溶出度和生物利用度,同时为减少剂型给药量和增加API载量的给药提供便利。其中每天两次给予200mg片剂或每天四次给予50mg片剂将提供用于治疗患有各种癌症的人类患者的治疗有效量,包括弥漫性内源性脑桥胶质母细胞瘤(DIPG)、卵巢癌、胰腺癌、肉瘤如平滑肌肉瘤和血液癌例如急性髓系白血病。
实施例13
将以上实例12中所述制备的50mg和200mg片剂悬浮在水或苹果汁中,并且在室温下测试每个所得悬浮液24小时内的稳定性。每个片剂在不到3分钟内崩解。XRPD和HPLC显示化合物A在每个悬浮液中保持非晶态,没有检测到杂质。
已经充分描述了权利要求的主题,本领域普通技术人员将理解,可以在广泛的等效范围内执行相同的内容而不影响本文描述的主题或方面的范围。
实施例14
测试具有如表10所述组成的活性制剂片剂在不同储存条件下的稳定性。在25℃/60%相对湿度(RH)下,50mg和200mg化合物A片剂在24个月内均表现出可接受的稳定性。然而,在40℃/75%相对湿度(RH)下,6个月时,50mg和200mg片剂均未能崩解。这种不完全溶解与pH无关,X射线粉末衍射(XRPD)和mDSC分析证实化合物A在片剂形式中具有化学和物理稳定性,即使在40℃/75%相对湿度(RH)下一年后仍保持非晶态状态。
为了确定降低活性片剂制剂中泊洛沙姆407(5%w/w)的浓度是否可以减轻观察到的溶出减慢,用不同浓度的泊洛沙姆407(1%w/w、2%w/w或5%w/w;表11)制备25mg强度的片剂,并放置在5℃(对照)、25℃/60%RH的封闭条件下或40℃/75%RH的开放和封闭条件下。所有测试片剂的硬度保持在平均4.3kP。
表11:具有不同浓度泊洛沙姆407的活性片剂制剂的组成
缩写:羟丙基甲基纤维素+醋酸琥珀酸酯:HPMCAS;喷雾干燥分散体:SDD;USP/NF分别是指美国药典(USP)和国家处方集(NF)。
在溶出介质(500mL的0.1N HCl+0.2%w/v CTAB、37℃、桨叶速度:75rpm;参见表12和图21)中,评估在开放条件下在40℃/75%RH下储存2周的活性片剂制剂的崩解和溶出曲线。含有5%w/w泊洛沙姆407的活性片剂制剂显示出片剂溶胀但没有崩解。与该发现一致,即使在溶出度测试中60分钟后,也仅测量到最小的API释放(-6%释放)。含有2%w/w泊洛沙姆407的活性片剂崩解成更大的块,虽然比含有5%w/w泊洛沙姆407的片剂更好,但溶出曲线在60分钟后没有达到完全释放(-89%)。然而在溶解试验中,含有1%w/w泊洛沙姆407的活性片剂制剂容易崩解成小颗粒,并且溶出曲线与含有0%w/w泊洛沙姆407的活性片剂制剂相似(-100%释放)。
表12:具有不同浓度泊洛沙姆407的活性制剂在40℃/75%RH、开放条件下2周的溶出释放概况
初始:指指定的活性片剂制剂(未储存)在10-60分钟后的溶出%
然后在溶出介质(500mL的0.1N HCl+0.2%w/v CTAB、37℃、桨速:75rpm;见表13)中测定在封闭条件下在40℃/75%RH下储存6个月的这些片剂制剂的崩解和溶出曲线。
与含有0%w/w泊洛沙姆407的活性片剂配方(-100%释放)相比,含有5%w/w泊洛沙姆407的活性片剂制剂溶胀但不崩解,并且API在60分钟时释放最少(-6%释放)。
与含有0%w/w泊洛沙姆407的活性片剂制剂相比,含有2%w/w泊洛沙姆407的活性片剂制剂在60分钟时崩解成更大的块,API几乎完全释放。然而,在30分钟的时间点,与含有0%w/w泊洛沙姆407的活性片剂制剂相比,API释放有-10%的差异。
与具有0%w/w泊洛沙姆407的活性片剂制剂相比,含有1%w/w泊洛沙姆407的活性片剂制剂崩解成更小的颗粒,并且溶出曲线显示在60分钟时完全释放。
表13:具有不同浓度泊洛沙姆407的活性制剂在40℃/75%RH下、封闭条件下6个月的溶出释放概况
当在猴子中测试时,改变活性片剂制剂中泊洛沙姆407的浓度对化合物A的动力学溶解度或其PK特征和PK参数没有重大影响。
Claims (18)
2.根据权利要求1所述的形式,其中化合物A的非晶态形式至少90%是非晶态的。
3.根据权利要求2所述的形式,其中化合物A的非晶态形式是基本上纯的非晶态形式。
4.非晶态固体分散体,其包含权利要求1、2或3中任一项所述的非晶态形式和稳定聚合物。
5.根据权利要求4所述的分散体,其中所述稳定聚合物选自聚乙烯吡咯烷酮或乙酸琥珀酸羟丙基甲基纤维素。
6.根据权利要求5所述的分散体,其中所述稳定聚合物是乙酸琥珀酸羟丙基甲基纤维素。
7.根据权利要求4所述的分散体,其中化合物A的重量与稳定聚合物的重量的比为约5:95至约60:40。
8.根据权利要求7所述的分散体,其中化合物A的重量与稳定聚合物的重量的比为约10:90至约40:60。
9.根据权利要求4所述的分散体,其中所述分散体通过溶剂浇铸包含化合物A和稳定聚合物的溶液获得。
10.根据权利要求4所述的分散体,其中所述分散体通过喷雾干燥包含化合物A和稳定聚合物的溶液获得。
11.制备权利要求4所述的分散体的方法,所述方法包括:
(a)将化合物A和一种或多种稳定聚合物溶解在溶剂中形成溶液;和
(b)干燥所述溶液以形成权利要求4的分散体。
12.根据权利要求11所述的方法,其中所述溶剂选自丙酮、甲乙酮、二氯甲烷或甲醇。
13.根据权利要求11所述的方法,其中通过溶剂浇铸将所述溶液干燥以形成权利要求4的分散体。
14.根据权利要求11所述的方法,其中通过喷雾干燥将所述溶液干燥以形成权利要求4的分散体。
15.药物组合物,其包含权利要求4的分散体和一种或多种药学上可接受的辅料的混合物。
16.根据权利要求15所述的药物组合物,其中所述一种或多种药学上可接受的辅料选自稀释剂、崩解剂、润滑剂或表面活性剂。
17.根据权利要求16所述的药物组合物,其中所述表面活性剂选自十二烷基硫酸钠或泊洛沙姆407。
18.制备权利要求15所述的药物组合物的方法,所述方法包括:
(a)研磨权利要求4的分散体形成固体分散体粉末;
(b)将所述粉末与一种或多种药学上可接受的辅料混合形成混合物;
(c)将所述混合物造粒形成颗粒;和
(d)分别将颗粒压片或包囊形成片剂或胶囊。
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