CN115054586B - 改性的释放制剂 - Google Patents
改性的释放制剂 Download PDFInfo
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- CN115054586B CN115054586B CN202210686970.6A CN202210686970A CN115054586B CN 115054586 B CN115054586 B CN 115054586B CN 202210686970 A CN202210686970 A CN 202210686970A CN 115054586 B CN115054586 B CN 115054586B
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Abstract
本发明提供了改性释放制剂诸如固体口服剂型,其包含:含有化合物(I)和/或其药学上可接受的盐的核心组合物;包覆所述核心组合物的底部包衣层,所述底部包衣层包含聚乙烯醇和/或羟丙基甲基纤维素;以及包封所述底部包衣层和所述核心组合物的肠溶包衣层,所述肠溶包衣层包含至少一种选自丙烯酸/甲基丙烯酸/乙基丙烯酸均聚物及其共聚物、纤维素衍生物和聚乙烯吡咯烷酮的聚合物;本发明还提供了使用所述制剂施用布鲁顿酪氨酸激酶(BTK)抑制剂的方法。
Description
本申请是2017年6月29日提交的发明名称为“2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈的改性的释放制剂”的第201780049475.1号发明专利申请的分案申请,第201780049475.1号发明专利申请对应于国际申请PCT/US2017/040075,所述国际申请于2019年2月12日进入中国国家阶段。
相关申请的交叉引用
本申请要求2016年6月29日提交的美国临时申请62/356,345的权益,该申请以引用方式全文并入本文。
技术领域
本公开涉及布鲁顿酪氨酸激酶(BTK)抑制剂的改性释放制剂和施用方法。
布鲁顿酪氨酸激酶(BTK)抑制剂是本文公开的化合物(I)和/或其药学上可接受的盐。化合物(I)和/或其药学上可接受的盐是有效的BTK抑制剂,因此可用于治疗疾病诸如癌症、自身免疫疾病和炎性疾病。
背景技术
治疗剂可通过几种不同的途径(诸如,口服、局部、静脉内、皮下、吸入等)施用给患者。治疗剂的口服给药是迄今为止最优选的施用途径,并且提供了优于其他施用途径的多种优点。口服递送的药物易于自我施用,从而增加了患者的依从性并且不需要用于注射或吸入治疗的专门递送装置,也不需要在治疗环境中进行递送。口服施用通常是使药物进入体内最安全的途径,因为它不需要复杂的装置,也不需要刺穿体表或体膜。另外,剂量易于控制,这对于其他施用模式诸如吸入治疗可能具有挑战性。
尽管有许多优点,但是由于以下因素,通过口服给药获得一致且足够的药物循环水平可能具有挑战性:水溶性差;在生物液体中的溶解速率慢;药物在生理pH下的稳定性差;透过生物膜的渗透性差;系统前代谢广泛;以及个体之间或胃肠系统的特定区域内的系统吸收不足或不一致。另外,药物吸收可在治疗与治疗之间不同,并且取决于许多因素,诸如患者在施用时是处于进食状态还是禁食状态,或者药物是否与其他药物同时服用。从安全的角度来看,最小化功效的总剂量要求以及减少吸收的可变性应允许具有更少的不希望的副作用。因此,迫切需要允许有效且一致地暴露药物的用于递送口服药物的特定方法。
由于激酶抑制剂作为抗癌剂在临床上获得成功,因此靶向治疗受到越来越多的关注,特别是在肿瘤学领域。开发靶向治疗面临的挑战包括实现对主要靶标的高选择性以及延长抑制以最大化其治疗功效。共价药物已成为设计下一代靶向治疗的极具吸引力的方法,因为它们实现高选择性的能力强并且即使药物的系统暴露显著降低也能延长抑制。共价药物由于与药物分子所结合的蛋白质的活性位点中特定半胱氨酸残基的共价相互作用,实现了其高选择性和优异效力。这种共价结合还通过增加延长药物系统暴露的作用持续时间,提供了延长的功效。含有丙烯酰胺部分作为迈克尔受体的药物通常与硫醇如谷胱甘肽不可逆地反应,并且还可与所需靶标之外的蛋白质、尤其是具有高反应性半胱氨酸的蛋白质不可逆地反应。
可逆共价药物分子(即,含有具有第二吸电子基团的迈克尔受体的药物)在口服用药时可表现出较差的生物利用度或延迟的系统吸收(这可由曲线下的低血浆面积(AUC)和/或Cmax值体现),从而导致体内功效不理想。这类新药的生物利用度差可部分归因于这些药物中可逆共价迈克尔受体部分具有反应性。因此,通过限制可逆共价药物暴露于胃(其中发生低pH和消化酶或代谢酶和其他硫醇源的组合),可以实现药物系统暴露的显著增加。
另外,限制不可逆共价药物分子暴露于胃也可导致药物系统暴露的显著增加,以及潜在不良副作用诸如腹泻、恶心、呕吐和头晕的减少。例如,当在十二指肠内施用依鲁替尼(一种不可逆共价结合的药物分子)时,与直接口服施用相比,生物利用度意外地从21%增加至100%,如通过AUC测定(D.M.Goldstein,“Formulations Comprising Ibrutinib”,WO2014/004707,2014年1月3日公布)。依鲁替尼从胃绕道应当提高生物利用度和/或减少或完全消除该药物的潜在不良副作用,诸如腹泻、恶心、呕吐和头晕。
此外,代谢酶(诸如,半胱氨酸蛋白酶、粘蛋白、转运蛋白)和胃中含有活性硫醇的分子(诸如,谷胱甘肽)的表达也可导致含有可逆共价迈克尔受体的药物的口服生物利用度低(参见例如,Johnson D.S.等人,Future Med Chem.,2010年6月1日,第2卷(第6期):第949-964页;以及Potashman M.H.等人J.Med.Chem.,第52卷,第5期,第1231-1246页)。例如,消化酶(诸如,半胱氨酸蛋白酶、胃蛋白酶、转运蛋白)和代谢酶(诸如,胃粘膜中的CYP酶)的组合可导致可逆和不可逆的共价迈克尔受体在低pH值下发生高化学和/或代谢转化。因此,通过避免可逆共价药物暴露于胃(其中发生低pH和消化酶或代谢酶和其他硫醇源的组合),可以实现这些药物系统暴露的显著增加。另外,避免暴露于胃可减少或完全消除这些药物的潜在不良副作用,诸如腹泻和呕吐(通常称为消化性呕吐)。
因此,希望具有能够避免广泛暴露于胃的共价药物分子的改性释放制剂。本公开提供了此类有利制剂。
化合物(I)是布鲁顿酪氨酸激酶(BTK)(其为Tec酪氨酸激酶家族的成员)的可逆共价抑制剂。BTK在大多数造血细胞诸如B细胞、肥大细胞和巨噬细胞中表达,但在T细胞、自然杀伤细胞和浆细胞中不表达。BTK在B细胞的发育和活化中起作用。人BTK基因的突变导致遗传性疾病X连锁无丙种球蛋白血症(XLA),伴随缺乏外周B细胞并且血清Ig水平低。在XLA中,原发性免疫缺陷是B细胞特异性的。开发抑制BTK的药物在治疗B细胞相关的血液学癌症(例如,非霍奇金淋巴瘤(NHL)和B细胞慢性淋巴细胞白血病(B-CLL))和自身免疫疾病(例如,类风湿性关节炎、干燥综合征、天疱疮、IBD、狼疮和哮喘)中都有治疗意义。
目前正在开发用于治疗自身免疫疾病的化合物(I)在2013年9月6日提交的PCT国际申请PCT/US2013/058614的实施例31中公开。
2015年12月23日提交的PCT国际申请PCT/US2015/000303涉及化合物(I)和/或其药学上可接受的盐的位点特异性施用。
2015年12月23日提交的PCT国际申请PCT/US2015/000515涉及将可逆和不可逆的共价激酶抑制剂递送到小肠中、具体地递送到小肠的回肠和空肠中的制剂。
发明内容
本公开提供了一种改性的释放固体口服剂型,其包含:
(a)含有化合物(I)和/或其药学上可接受的盐的核心组合物;
(b)包覆核心组合物的底部包衣层,所述底部包衣层包含聚乙烯醇和/或羟丙基甲基纤维素;以及
(c)包封底部包衣层和核心组合物的肠溶包衣层,所述肠溶包衣层包含至少一种选自丙烯酸/甲基丙烯酸/乙基丙烯酸均聚物及其共聚物、纤维素衍生物和聚乙烯吡咯烷酮的聚合物。
本公开还提供了一种治疗对其有需要的受试者的由BTK介导的疾病的方法,该方法包括向需要这种治疗的受试者施用本公开的改性的释放固体口服剂型。
附图说明
图1是本公开的改性的释放固体口服剂型的示意图,该改性的释放固体口服剂型包含核心组合物、底部包衣层和肠溶包衣层。
图2描绘了优化化合物(I)的改性释放组合物/制剂的性能的“设计空间”概念。“设计空间”是三维的,其具有不同的剂量、药物释放调节剂百分比和聚合物包衣百分比来控制药物释放区域,因此控制药物释放延迟时间。
示出了“设计空间”的八个角:
角1-30mg,快速释放核心,快速包衣;
角2-30mg,缓慢释放核心,快速包衣;
角3-30mg,缓慢释放核心,缓慢包衣;
角4-30mg,快速释放核心,缓慢包衣;
角5-100mg,快速释放核心,缓慢包衣;
角6-100mg,快速释放核心,快速包衣;
角7-100mg,缓慢释放核心,快速包衣;
角8-100mg,缓慢释放核心,缓慢包衣;
图3描绘了“设计空间”的所有八个角在pH 6溶解介质中的溶解曲线。
具体实施方式
定义:
除非另有说明,否则说明书和权利要求书中使用的以下术语是出于本申请的目的而定义的并且具有以下含义。本申请中使用的所有未定义的技术和科学术语具有本公开所属领域的普通技术人员通常理解的含义。
如本文所用,“一个”或“一种”实体是指一个或多个该实体;例如,除非另有说明,否则化合物是指一种或多种化合物或至少一种化合物。因此,术语“一个”(或“一种”)、“一个或多个”和“至少一个”在本文中可互换使用。
术语“约”在本文中用于表示大概、在…附近、大致或大约。当术语“约”与数值范围结合使用时,它通过将边界扩展到所述数值以上和以下来修改该范围。一般来讲,术语“约”在本文中用于将数值修改为所述值以上和以下5%的变化。
如本文所用的化合物(I)是指以下物质的(E)异构体、(Z)异构体或者(E)异构体和(Z)异构体的混合物或其药学上可接受的盐:(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈、(S)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈、或者2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈的(R)异构体和(S)异构体的混合物,2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈具有以下结构:
其中*C是立体化学中心。
本领域普通技术人员将理解,当化合物(I)表示为(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈时,它可含有小于约1重量%的相应(S)对映体作为杂质。因此,当化合物(I)表示为2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈的(R)异构体和(S)异构体的混合物时,意味着混合物中(R)对映体或(S)对映体的量大于约1重量%。类似的分析在化合物(I)表示为(E)异构体、(Z)异构体或者(E)异构体和(Z)异构体的混合物时也适用。化合物(I)或其药学上可接受的盐在本说明书中也可称为“药物”、“活性剂”或“治疗活性剂”或“API”。
如本文所用的“哺乳动物”是指驯养的动物(诸如,狗、猫和马)和人。在一个实施方案中,哺乳动物为人。
如本文所用的“药学上可接受的盐”是指药学上可接受的酸加成盐,并且其具有制备盐的化合物(下文有时称为“母体化合物”)的所需药理学活性。这些盐包括与无机酸(诸如,盐酸、氢溴酸、硫酸、磷酸等)形成的盐;或与有机酸(诸如,甲酸、乙酸、丙酸、己酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、苯磺酸,4-甲苯磺酸等)形成的盐。
“药学上可接受的载体或赋形剂”是指可用于制备药物组合物的载体或赋形剂;其通常是安全的,既不是生物学上也不是其他方面不需要的,并且包括哺乳动物药学用途可接受的载体或赋形剂。
如本文所用,应用于药物产品的“改性释放”是指改变药物物质的释放时间和/或速率的药物产品。改性释放剂型是这样的制剂,其中选择时间过程和/或位置的药物释放特征以实现常规剂型(诸如,溶液、软膏或快速溶解剂型)所不能提供的治疗或方便目的。已经认识了几种类型的改性释放口服药物产品。非限制示例包括:
1.延长释放药物产品。与作为立即释放(常规)剂型呈现的那种药物相比,允许剂量频率降低至少约1/2的剂型。延长释放剂型的示例包括受控释放、持续释放和长效药物产品。
2.延迟释放药物产品。施用后一次释放药物的一个或多个不连续部分而不是立即释放的剂型。施用后可立即释放初始部分。肠溶包衣剂型是常见的延迟释放产品(例如,肠溶包衣阿司匹林和其他NSAID产品)。
3.靶向释放药物产品。在预期的生理作用部位处或附近释放药物的剂型。靶向释放剂型可具有立即释放或延长释放特征。
4.口腔崩解片剂(ODT)。已经开发出ODT在口服施用后在唾液中快速崩解。ODT可在不加水的情况下使用。药物在唾液中分散并且在有很少水或没有水的情况下被吞咽。
“治疗”疾病或疾病的“治疗”包括:
(1)抑制疾病,即停滞或减少疾病或其临床症状的发展;或者
(2)减轻疾病,即引起疾病或其临床症状的消退。
“治疗有效量”是指化合物(I)和/或其药学上可接受的盐在施用给需要或认识到需要治疗来治疗疾病的哺乳动物时足以对该疾病的这种治疗起效的量。“治疗有效量”将根据化合物、疾病及其严重程度以及待治疗的哺乳动物的年龄、体重等而变化。
如本文所用的“基本上纯的”是指化合物(或其盐)诸如化合物(I)(或其盐),其中至少约70重量%的化合物(或其盐)作为给定的固态形式存在。例如,短语“基本上纯的无定形形式的化合物(I)(或其盐)的盐的无定形形式”是指化合物(I)(或其盐)的固态形式,其中超过约70重量%的化合物(I)(或其盐)是无定形形式,其余的以结晶形式存在。在一个实施方案中,这类组合物含有至少约80重量%的无定形形式的化合物(I)(或其盐)。在另一个实施方案中,至少约85重量%的化合物(I)(或其盐)为无定形形式。在又一个实施方案中,至少约90重量%的化合物(I)(或其盐)为无定形形式。在又一个实施方案中,至少约95重量%的化合物(I)(或其盐)为无定形形式。在又一个实施方案中,至少约97重量%或至少约98重量%的化合物(I)(或其盐)为无定形形式。在又一个实施方案中,至少约99重量%的化合物(I)为无定形形式。固体混合物中结晶形式和/或无定形形式的相对量可通过本领域熟知的方法测定。例如,X射线衍射提供了一种方便实用的方法来定量测定固体混合物中结晶形式和/或无定形形式的相对量。X射线衍射适用于定量应用,因为混合物中给定化合物的衍射峰强度与混合物中相应粉末的份数成正比。尽管化合物(I)的所有盐都是无定形的,但如果在混合物中存在任何结晶形式的化合物(I)(或其盐),则可测定未知组合物中结晶化合物(I)(或其盐)的百分比组成。优选地,测量在化合物(I)(或其盐)的固体粉末上进行。可将未知组合物的X射线粉末衍射图案与化合物(I)(或其盐)的已知的含有纯结晶形式(如果有的话)的定量标准品进行比较,以鉴定特定结晶形式的百分比。如果无定形形式是组合物的主要级分,则可将该量进一步与经受分析的固体的总重量进行比较。这通过将来自未知固体粉末组合物的衍射图案的峰的相对强度与来源于纯已知样品的X射线衍射图案的校准曲线进行比较来完成。可基于来自化合物(I)(或其盐)的结晶形式的纯样品的最强峰的X射线粉末衍射图案来校准曲线。可以本领域技术人员已知的方式创建校准曲线。例如,可制备不同量的化合物(I)(或其盐)的结晶形式的五种或更多种人工混合物。在非限制性示例中,对于每种结晶形式,此类混合物可含有约2%、约5%、约7%、约8%和约10%的化合物(I)(或其盐)。然后,使用标准X射线衍射技术获得每种人工混合物的X射线衍射图案。峰值位置的轻微变化(如果有的话)可通过调节待测量的峰的位置来解决。然后将每种人工混合物的所选特征峰的强度相对于结晶形式的已知重量百分比作图。得到的图是校准曲线,其允许测定未知样品中化合物(I)(或其盐)的结晶形式的量。对于化合物(I)(或其盐)的结晶形式和无定形形式的未知混合物,可使用混合物中所选特征峰的强度(相对于校准混合物中该峰的强度)来测定组合物中给定结晶形式的百分比,将其余部分确定为无定形物质。总结晶度可如下确定:
%结晶度=(C/A+C-B)×100
其中C是结晶峰下的面积,A是无定形晕圈下的面积,并且B是由于空气散射、荧光等引起的背景噪声。
“无定形形式”是指不具有可区分晶格的固体,并且分子的分子排列缺乏晶体的长程有序特征。具体地讲,无定形表示不显示尖锐布拉格衍射峰的物质。
术语“纤维素衍生物”或“多糖衍生物”是指纤维素聚合物或多糖,其中糖重复单元上的至少一部分羟基已经反应形成醚键或酯键。示例包括但不限于羟烷基纤维素、羟烷基烷基纤维素和羧烷基纤维素酯,诸如羟丙基甲基纤维素(例如,羟丙甲纤维素或HPMC)、羟丙基纤维素(例如,HPC)等。
出于本公开的目的,术语“亲水性”涉及对水具有亲和力的物质。
出于本公开的目的,术语“水溶性”涉及在pH为约1至约8的水性介质中溶解至所需程度的物质,并且没有特别限制。
出于本公开的目的,术语“水溶胀性”涉及在水中相对不溶但可吸收水的物质。
实施方案:
非限制性地,本公开的一些具体实施方案包括:
实施方案1:一种改性的释放固体口服剂型,包括:
(a)含有如上定义的化合物(I)和/或其药学上可接受的盐的核心组合物;
(b)包覆所述核心组合物的底部包衣层,所述底部包衣层包含聚乙烯醇或羟丙基甲基纤维素;以及
(c)包封所述底部包衣层和所述核心组合物的肠溶包衣层,所述肠溶包衣层包含至少一种选自丙烯酸/甲基丙烯酸/乙基丙烯酸均聚物及其共聚物、纤维素衍生物和聚乙烯吡咯烷酮的聚合物。
实施方案2:根据实施方案1所述的改性的释放固体口服剂型,其中所述纤维素衍生物选自纤维素乙酸邻苯二甲酸酯、纤维素乙酸三苯甲酸酯、甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、羟丙基甲基纤维素琥珀酸酯(HPMCS)和羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)。
实施方案3:根据实施方案1或2所述的改性的释放固体口服剂型,其中所述底部包衣层(b)包含聚乙烯醇,并且肠溶包衣层(c)包含聚(甲基丙烯酸-共-丙烯酸乙酯)共聚物。
实施方案4:根据实施方案3所述的改性的释放固体口服剂型,其中所述聚乙烯醇是有色聚乙烯醇。
在一个实施方案中,有色聚乙烯醇(PVA)是购自Colorcon的II。II是一种含有聚合物、增塑剂和颜料的高生产率、水溶性、pH值独立的全干粉膜包衣系统,其可立即崩解以实现快速主动释放。
在一个实施方案中,包含在本公开的肠溶包衣层中的聚(甲基丙烯酸-共-丙烯酸乙酯)是购自Evonik Industries的L30D-55。该聚合物是聚(甲基丙烯酸-共-丙烯酸乙酯)1:1共聚物,可以30%水分散体的形式获得。其摩尔质量为约320,000g/mol,并且酸值为约315mg KOH/g聚合物。
在另一个实施方案中,包含在本公开的肠溶包衣层中的聚(甲基丙烯酸-共-丙烯酸乙酯)是同样购自Evonik的L 100-55。它也是聚(甲基丙烯酸-共-丙烯酸乙酯)1:1共聚物,为固体(白色粉末)的形式,并且其摩尔质量为约320,000g/mol,并且酸值为约315mg KOH/g聚合物。
实施方案5:根据实施方案1至4中任一项所述的改性的释放固体口服剂型,其中所述固体口服剂型在小于或等于约2.0的pH下在少于约两小时内释放小于约10重量%的化合物(I)和/或其药学上可接受的盐;在等于或大于约6.0的pH下在约15分钟至约两小时内释放至少约80重量%的化合物(I)和/或其药学上可接受的盐;并且在等于或大于约6.0的pH下在约7.5小时之前释放任何未释放量的化合物(I)和/或其药学上可接受的盐。
实施方案6:根据实施方案1至5中任一项所述的改性的释放固体口服剂型,其中所述核心组合物包含化合物(I)。
实施方案7:根据实施方案1至6中任一项所述的改性的释放固体口服剂型,其中化合物(I)为2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈的(R)异构体和(S)异构体的混合物的(E)和(Z)混合物。
实施方案8:根据实施方案1至7中任一项所述的改性的释放固体口服剂型,其中化合物(I)为(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈的(E)和(Z)混合物。
实施方案9:根据实施方案1至8中任一项所述的改性的释放固体口服剂型,其中至少约85重量%的化合物(I)和/或其药学上可接受的盐为(E)异构体。
实施方案10:根据实施方案1至9中任一项的改性的释放固体口服剂型,其中至少约90重量%的化合物(I)和/或其药学上可接受的盐为(E)异构体。
实施方案11:根据实施方案1至10中任一项所述的改性的释放固体口服剂型,其中化合物(I)和/或其药学上可接受的盐为基本上纯的无定形形式。
实施方案12:根据实施方案1至11中任一项所述的改性的释放固体口服剂型,其中所述核心组合物包含约30mg至约100mg的化合物(I)和/或其药学上可接受的盐。
实施方案13:根据实施方案1至12中任一项的改性的释放固体口服剂型,其中所述核心组合物还包含至少一种选自填料、药物释放调节剂(也称为“溶解调节剂”或“溶解助剂”)、崩解剂和润滑剂的赋形剂。
实施方案14:根据实施方案13所述的
改性的释放固体口服剂型,其中所述填料包含纤维素衍生物和糖分子中的至少一种。
实施方案15:根据实施方案14所述的改性的释放固体口服剂型,其中所述纤维素衍生物是微晶纤维素。
实施方案16:根据实施方案15所述的改性的释放固体口服剂型,其中所述微晶纤维素是PH-101。该物质可从许多供应商诸如Sigma-Aldrich和FMC Corporation获得。该物质的粒度为约50微米。
实施方案17:根据实施方案14至16中任一项所述的改性的释放固体口服剂型,其中所述糖分子是甘露糖醇。
实施方案18:根据实施方案17所述的改性的释放固体口服剂型,其中所述甘露糖醇是喷雾干燥的甘露糖醇,其可从许多供应商诸如Roquette-Pharma以“Pearlitola100SD”获得,并且具有约100微米的平均粒径。
实施方案19:根据实施方案13至18中任一项所述的改性的释放固体口服剂型,其中所述药物释放调节剂是羟丙基甲基纤维素(也称为“羟丙甲纤维素”)。
实施方案20:根据实施方案19所述的改性的释放固体口服剂型,其中所述羟丙基甲基纤维素是METHOCELTM K 100 Premium LV CR。该物质可从The Dow Chemical Company获得。字母“K”表示其为羟丙甲纤维素产品;化学名称后面的数字“100”表示产品的粘度,在20℃下在水中的浓度为2%的情况下测量时其为约100毫帕-秒(mPa.s)。“LV”是指特殊的低粘度产品,并且“CR”表示受控释放级别。
实施方案21:根据实施方案13至20中任一项所述的改性的释放固体口服剂型,其中所述崩解剂是N-乙烯基-2-吡咯烷酮的交联均聚物(交联聚维酮)。
实施方案22:根据实施方案21所述的改性的释放固体口服剂型,其中所述交联聚维酮是可从供应商诸如BASF获得的KollidonTM CL。
实施方案23:根据实施方案13至22中任一项所述的改性的释放固体口服剂型,其中所述润滑剂是硬脂酰富马酸钠。
实施方案24:根据实施方案13至23中任一项所述的改性的释放固体口服剂型,其包含按所述核心组合物的重量计:
约6%至约20%的化合物(I)和/或其药学上可接受的盐;
约34%至约72%的微晶纤维素;
约5%至约25%的甘露糖醇;
约0%至约20%的羟丙基甲基纤维素;
约0.5%至约1.5%的N-乙烯基-2-吡咯烷酮的交联均聚物;以及
约0.5%至约1.5%的硬脂酰富马酸钠。
实施方案25:根据实施方案1至24中任一项所述的改性的释放固体口服剂型,其中所述核心组合物占所述固体口服剂型的总重量(即,核心组合物+底部包衣层+肠溶包衣的重量)的约83%至约91%。
实施方案26:根据实施方案1至25中任一项所述的改性的释放固体口服剂型,其中所述有色聚乙烯醇是II。
实施方案27:根据实施方案1至26中任一项所述的改性的释放固体口服剂型,其中所述底部包衣层占所述固体口服剂型的重量(即,核心组合物+底部包衣层+肠溶包衣的重量)的约2%至约4%。
实施方案28:根据实施方案1至27中任一项所述的改性的释放固体口服剂型,其中所述肠溶包衣层的聚(甲基丙烯酸-共-丙烯酸乙酯)共聚物是L 30D-55或L 100-55。
实施方案29:根据实施方案1至28中任一项所述的改性的释放固体口服剂型,其中所述肠溶包衣层还包含增溶剂和增塑剂/抗粘剂。
实施方案30:根据实施方案29所述的改性的释放固体口服剂型,其中所述增溶剂是油酸的聚乙氧基化脱水山梨糖醇酯。
实施方案31:根据实施方案29或30所述的改性的释放固体口服剂型,其中所述增溶剂是可从供应商诸如Sigma-Aldrich获得的聚山梨酸酯80(TweenTM 80)。聚山梨酸酯80来源于聚乙氧基化脱水山梨糖醇和油酸。该化合物中的亲水基团是聚醚(也称为聚氧乙烯基团),其为环氧乙烷的聚合物。在聚山梨酸酯的命名中,聚山梨酸酯后面的数字标志是指亲脂基团,在这种情况下是指油酸。聚山梨酸酯80的完整化学名称是:聚氧乙烯(20)脱水山梨糖醇单油酸酯和(x)-脱水山梨糖醇单-9-十八碳烯酸酯聚(氧-1,2-乙二基)。
实施方案32:根据实施方案29所述的改性的释放固体口服剂型,其中所述增塑剂/抗粘剂是可从供应商诸如Emerson Resources和Evonik Industries获得的PlasACRYLTMT20。PlasACRYLTM T20是一种20%的抗粘剂和增塑剂的乳液,可以简化强力喷雾悬浮液的制备。
实施方案33:根据实施方案1至32中任一项所述的改性的释放固体口服剂型,其中所述肠溶包衣层占所述固体口服剂型的总重量(即,核心组合物+底部包衣层+肠溶包衣的重量)的约6%至约20%。
实施方案34:根据实施方案1至33中任一项所述的改性的释放固体口服剂型,其中所述肠溶包衣层包含按所述固体口服剂型的总重量(即,核心组合物+底部包衣层+肠溶包衣层的重量)计:
约5%至约16%的L 30D-55或L 100-55;
约1%至约3%的PlasACRYLTM T20;以及
约0.3%至约0.8%的聚山梨酸酯80。
实施方案35:根据实施方案1至34中任一项所述的改性的释放固体口服剂型,其中所述核心组合物占所述固体口服剂型的总重量(即,核心组合物+底部包衣层+肠溶包衣的重量)的约80%至约91%。
实施方案36:根据实施方案1至35中任一项所述的改性的释放固体口服剂型,其中所述底部包衣层占所述固体口服剂型的总重量(即,核心组合物+底部包衣层+肠溶包衣的重量)的约2%至约4%。
实施方案37:一种抑制对其有需要的哺乳动物中的布鲁顿酪氨酸激酶(BTK)的方法,包括向需要这种BTK抑制的哺乳动物施用治疗有效量的根据实施方案1至36中任一项所述的改性的释放固体口服剂型的化合物(I)和/或其药学上可接受的盐。
实施方案38:一种治疗对其有需要的哺乳动物中的由BTK介导的疾病的方法,包括向需要这种疾病治疗的哺乳动物施用治疗有效量的根据实施方案1至36中任一项所述的改性的释放固体口服剂型的化合物(I)和/或其药学上可接受的盐。
实施方案39:根据实施方案38所述的方法,其中所述疾病是自身免疫疾病、癌症或炎性疾病。
实施方案40:根据实施方案38或39所述的方法,其中所述疾病是急性坏死性出血性脑白质炎、急性播散性脑脊髓炎、自身免疫内耳疾病(AIED)、自身免疫视网膜病变、轴索和神经元神经病变、慢性炎性脱髓鞘性多发性神经病(CIDP)、脱髓鞘性神经病变、德维克氏病(视神经脊髓炎)、实验性变应性脑脊髓炎、巨细胞动脉炎(颞动脉炎)、格林-巴利综合征、兰伯特-伊顿综合征、慢性梅尼埃病、重症肌无力、神经性肌强直、眼阵挛-肌阵挛综合征、视神经炎、副肿瘤性小脑变性、周围神经病变、周围性脑脊髓炎、多动腿综合征、僵人综合征、交感性眼炎、高安氏动脉炎、颞动脉炎/巨细胞动脉炎、横贯性脊髓炎、多发性硬化症、自主神经功能障碍、年龄相关性黄斑变性(湿性和干性)、角膜移植、脑炎、脑膜炎、血管炎或系统性红斑狼疮(SLE)。
实施方案41:根据实施方案38或39所述的方法,其中所述疾病是类风湿性关节炎、银屑病性关节炎、狼疮、葡萄膜炎、重症肌无力、温抗体型自身免疫溶血性贫血、韦格纳氏肉芽肿病、干燥综合征、干燥综合征干眼症、非干燥综合征干眼病、牛皮癣、天疱疮、荨麻疹或哮喘。
实施方案42:根据实施方案38或39所述的方法,其中所述疾病是弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞性淋巴瘤、慢性淋巴细胞白血病、B细胞前淋巴细胞白血病、小淋巴细胞淋巴瘤(SLL)、多发性骨髓瘤、B细胞非霍奇金淋巴瘤、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性积液淋巴瘤、伯基特淋巴瘤/白血病或淋巴瘤样肉芽肿病。
实施方案43:可通过本公开的改性的释放固体口服剂型治疗的疾病包括:急性坏死性出血性脑白质炎、急性播散性脑脊髓炎、爱迪生氏病、无丙种球蛋白血症、斑秃、普秃、淀粉样变性、强直性脊柱炎、抗GBM/抗TBM肾炎、抗磷脂综合征(APS)、抗磷脂抗体综合征、再生障碍性贫血、关节炎、自身免疫血管性水肿、自身免疫自主神经功能障碍、自身免疫肝炎、自身免疫高脂血症、自身免疫免疫缺陷、自身免疫内耳病(AIED)、自身免疫心肌炎、自身免疫卵巢炎、自身免疫胰腺炎、自身免疫视网膜病变、自身免疫血小板减少性紫癜(ATP)、自身免疫甲状腺疾病、自身免疫荨麻疹、自身免疫溶血性贫血、轴索和神经元神经病、巴娄病、白塞氏病、大疱性类天疱疮、心肌病变、卡斯尔门病(Castleman disease)、乳糜泻、查加斯病、慢性疲劳综合征、慢性炎性脱髓鞘性多发性神经病(CIDP)、慢性复发性多病灶骨髓炎(CRMO)、许尔-斯特劳斯综合征、瘢痕性类天疱疮/良性粘膜类天疱疮、乳糜泄、科干综合征、冷凝集素病、先天性心脏传导阻滞、柯萨奇心肌炎、CREST病、克罗恩氏病、脱髓鞘性神经病变、疱疹样皮炎、皮肌炎、德维克氏病(视神经脊髓炎)、糖尿病、盘状狼疮、德雷斯勒氏综合征、干眼症、自主神经功能障碍、子宫内膜异位症、嗜酸细胞性食道炎、嗜酸细胞性筋膜炎、结节性红斑、基本混合性冷球蛋白血症、伊文氏综合征、实验性变应性脑脊髓炎、纤维肌痛、纤维性肺泡炎、巨细胞动脉炎(颞动脉炎)、巨细胞心肌炎、肾小球肾炎、古德帕斯彻氏综合征、肉芽肿伴多血管炎(GPA)(以前称为韦格纳氏肉芽肿病)、格雷夫斯氏病、格林-巴利综合征、桥本氏甲状腺炎、溶血性贫血、亨-舍二氏紫癜、妊娠疱疹、低丙种球蛋白血症、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、IgA肾病、IgG4相关性硬化病、免疫调节脂蛋白、包涵体肌炎、炎性肠病、间质性膀胱炎、青少年关节炎、青少年糖尿病(1型糖尿病)、青少年肌炎、川崎综合征、兰伯特-伊顿综合征、白细胞破碎性血管炎、扁平苔癣、硬化性苔藓、木样结膜炎、线性IgA病(LAD)、狼疮(SLE)、包括狼疮性肾炎在内的狼疮、莱姆病、慢性梅尼埃病、显微镜下多血管炎、混合性结缔组织病(MCTD)、蚕蚀性角膜溃疡、木栅-赫伯曼病(Mucha-Habermann disease)、粘膜类天疱疮、多发性硬化症、重症肌无力、肌炎、发作性睡病、神经性肌强直、中性粒细胞减少、眼瘢痕性类天疱疮、眼阵挛-肌阵挛综合征、视神经炎、奥德氏甲状腺炎、骨关节炎、复发性风湿病、PANDAS(与链球菌相关的小儿自身免疫神经精神疾病)、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿症(PNH)、帕里隆伯格综合征、睫状体扁平部炎(周围葡萄膜炎)、Parsonnage-Turner综合征、周围神经病变、周围性脑脊髓炎、恶性贫血、天疱疮(诸如寻常天疱疮、落叶型天疱疮)、POEMS综合征、结节性多动脉炎、风湿性多肌痛、多肌炎、心肌梗塞后综合征、心包切开术后综合征、原发性胆汁性肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化、黄体酮性皮炎、牛皮癣、银屑病性关节炎、银屑病性关节炎、纯红细胞再生障碍、坏疽性脓皮病、雷诺氏现象、反应性关节炎、反射性交感神经营养不良、莱特尔氏综合征、复发性多软骨炎、多动腿综合征、腹膜后纤维化、风湿热、类风湿性关节炎、结节病、施密特综合征、巩膜炎、硬皮病、干燥综合征、精子和睾丸自身免疫、僵人综合征、斯提耳氏病、亚急性细菌性心内膜炎(SBE)、苏萨克氏综合征、交感性眼炎、高安氏动脉炎、颞动脉炎/巨细胞动脉炎、血小板减少性紫癜(TTP)、托-亨综合征、横贯性脊髓炎、I型、II型和III型自身免疫多腺体综合征、溃疡性结肠炎、未分化结缔组织病(UCTD)、葡萄膜炎、血管炎、膀胱疱疹性皮肤病、白癜风、外阴痛和狼疮。
其他疾病包括自身免疫疾病,例如炎性肠病、关节炎、包括狼疮肾炎在内的狼疮、类风湿性关节炎、银屑病性关节炎、骨关节炎、斯提耳氏病、青少年关节炎、糖尿病、重症肌无力、肉芽肿伴多血管炎、桥本氏甲状腺炎、奥德氏甲状腺炎、格雷夫斯氏病、干燥综合征、干眼症(包括干燥综合征干眼症和非干燥综合症干眼症)、多发性硬化症、格林-巴利综合征、急性播散性脑脊髓炎、爱迪生氏病、眼阵挛-肌阵挛综合征、强直性脊柱炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫肝炎、乳糜泄、古德帕斯彻氏综合征、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔氏综合征、高安氏动脉炎、颞动脉炎、自身免疫溶血性贫血、韦格纳氏肉芽肿病、牛皮癣、普秃、白塞氏病、慢性疲劳、自主神经功能障碍、子宫内膜异位症、间质性膀胱炎、神经性肌强直、硬皮病、天疱疮(诸如寻常天疱疮和/或落叶型天疱疮)、大疱性类天疱疮、年龄相关性黄斑变性(湿性和干性)、糖尿病性黄斑水肿、角膜移植、腹主动脉瘤、粘膜类天疱疮和外阴痛。
在另一个实施方案中,自身免疫疾病是狼疮、寻常天疱疮、重症肌无力、干燥综合征、干眼症、多发性硬化症、韦格纳氏肉芽肿病、自身免疫溶血性贫血、特发性血小板减少性紫癜、肉芽肿伴多血管炎或类风湿性关节炎。
在另一个实施方案中,疾病是异源免疫病症或疾病,例如移植物抗宿主病、移植、输血、过敏反应、过敏症、I型超敏反应、过敏性结膜炎、过敏性鼻炎或特应性皮炎。在另一个实施方案中,疾病是特应性皮炎。
在另一个实施方案中,疾病是炎性疾病,例如哮喘、阑尾炎、睑缘炎、细支气管炎、支气管炎、滑囊炎、宫颈炎、胆管炎、胆囊炎、结肠炎、结膜炎、膀胱炎、泪腺炎、皮炎、皮肌炎、脑炎、心内膜炎、子宫内膜炎、肠炎、小肠结肠炎、上髁炎、附睾炎、筋膜炎、纤维组织炎、胃炎、肠胃炎、肝炎、化脓性汗腺炎、喉炎、乳腺炎、脑膜炎、脊髓炎心肌炎、肌炎、肾炎、卵巢炎、睾丸炎、骨炎、耳炎、胰腺炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉炎、局限性肺炎、肺炎、直肠炎、前列腺炎、肾盂肾炎、鼻炎、输卵管炎、鼻窦炎、口腔炎、滑膜炎、肌腱炎、扁桃体炎、葡萄膜炎、阴道炎、血管炎或外阴炎。在该方面的另一个实施方案中,哺乳动物患有炎性皮肤病,其包括例如皮炎、接触性皮炎、湿疹、荨麻疹、天疱疮(诸如寻常天疱疮和/或落叶型天疱疮)、大疱性类天疱疮、红斑痤疮以及皮肤、关节或其他组织或器官中的瘢痕性银屑病病变。在另一个实施方案中,炎性疾病是哮喘或皮炎。
在又一个实施方案中,疾病是炎性和/或自身免疫疾病,包括急性炎性和/或自身免疫疾病,其中使用皮质类固醇疗法作为第一线或第二线疗法或者第一线或第二线维持疗法。在一个实施方案中,本公开的固体口服剂型用于治疗以下疾病:
内分泌失调:原发性或继发性肾上腺皮质功能不全(氢化可的松或可的松是首选:如适用,合成类似物可与盐皮质激素一起使用;在婴儿期,盐皮质激素补充剂特别重要);先天性肾上腺皮质增生症;非化脓性甲状腺炎;与癌症相关的高钙血症。
风湿性疾病:在以下疾病中作为短期施用的辅助治疗(使患者渡过急性发作期或恶化期):银屑病性关节炎、类风湿性关节炎(包括青少年类风湿性关节炎(所选病例可能需要低剂量维持治疗))、强直性脊柱炎、急性和亚急性滑囊炎、急性非特异性腱鞘炎、痛风、急性痛风性关节炎、创伤后骨关节炎、骨关节炎滑膜炎、上髁炎。
胶原疾病:在以下所选病例的恶化期或作为其维持治疗:系统性红斑狼疮、系统性皮肌炎(多肌炎)和急性风湿性心脏炎。
皮肤疾病:天疱疮;大疱性疱疹样皮炎;重症多形性红斑(史蒂文斯-约翰逊综合征);剥脱性皮炎;蕈样肉芽肿病;重症银屑病;重症脂溢性皮炎。
过敏状态:对以下难以进行常规治疗的充分试验的严重或失能过敏性病症进行控制:季节性或常年性过敏性鼻炎;支气管哮喘;接触性皮炎;特应性皮炎;血清病;药物超敏反应。
眼科疾病:涉及眼睛及其附件的严重急性和慢性过敏和炎症过程,诸如:过敏性角膜边缘性溃疡、眼部带状疱疹、前段炎症、弥漫性后葡萄膜炎和脉络膜炎、交感性眼炎、过敏性结膜炎、角膜炎、脉络膜视网膜炎、视神经炎、虹膜炎和虹膜睫状体炎。
呼吸道疾病:症状性结节病;无法通过其他方式控制的吕弗勒氏综合征;铍中毒;与适当的抗结核化疗同时使用时,用于治疗吸入性肺炎、暴发性或播散性肺结核。
血液学疾病:成人特发性血小板减少性紫癜;成人继发性血小板减少症;获得性(自身免疫)溶血性贫血;红细胞减少症(红细胞贫血症);先天性(红细胞)发育不良性贫血。
肿瘤性疾病:用于以下疾病的姑息治疗:成人白血病和淋巴瘤、儿童急性白血病。
水肿状态:在特发性类型或由于红斑狼疮引起的肾病综合征(没有尿毒症)中诱导蛋白尿的排出或解少。
胃肠疾病:使患者渡过以下疾病的关键时期:溃疡性结肠炎、局限性肠炎。
其他:与适当的抗结核化疗同时使用时,用于治疗结核性脑膜炎伴蛛网膜下腔阻滞或即将阻滞;旋毛虫病伴神经或心肌损伤。
本公开的固体口服剂型可任选地与皮质类固醇、非皮质类固醇、免疫抑制剂和/或抗炎剂组合用于治疗上述疾病。在一个实施方案中,免疫抑制剂选自干扰素α、干扰素γ、环磷酰胺、他克莫司、霉酚酸酯、甲氨蝶呤、氨苯砜、柳氮磺胺吡啶、硫唑嘌呤、抗CD20剂(诸如利妥昔单抗、奥法木单抗、奥滨尤妥珠(obinutuzumab)或维妥珠单抗(veltuzumab),或其生物仿制版本)、抗TNFα剂(诸如依那西普、英利昔单抗、戈里卢单抗(golilumab)、阿达木单抗或赛妥珠单抗,或其生物仿制版本)、针对配体或其受体的抗IL6剂(诸如托珠单抗、萨瑞鲁单抗(sarilumab)、奥洛珠单抗(olokizumab)、elsililumab或siltuximab)、针对配体或其受体的抗IL17剂(诸如苏金单抗、优特克单抗、brodalumab或ixekizumab)、针对配体或其受体的抗IL1剂(诸如利纳西普、康纳单抗或阿那白滞素)、针对配体或其受体的抗IL2剂(诸如巴利昔单抗或达利珠单抗)、抗CD2剂诸如阿法西普、抗CD3剂诸如muromonab-cd3、抗CD80/86剂诸如阿巴西普或贝拉西普、抗鞘氨醇-1-磷酸盐受体剂诸如芬戈莫德、抗C5剂诸如依库丽单抗、抗整联蛋白α4剂诸如那他珠单抗、抗α4β7剂诸如维多珠单抗、抗mTOR剂诸如西罗莫司或依维莫司、抗钙调磷酸酶剂诸如他克莫司,以及抗BAFF-/BlyS剂(诸如贝利木单抗、VAY736或blisibimod)、来氟米特和特立氟胺。优选地,免疫抑制剂是利妥昔单抗、奥法木单抗、奥滨尤妥珠或维妥珠单抗,或其生物仿制版本。
在又一个实施方案中,待通过本公开的固体口服剂型治疗的疾病是癌症。在一个实施方案中,癌症是B细胞增殖性疾病,例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞性淋巴瘤(CLL)、慢性淋巴细胞白血病、慢性髓性白血病、B细胞急性淋巴细胞白血病(B-ALL)、费城染色体阳性B-ALL、B细胞前淋巴细胞白血病、小淋巴细胞淋巴瘤(SLL)、多发性骨髓瘤、B细胞非霍奇金淋巴瘤、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性积液淋巴瘤、伯基特淋巴瘤/白血病或淋巴瘤样肉芽肿病。
在又一个实施方案中,待通过本公开的固体口服剂型治疗的疾病是血栓栓塞疾病,例如心肌梗塞、心绞痛、血管成形术后再闭塞、血管成形术后再狭窄、主动脉冠状动脉旁路术后再闭塞、主动脉冠状动脉旁路术后再狭窄、中风、短暂性局部缺血、外周动脉闭塞性疾病、肺栓塞或深静脉血栓形成。
当受试者患有自身免疫疾病、炎性疾病或过敏性疾病或者有患这些疾病的风险时,本发明口服剂型的化合物(I)和/或其药学上可接受的盐可以任何组合与一种或多种以下治疗剂一起使用:免疫抑制剂(诸如他克莫司、环孢菌素、雷帕霉素、甲氨蝶呤、环磷酰胺、硫唑嘌呤、巯嘌呤、霉酚酸酯或FTY720)、糖皮质激素(例如强的松、醋酸可的松、强的松龙、甲基强的松龙、地塞米松、倍他米松、曲安奈德、倍氯米松、醋酸氟氢可的松、醋酸去氧皮质酮、醛固酮)、非甾体抗炎药(例如水杨酸盐、芳基链烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、昔布类或磺酰苯胺)、Cox-2-特异性抑制剂(例如伐地昔布、塞来昔布或罗非昔布)、来氟米特、硫代葡萄糖金、硫代苹果酸金、金刚酚、柳氮磺胺吡啶、羟基氯喹、米诺环素、TNF-α结合蛋白(例如英利昔单抗、依那西普、或阿达木单抗)、阿巴西普、阿那白滞素、干扰素β、干扰素γ、白介素-2、过敏疫苗、抗组胺、抗白三烯、β-激动剂、茶碱、或抗胆碱能药。
当受试者患有B细胞增殖性疾病(例如,浆细胞骨髓瘤)或有患该疾病的风险时,可用本公开的固体口服剂型与一种或多种其他抗癌症剂的任何组合来治疗受试者。在一些实施方案中,一种或多种抗癌剂是促凋亡剂。抗癌剂的示例包括但不限于以下各项中的任一种:棉子酚、genasense、多酚E、Chlorofusin、所有反式视黄酸(ATRA)、苔藓抑素、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)、5-氮杂-2'-脱氧胞苷、所有反式视黄酸、多柔比星、长春新碱、依托泊苷、吉西他滨、伊马替尼(GleevecTM)、格尔德霉素、17-N-烯丙基氨基-17-去甲氧基格尔德霉素(17-AAG)、夫拉平度、LY294002、硼替佐米、曲妥珠单抗、BAY 11-7082、PKC412或PD184352、TaxolTM(也称为“紫杉醇”,是一种众所周知的抗癌药物,通过增强和稳定微管形成起作用)以及TaxolTM的类似物(诸如TaxotereTM)。还证明了具有基本紫杉烷骨架作为共同结构特征的化合物能够使细胞由于稳定的微管而停滞在G2-M期,并且可与本文所述的化合物组合用于治疗癌症。
与本公开的固体口服剂型组合使用的抗癌剂的其他示例包括促分裂原活化蛋白激酶信号传导的抑制剂,例如U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青霉素或LY294002;Syk抑制剂;mTOR抑制剂;和抗体(例如利妥昔单抗)。
可与本公开的固体口服剂型组合使用的其他抗癌剂包括亚德里亚霉素、更生霉素、博来霉素、长春花碱、顺铂、阿西维辛;阿柔比星;盐酸阿可达佐;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;安波霉素;乙酸阿美蒽醌;氨鲁米特;安吖啶;阿那曲唑;氨茴霉素;天门冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;盐酸必桑郡;双奈法德;比折来新;硫酸博来霉素;布喹那钠;溴匹立明;白消安;放线菌素;卡普睾酮;卡拉酰胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔比星;卡折来新;西地芬戈;chiorambucil;西罗霉素;克拉屈滨;甲磺酸克雷斯托;环磷酰胺;阿糖胞苷;达卡巴嗪;盐酸柔红霉素;地西他滨;右奥马铂;地扎胍宁;甲磺酸地扎胍宁;亚丝醌;多柔比星;盐酸多柔比星;屈洛昔芬;柠檬酸屈洛昔芬;丙酸屈他雄酮;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸依索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;艾托卜宁;盐酸法倔唑;法扎拉滨;维甲酰酚胺;氟尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;白介素II(包括重组白介素II或rIL2)、干扰素α-2a;干扰素α-2b;干扰素α-nl;干扰素α-n3;干扰素β-1a;干扰素γ-1b;异丙铂;盐酸伊立替康;醋酸兰瑞肽;来曲唑;醋酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索罗酚;美登素;盐酸氮芥;醋酸甲地孕酮;醋酸美仑孕酮;美法仑;美诺立尔;巯嘌呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托克星(mitocarcin);米托罗米(mitocromin);米托洁林;米托马星;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑;诺加霉素;奥马铂;奥昔舒仑;培门冬酶;培利霉素;戊氮芥;硫酸培洛霉素;培磷酰胺;哌泊溴烷;哌泊舒凡;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;泊非霉素;泼尼莫司汀;盐酸甲苄肼;嘌呤霉素;盐酸嘌呤霉素;吡唑呋喃菌素;利波腺苷;罗谷亚胺;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;斯帕福斯特钠(sparfosatesodium);司帕索霉素;盐酸锗螺胺;螺莫司汀;螺铂;链黑菌素;链脲菌素;磺氯苯脲;他利霉素;替可加兰钠;替加氟;盐酸替洛蒽醌;替莫卟吩;替尼泊苷;替罗昔隆;睾内酯;硫咪嘌呤;硫鸟嘌呤;噻替哌;噻唑呋林(tiazofurin);替拉扎明;柠檬酸托瑞米芬;醋酸曲托龙;磷酸曲西立滨;三甲曲沙;葡萄糖醛酸三甲曲沙;曲普瑞林;盐酸九布洛唑;尿嘧啶氮芥;乌瑞替哌;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;伏氯唑;折尼铂;净司他丁;以及盐酸佐柔比星。
可与本公开的固体口服剂型组合使用的其他抗癌剂包括:20-epi-1,25二羟基维生素D3;5-乙炔基尿嘧啶;阿比特龙;阿柔比星;acylfulvene;腺环戊醇;阿多来新;阿地白介素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀;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;抗背侧化形态发生蛋白-1;抗雄激素、前列腺癌;抗雌激素;抗瘤酮;反义寡核苷酸;阿非迪霉素甘氨酸;细胞凋亡基因调节剂;细胞凋亡调控剂;无嘌呤酸;ara-CDP-DL-PTBA;精氨酸脱氨酶;asulacrine;阿他美坦;阿莫司汀;阿新司坦汀1;阿新司坦汀2;阿新司坦汀3;阿扎司琼;azatoxin;重氮酪氨酸;baccatin III衍生物;balanol;巴马司他;BCR/ABL拮抗剂;benzochlorins;苯甲酰星孢菌素;β-内酰胺衍生物;β-alethine;β-clamycin B;桦木酸;bFGF抑制剂;比卡鲁胺;必桑郡;双吖丙啶基精胺;双奈法德;双曲群A;比折来新;breflate;溴匹立明;布朵替坦;丁硫氨酸硫酸亚胺;卡泊三醇;卡弗他丁C;喜树碱衍生物;金丝雀痘IL-2;卡培他滨;甲酰胺-氨基-三唑;羧胺三唑;CaRest M3;CARN700;软骨衍生的抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);粟树精胺;杀菌肽B;西曲瑞克;氯代喹喔啉磺酰胺;西卡前列素;顺式卟啉;克拉屈滨;氯米芬类似物;克霉唑;克里霉素A;克里霉素B;考布他汀A4;考布他汀类似物;conagenin;crambescidin 816;克立那托;念珠藻素8;念珠藻素A衍生物;curacin A;环戊蒽醌;cycloplatam;cypemycin;阿糖胞苷烷磷酯(cytarabineocfosfate);溶细胞因子;胞他汀(cytostatin);达昔单抗;地西他滨;脱氢膜海鞘素B;德舍瑞林;地塞米松;右异环磷酰胺;右丙亚胺;右维拉帕米;亚丝醌;膜海鞘素B;didox;二乙基去甲精胺;二氢-5-氮杂胞苷;9-dioxamycin;二苯基螺莫司汀;二十二醇;多拉司琼;去氧氟尿苷;屈洛昔芬;屈大麻酚;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;爱普列特;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;维甲酰酚胺;非格司亭;非那雄胺;夫拉平度;氟卓斯汀;fluasterone;氟达拉滨;盐酸氟道诺霉素(fluorodaunorunicin hydrochloride);福酚美克;福美司坦;福司曲星;福莫司汀;钆替沙林;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;hepsulfam;调蛋白;六亚甲基二乙酰胺;金丝桃素;伊班膦酸;伊达比星;吲哚昔酚;伊决孟酮;伊莫福新;伊洛马司他;咪唑并吖啶酮(imidazoacridones);咪喹莫特;免疫刺激剂肽;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;4-甘薯苦醇;伊罗普拉;伊索拉定;isobengazole;isohomohalicondrin B;伊他司琼;jasplakinolide;kahalalide F;片螺素-N三乙酸酯;兰瑞肽;leinamycin;来格司亭;香菇多糖硫酸酯;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;亮丙瑞林;左旋咪唑;利阿唑;线性聚胺类似物;亲脂性二糖肽;亲脂性铂化合物;lissoclinamide 7;乐巴铂;蚯蚓磷脂;洛美曲索;氯尼达明;洛索蒽醌;洛伐他汀;洛索立宾;勒托替康;镥泰克萨菲瑞(lutetium texaphyrin);lysofylline;裂解肽;美坦辛;mannostatin A;马立马司他;马索罗酚;乳腺丝抑蛋白;基质溶解因子抑制剂;基质金属蛋白酶抑制剂;美诺立尔;美巴龙;meterelin;methioninase;甲氧氯普胺;MIF抑制剂;米非司酮;米替福新;米立司亭;不匹配的双链RNA;米托胍腙;卫矛醇;丝裂霉素类似物;米托萘胺;迈托毒素成纤维细胞生长因子-皂草素;米托蒽醌;莫法罗汀;moigramostim;单克隆抗体、人绒膜促性腺激素;单磷酰基脂质A+分支杆菌细胞壁sk;莫哌达醇;多药耐药基因抑制剂;多肿瘤抑制因子1类治疗剂;芥菜抗癌剂;mycaperoxide B;分枝杆菌细胞壁提取物;myriaporone;N-乙酰地那林;N-取代的苯甲酰胺;那法瑞林;nagrestip;纳洛酮+喷他佐辛;napavin;naphterpin;那托司亭;奈达铂;奈莫柔比星;奈立膦酸;中性肽链内切酶;尼鲁米特;nisamycin;一氧化氮调节剂;硝基氧抗氧化剂;nitrullyn;O6-苄基鸟嘌呤;奥曲肽;okicenone;寡核苷酸;奥那司酮;昂丹司琼;昂丹司琼;oracin;口腔细胞因子诱导剂;奥马铂;奥沙特隆;奥沙利铂;oxaunomycin;palauamine;palmitoylrhizoxin;帕米膦酸;人参炔三醇;帕诺米芬;parabactin;帕折普汀;培门冬酶;peldesine;戊聚糖聚硫酸钠;喷司他丁;pentrozole;全氟溴烷;培磷酰胺;紫苏醇;phenazinomycin;乙酸苯酯;磷酸酶抑制剂;溶链菌制剂;盐酸毛果芸香碱;吡柔比星;吡曲克辛;placetin A;placetin B;纤溶酶原激活因子抑制剂;铂络合物;铂化合物;铂三胺络合物;卟吩姆钠;泊非霉素;强的松;丙基二吖啶酮;前列腺素J2;蛋白酶体抑制剂;蛋白质A类免疫调节剂;蛋白激酶C抑制剂;微藻蛋白激酶C抑制剂;蛋白质酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;红紫素;甲氧基吡唑啉吖啶;吡哆醛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法呢基蛋白质转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;脱甲基瑞替普汀;铼Re 186依替膦酸盐;根霉素;核酶;R.sub.11维甲酸;罗谷亚胺;罗希吐碱;罗莫肽;罗喹美克;rubiginone B1;ruboxyl;沙芬戈;saintopin;SarCNU;sarcophytol A;沙格司亭;Sdi 1模拟物;司莫司汀;衰老衍生的1;正义寡核苷酸;信号转导抑制剂;信号转导调节剂;单链抗原结合蛋白;sizofuran;索布佐生;硼卡钠;苯乙酸钠;solverol;生长调节素结合蛋白;索纳明;斯帕磷酸;spicamycin D;螺莫司汀;斯耐潘定;spongistatin 1;角鲨胺;干细胞抑制剂;干细胞分裂抑制剂;stipiamide;溶基质素抑制剂;sulfinosine;超活性血管活性肠肽拮抗剂;suradista;苏拉明;苦马豆素;合成糖胺聚糖;他莫司汀;他莫昔芬甲碘化物;牛磺莫司汀;他扎罗汀;替可加兰钠;替加氟;tellurapyrylium;端粒酶抑制剂;替莫卟吩;替莫唑胺;替尼泊苷;四氯十氧化物;tetrazomine;thaliblastine;thiocoraline;血小板生成素;血小板生成素模拟物;胸腺法新;胸腺生成素受体激动剂;胸腺曲南;甲状腺刺激激素;本紫红素乙酯锡(tin ethyl etiopurpurin);替拉扎明;二氯环戊二烯钛;topsentin;托瑞米芬;全能干细胞因子;翻译抑制剂;维甲酸;三乙酰基尿苷;triciribine;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;UBC抑制剂;乌苯美司;泌尿生殖窦源的生长抑制因子;尿激酶受体拮抗剂;伐普肽;variolin B;载体系统,红细胞基因治疗剂;维拉雷琐;藜芦胺;弗丁斯;维替泊芬;长春瑞滨;vinxaltine;vitaxin;伏氯唑;扎诺特隆;折尼铂;亚苄维;以及净司他丁苯马聚合物。
可与本公开的固体口服剂型组合使用的其他抗癌剂包括烷化剂、抗代谢物、天然产物或激素,例如氮芥(例如氯代乙胺、环磷酰胺、苯丁酸氮芥等)、烷基磺酸盐(例如白消安)、亚硝基脲(例如卡莫司汀、洛莫司汀等)和三氮烯(例如达卡巴嗪等)。抗代谢物的示例包括但不限于叶酸类似物(例如甲氨蝶呤)、嘧啶类似物(例如阿糖胞苷)和嘌呤类似物(例如巯嘌呤、硫鸟嘌呤、喷司他丁)。
可与本公开的固体口服剂型组合使用的天然产物的示例包括但不限于长春花生物碱(例如长春花碱、长春新碱)、表鬼臼毒素(例如依托泊苷)、抗生素(例如柔红霉素、多柔比星、博来霉素)、酶(例如L-天冬酰胺酶)和生物反应调节剂(例如干扰素α)。
可与本公开的固体口服剂型组合使用的烷化剂的示例包括但不限于氮芥(例如,氯代乙胺、环磷酰胺、苯丁酸氮芥、美法仑等)、乙烯亚胺和甲基三聚氰胺(例如六甲基三聚氰胺、噻替派)、烷基磺酸盐(例如白消安)、亚硝基脲(例如卡莫司汀、洛莫司汀、司莫司汀、链脲佐菌素等)和三氮烯(例如达卡巴嗪等)。抗代谢物的示例包括但不限于叶酸类似物(例如甲氨蝶呤)和嘧啶类似物(例如氟尿嘧啶、氟尿苷、阿糖胞苷)和嘌呤类似物(例如巯嘌呤、硫鸟嘌呤、喷司他丁)。
可与本公开的固体口服剂型组合使用的激素和拮抗剂的示例包括但不限于肾上腺皮质激素(例如强的松)、孕激素(例如己酸羟孕酮、醋酸甲地孕酮、醋酸甲羟孕酮)、雌激素(例如二乙烯雌酚、乙炔雌二醇)、抗雌激素(例如他莫昔芬)、雄激素(例如丙酸睾酮、氟甲睾酮)、抗雄激素(例如氟他胺)和促性腺激素释放激素类似物(例如亮丙瑞林)。可用于本文所述的方法和组合物中来治疗或预防癌症的其他药剂包括铂配位络合物(例如顺铂、卡铂)、蒽二酮(例如米托蒽醌)、取代的脲(例如羟基脲)、甲基肼衍生物(例如丙卡巴肼)和肾上腺皮质抑制剂(例如米托坦、氨鲁米特)。
通过使细胞由于稳定的微管而停滞在G2-M期来起作用并且可与本公开的BTK抑制剂化合物组合使用的抗癌剂的示例包括但不限于以下市售的药物和研发中的药物:Erbulozole(也称为R-55104)、Dolastatin 10(也称为DLS-10和NSC-376128)、Mivobulin羟乙基磺酸盐(也称为CI-980)、长春新碱、NSC-639829、Discodermolide(也称为NVP-XX-A-296)、ABT-751(Abbott,也称为E-7010)、Altorhyrtins(诸如Altorhyrtin A和AltorhyrtinC)、Spongistatin(诸如Spongistatin 1、Spongistatin 2、Spongistatin 3、Spongistatin4、Spongistatin 5、Spongistatin 6、Spongistatin7、Spongistatin 8和Spongistatin9)、西马多丁盐酸盐(也称为LU-103793和NSC-D-669356)、埃博霉素(诸如埃博霉素A、埃博霉素B、埃博霉素C(也称为脱氧埃博霉素A或dEpoA)、埃博霉素D(也称为KOS-862、dEpoB和脱氧埃博霉素B)、埃博霉素E、埃博霉素F、埃博霉素B N-氧化物、埃博霉素A N-氧化物、16-氮杂-埃博霉素B、21-氨基埃博霉素B(也称为BMS-310705)、21-羟基埃博霉素D(也称为脱氧埃博霉素F和dEpoF)、26-氟代埃博霉素)、Auristatin PE(也称为NSC-654663)、Soblidotin(也称为TZT-1027)、LS-4559-P(Pharmacia,也称为LS-4577)、LS-4578(Pharmacia,也称为LS-477-P)、LS-4477(Pharmacia)、LS-4559(Pharmacia)、RPR-112378(Aventis)、长春新碱硫酸盐、DZ-3358(Daiichi)、FR-182877(Fujisawa,也称为WS-9885B)、GS-164(Takeda)、GS-198(Takeda)、KAR-2(匈牙利科学院)、BSF-223651(BASF,也称为ILX-651和LU-223651)、SAH-49960(Lilly/Novartis)、SDZ-268970(Lilly/Novartis)、AM-97(Armad/KyowaHakko)、AM-132(Armad)、AM-138(Armad/Kyowa Hakko)、IDN-5005(Indena)、念珠藻素52(也称为LY-355703)、AC-7739(Ajinomoto,也称为AVE-8063A和CS-39.HC1)、AC-7700(Ajinomoto,也称为AVE-8062、AVE-8062A、CS-39-L-Ser.HCI和RPR-258062A)、Vitilevuamide、Tubulysin A、Canadensol、Centaureidin(也称为NSC-106969)、T-138067(Tularik,也称为T-67、TL-138067和TI-138067)、COBRA-1(Parker Hughes Institute,也称为DDE-261和WHI-261)、H10(堪萨斯州立大学)、H16(堪萨斯州立大学)、Oncocidin Al(也称为BTO-956和DIME)、DDE-313(Parker Hughes Institute)、FijianolideB.Laulimalide、SPA-2(Parker Hughes Institute)、SPA-1(Parker Hughes Institute,也称为SPIKET-P)、3-IAABU(细胞骨架/西奈山医学院,也称为MF-569)、Narcosine(也称为NSC-5366)、Nascapine、D-24851(Asta Medica)、A-105972(Abbott)、Hemiasterlin、3-BAABU(细胞骨架/西奈山医学院,也称为MF-191)、TMPN(亚利桑那州立大学)、Vanadocene乙酰丙酮化物、T-138026(Tularik)、Monsatrol、Inanocine(也称为NSC-698666)、3-1AABE(细胞骨架/西奈山医学院)、A-204197(Abbott)、T-607(Tuiarik,也称为T-900607)、RPR-115781(Aventis)、Eleutherobins(诸如Desmethyleleutherobin、Desaetyleleutherobin、Isoeleutherobin A和Z-Eleutherobin)、Caribaeoside、Caribaeolin、Halichondrin B、D-64131(Asta Medica)、D-68144(Asta Medica)、Diazonamide A、A-293620(Abbott)、NPI-2350(Nereus)、Taccalonolide A、TUB-245(Aventis)、A-259754(Abbott)、Diozostatin、(-)-Phenylahistin(也称为NSCL-96F037)、D-68838(Asta Medica)、D-68836(AstaMedica)、Myoseverin B、D-43411(Zentaris,也称为D-81862)、A-289099(Abbott)、A-318315(Abbott)、HTI-286(也称为SPA-110、三氟乙酸盐)(Wyeth)、D-82317(Zentaris)、D-82318(Zentaris)、SC-12983(NCI)、Resverastatin磷酸钠、BPR-OY-007(国家卫生研究院)和SSR-250411(Sanofi)。
当受试者患有血栓栓塞疾病(例如,中风)或有患该疾病的风险时,可用本公开的固体口服剂型与一种或多种其他抗血栓栓塞剂的任何组合来治疗受试者。抗血栓栓塞剂的示例包括但不限于以下各项中的任一种:血栓溶解剂(例如阿替普酶、阿尼普酶、链激酶、尿激酶或组织纤溶酶原激活物)、肝素、亭扎肝素、华法林、达比加群(例如达比加群酯)、Xa因子抑制剂(例如磺达肝素、依达肝素、利伐沙班、DX-9065a、奥米沙班、LY517717或YM150)、噻氯匹定、氯吡格雷、CS-747(普拉格雷、LY640315)、希美加群和BIBR 1048。
本公开的固体口服剂型的附加任选成分
亲水性物质:
合适的亲水性物质包括水溶性或水溶胀性物质。此类物质的示例包括盐、糖和聚合物,诸如羟烷基纤维素、羟烷基烷基纤维素和羧烷基纤维素酯,例如羟丙基甲基纤维素(羟丙甲纤维素或HPMC)、羟丙基纤维素(HPC),以及包含一种或多种前述物质的组合。本质上为亲水性并且可用于本公开的羟丙基甲基纤维素以不同的粘度等级出售,诸如可从DowChemical Co.获得且以商品MethocelTM出售的那些。低粘度等级的羟丙基甲基纤维素的示例包括可以商品名Methocel E5、Methocel E-15LV、Methocel E50 LV、Methocel K100 LV和Methocel F50 LV获得的那些,它们2重量%水性溶液的粘度分别为5cP、15cP、50cP、100cP和50cP。具有中粘度的羟丙基甲基纤维素的示例包括以商品名Methocel E4M和Methocel K4M获得的那些,它们2重量%水性溶液的粘度均为4000cP。具有高粘度的羟丙基甲基纤维素聚合物的示例包括以商品名Methocel K15M和Methocel K100M获得的那些,它们的2重量%水性溶液的粘度分别为15,000cP和100,000cP。羟丙基甲基纤维素聚合物可以约0.1重量%至约50重量%的量存在于本公开的药物组合物中。
可用于本公开的羟丙基纤维素聚合物还包括例如可从Nippon Soda Co.以商品名KlucelTM获得的聚合物。商品名为Klucel EF、Klucel LF、Klucel JF和Klucel GF(它们的2重量%水性溶液的粘度小于1000cP)的羟丙基纤维素聚合物是低粘度亲水性聚合物的示例。可商品名Klucel ME(其2重量%水性溶液的粘度在4,000cP至6,500cP的范围内)获得的羟丙基纤维素聚合物是中粘度的亲水性聚合物。可以HPC-SL、HPC-L和HPC-M(它们的2重量%水性溶液的粘度分别为3cP至6cP、6cP至10cP和150cP至400cP)出售的羟丙基纤维素聚合物是低粘度亲水性聚合物的示例,而HPC-H的粘度为1,000cP至4000cP,是中粘度亲水性聚合物的示例。羟丙基纤维素聚合物可以约0.1重量%至约50重量%的量存在。
适用于制备改性释放剂型的水溶胀性物质是在暴露于水性流体(诸如胃肠流体)时能够膨胀的化合物。一种或多种水溶胀性化合物可存在于包衣中,并且任选地存在于一种或多种药学上可接受的赋形剂中。
可用作水溶胀性物质的合适化合物包括例如低取代羟丙基纤维素(例如L-HPC)、交联聚乙烯吡咯烷酮(例如PVP-XL、KollidoneTM CL和PolyplasdoneTM XL)、羧甲基纤维素钠、交联羧甲基纤维素钠(例如Ac-di-solTM和PrimelloseTM)、羟基乙酸淀粉钠(例如PrimojelTM)、羧甲基纤维素钠(例如NymcelTM ZSB10)、羧甲基淀粉钠(例如ExplotabTM)、离子交换树脂(例如DowexTM或AmberliteTM产品)、微晶纤维素(例如AvicelTM产品)、淀粉和预胶化淀粉(例如Starch 1500TM和Sepistab ST200TM)、福尔马林-酪蛋白(例如Plas-VitaTM),以及包含一种或多种上述水溶胀性物质的组合。
在一些实施方案中,亲水性物质包括聚环氧烷、多糖树胶和交联聚丙烯酸。合适的聚环氧烷(诸如未取代的环氧乙烷的线性聚合物)包括来自The Dow Chemical Company,U.S.的PolyoxTM产品,其分子量为约100,000至约7,000,000Da。其他有用的聚环氧烷聚合物由环氧丙烷或者环氧乙烷和环氧丙烷的混合物制成。
可使用天然和改性(半合成)的多糖树胶。非限制性示例为右旋糖酐、黄原胶、结冷胶、文莱胶和鼠李聚糖胶。
可使用的交联聚丙烯酸包括具有与上述烷基取代纤维素和聚环氧烷聚合物的那些性质类似的性质的那些。有用的交联聚丙烯酸包括粘度为约4,000cP至约40,000cP(对于25℃下的1%水性溶液)的那些。三个具体示例为CARBOPOLTM等级971P、974P和934P(由TheLubrizol Corporation,Cleveland,Ohio,USA出售)。其他示例为称为WATER LOCKTM的聚合物,它们是可从Grain Processing Corporation,Muscatine,Iowa,USA获得的淀粉/丙烯酸酯/丙烯酰胺共聚物。
由于水的进入,这些聚合物的亲水性和水溶胀性导致底部包衣的尺寸在口服施用后溶胀。活性剂从底部包衣释放的速率主要取决于水抑制速率和活性剂从溶胀聚合物中溶解和扩散的速率,继而与活性剂的溶解度和溶解速率、活性剂粒度和/或活性剂在剂型中的浓度有关。
合适的“疏水性”物质是水不溶性中性或合成蜡、脂肪醇(诸如月桂醇、肉豆蔻醇、硬脂醇、十六烷醇或十八烷醇)、脂肪酸及其衍生物(包括脂肪酸酯,诸如单硬脂酸甘油酯、单油酸甘油酯、乙酰化甘油单酯)、硬脂精、棕榈精、月桂精、肉豆蔻酯、十六烷基酯蜡、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、氢化蓖麻油、棉籽油、脂肪酸甘油酯(甘油单酯、甘油二酯和甘油三酯)、氢化脂肪、碳氢化合物、正常蜡、硬脂酸、硬脂醇、具有烃骨架的物质,以及包含一种或多种前述材料的组合。合适的蜡包括但不限于蜂蜡、(来自Lonza的N,N'-二硬脂酰乙二胺)、蓖麻蜡、巴西棕榈蜡和蜡状物质。
本文所述的固体剂型包含肠溶包衣,即作为本文所述的药物组合物的口服剂型,其利用肠溶包衣来影响化合物在胃肠道的肠中的释放。“肠溶包衣”药物或片剂是指包覆有在胃中保持完整但在到达肠(在一个实施方案中,为小肠)后溶解并释放药物的物质(即包覆有“肠溶包衣”)的药物或片剂。如本文所用,“肠溶包衣”是一种将治疗活性剂包裹为剂型或颗粒的材料,诸如一种或多种聚合物材料。通常,大量或全部的肠溶包衣材料在治疗活性剂从剂型中释放之前被溶解,以实现治疗活性剂在肠中的延迟溶解。肠溶包衣在例如Loyd,V.Allen,“Remington:The Science and Practice of Pharmacy”,第21版,Pharmaceutical Press,2005年;和P.J.Tarcha,“Polymers for Controlled DrugDelivery”,第3章,CRC Press,1991年中有所讨论。用于将肠溶包衣施加到药物组合物的方法是本领域熟知的,并且包括例如美国专利公布2006/0045822中公开的方法。
剂型可以是压缩的或模制的或挤出的片剂(包覆有肠溶包衣或未包覆),其含有任选地与其他赋形剂混合的化合物(I)和/或其药学上可接受的盐(或其任何实施方案)的粒剂、粉末、丸剂、珠剂或颗粒,所述赋形剂本身包覆有肠溶包衣或未包覆,只要至少片剂和/或化合物(I)和/或其药学上可接受的盐的粒剂、粉末、丸剂、珠剂或颗粒被包覆。口服剂型还可以是胶囊,其含有任选地与其他赋形剂混合的化合物(I)和/或其药学上可接受的盐(或其任何实施方案)的丸剂、珠剂或粒剂。最初用作肠溶包衣的包衣的一些示例为蜂蜡和单硬脂酸甘油酯;蜂蜡、虫胶和纤维素、十六醇、和乳香和虫胶,以及虫胶和硬脂酸(美国专利2,809,918)和聚乙酸乙烯酯和乙基纤维素(美国专利3,835,221)。最近,使用的肠溶包衣是聚甲基丙烯酸酯的中性共聚物(Eudragit L30D)(F.W.Goodhart等人,PharmTech.,第64-71页,1984年4月)、甲基丙烯酸和甲基丙烯酸甲酯的共聚物(Eudragit S)、含有金属硬脂酸酯的聚甲基丙烯酸酯的中性共聚物(参见Mehta等人,美国专利4,728,512和4,794,001)、纤维素乙酸琥珀酸酯和羟丙甲纤维素邻苯二甲酸酯。
在一些实施方案中,本文所述的聚合物为离子羧酸聚合物。在其他实施方案中,聚合物及其相容的混合物及其一些性质包括但不限于:
虫胶:也称为纯化的lac,它是从昆虫的树脂分泌获得的精制产品。这种包衣在pH>7的介质中溶解;
丙烯酸类聚合物:丙烯酸类聚合物的性能(主要是它们在生物流体中的溶解度)可根据取代的程度和类型而变化。合适的丙烯酸类聚合物的示例包括甲基丙烯酸共聚物和甲基丙烯酸铵共聚物。Eudragit系列L、S和RS(由Rohm Pharma制造,被称为)可溶于有机溶剂、用作水性分散体或用作干粉。Eudragit系列RL、NE和RS不溶于胃肠道但可渗透并且主要用于靶向结肠。Eudragit系列L、L-30D和S不溶于胃但溶于肠中;
纤维素衍生物:合适的纤维素衍生物的示例为:乙基纤维素;纤维素的部分乙酸酯与邻苯二甲酸酐的反应混合物。其性能可根据取代的程度和类型而变化。纤维素乙酸邻苯二甲酸酯(CAP)在pH>6下溶解。Aquateric(FMC)是一种水基体系,并且是一种颗粒<1μm的喷雾干燥的CAP假胶乳。Aquateric中的其他成分可包括普郎尼克类、吐温类和乙酰化甘油单酯。其他合适的纤维素衍生物包括:纤维素乙酸三苯甲酸酯(Eastman);甲基纤维素(Pharmacoat,Methocel);羟丙基甲基纤维素邻苯二甲酸酯(HPMCP);羟丙基甲基纤维素琥珀酸酯(HPMCS);和羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS,例如AQOAT(Shin Etsu))。其性能可根据取代的程度和类型而变化。例如,HPMCP诸如HP-50、HP-55、HP-55S和HP-55F等级是合适的。其性能可根据取代的程度和类型而变化。例如,合适等级的羟丙基甲基纤维素乙酸琥珀酸酯包括但不限于在pH5下溶解的AS-LG(LF)、在pH5.5下溶解的AS-MG(MF)以及在较高pH下溶解的AS-HG(HF)。这些聚合物作为粒剂或作为用于水性分散体的精细粉末提供。
聚醋酸乙烯酯邻苯二甲酸酯(PVAP):PVAP在pH>5下溶解,其对水蒸气和胃液的渗透性要小得多。对上述聚合物及其pH依赖性溶解度的详细描述可参见Karl Thoma教授和Karoline Bechtold在题为“Enteric coated hard gelatin capsules”的文章,网址为http://pop.www.capsugel.com/media/library/enteric-coated-hard-gelatin-capsules.pdf。
在一个实施方案中,肠溶包衣由丙烯酸、甲基丙烯酸或乙基丙烯酸聚合物或共聚物、纤维素乙酸酯(及其琥珀酸酯和邻苯二甲酸酯衍生物)、羟丙基甲基纤维素邻苯二甲酸酯、聚乙烯乙酸邻苯二甲酸酯、羟乙基乙基纤维素邻苯二甲酸酯、纤维素乙酸四氢邻苯二甲酸酯、丙烯酸类树脂或虫胶制成。在另一个实施方案中,聚合物选自纤维素乙酸邻苯二甲酸酯(CAP;在pH6以上溶解)、聚乙烯乙酸邻苯二甲酸酯(PVAP,在pH5下崩解)、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP,HP50等级在pH5下崩解,HP50在5.5下崩解)、甲基丙烯酸共聚物(Eudragit L 100和L12.5在约6和约7之间崩解,Eudragit L-30和L100-55在pH大于5.5时崩解,并且Eudragit S100、S12.5和FS 30D在pH大于7时崩解)。
在一些实施方案中,肠溶包衣可以并且通常确实含有增塑剂和本领域熟知的可能的其他包衣赋形剂,诸如着色剂、滑石和/或硬脂酸镁。合适的增塑剂包括柠檬酸三乙酯(Citroflex 2)、三醋精(甘油三乙酸酯)、乙酰柠檬酸三乙酯(Citroflec A2)、Carbowax400(聚乙二醇400)、邻苯二甲酸二乙酯、柠檬酸三丁酯、乙酰化甘油单酯、甘油、脂肪酸酯、丙二醇和邻苯二甲酸二丁酯。具体地讲,离子羧酸丙烯酸聚合物通常将含有约10重量%至约25重量%的增塑剂,特别是邻苯二甲酸二丁酯、聚乙二醇、柠檬酸三乙酯和三醋精。
使用常规包衣技术诸如流化床或Wurster包衣机或者喷包衣或锅包衣来施加包衣。包衣厚度必须足以确保口服剂型保持完整,直至到达肠道中所需的递送部位。以这样的方式针对每个肠溶包衣层和所述聚合物的施加量对增塑剂的量进行优化,该方式使得可以调节机械性质(即肠溶包衣层的柔韧性和硬度,例如维氏硬度),使得如果需要片剂,则包覆有肠溶包衣层的片剂的耐酸性在将丸剂压制成片剂期间不会显著降低。增塑剂的量通常高于肠溶包衣层聚合物的约5重量%。在一个实施方案中,增塑剂的量为肠溶包衣层聚合物的约15重量%至50重量%。在另一个实施方案中,增塑剂的量为肠溶包衣层聚合物的约20重量%至约50重量%。所施加的肠溶包衣的最大厚度通常仅受加工条件和所需溶解曲线的限制。
除了增塑剂之外,可将着色剂、表面活性剂、抗粘附剂、消泡剂、润滑剂(例如巴西棕榈蜡或PEG)和其他添加剂加入包衣中以溶解或分散包衣材料,并改善包衣性能和所包覆的产品。为了加速肠溶包衣的溶解,可应用半厚度的双层肠溶聚合物包衣(例如,EudragitL30 D-55),并且在存在约10%柠檬酸的情况下,内部肠溶包衣可具有高达约pH6.0的缓冲液,然后是标准Eudragit L 30D-55的最后层。施用两层肠溶包衣(每层的厚度为典型肠溶包衣的一半),与作为单层施加且无缓冲的相似包衣系统相比,Liu和Basit能够加速肠溶包衣溶解(Liu,F.和Basit,A.,“Journal of Controlled Release”,第147卷(2010年),第242-245页)。肠溶包衣的完整性可例如通过微丸内药物的降解来测量。肠溶包衣剂型或丸剂可首先在胃液中进行溶解测试中测试,并且如USP中所述分别在肠液中进行测试以确定其功能。添加剂诸如分散剂、着色剂、有色聚合物(例如聚丙烯酸乙酯、甲基丙烯酸甲酯)、抗粘剂和消泡剂也可包含在肠溶包衣层中。可添加其他化合物以增加膜厚度并减少酸性胃液扩散到酸敏感物质中。
除非另有说明,否则本文公开的制剂包含一种或多种药学上可接受的赋形剂,诸如粘合剂、表面活性剂、稀释剂、缓冲试剂、抗粘附剂、助流剂、亲水性或疏水性聚合物、阻滞剂、稳定试剂或稳定剂、崩解剂或超级崩解剂、分散剂、抗氧化剂、消泡剂、填料、调味剂、着色剂、润滑剂、吸附剂、防腐剂、增塑剂或甜味剂或它们的混合物,它们有助于将药物分子(或本文公开的其实施方案)或其药学上可接受的盐加工成可在药学上使用的制剂。药学上可接受的赋形剂可在包衣和/或核心中。可使用本领域合适且理解的任何熟知技术和赋形剂,参见例如“Remington:The Science and Practice of Pharmacy”,第21版(Pharmaceutical Press,2005年);Liberman,H.A.、Lachman,L.和Schwartz,J.B.编辑,“Pharmaceutical Dosage Forms”,第1-2卷,Taylor&Francis,1990年,以及R.I.Mahato,“Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems”,第2版,(Taylor&Francis,2012年)。
在一些实施方案中,制剂可包含一种或多种pH调节剂或缓冲试剂,例如:酸,诸如乙酸、硼酸、柠檬酸、乳酸、磷酸和盐酸;碱,诸如氢氧化钠、磷酸钠、硼酸钠、柠檬酸钠、乙酸钠、乳酸钠和三羟甲基氨基甲烷;以及缓冲剂,诸如柠檬酸盐/右旋糖、碳酸氢钠、氯化铵等。包含这些酸、碱和缓冲剂的量是将组合物的pH维持在可接受范围内所需的量。
在一些实施方案中,制剂还可包含一种或多种盐,其量为使组合物的渗透度在可接受范围内所需的量。这些盐包括具有钠、钾或铵阳离子以及氯化物、柠檬酸根、抗坏血酸根、硼酸根、磷酸根、碳酸氢根、硫酸根、硫代硫酸根或亚硫酸氢根阴离子的盐;合适的盐包括氯化钠、氯化钾、硫代硫酸钠、亚硫酸氢钠和硫酸铵。
在一些实施方案中,制剂还可包含一种或多种消泡剂以减少加工过程中的起泡,起泡可导致水性分散体凝结、在成品膜中形成气泡或通常损害加工。示例性消泡剂包括硅乳液和脱水山梨糖醇倍半油酸酯。
在一些实施方案中,制剂还可包含一种或多种抗氧化剂,诸如非硫醇抗氧化剂,例如丁基化羟基甲苯(BHT)、抗坏血酸钠、抗坏血酸和生育酚。在某些实施方案中,抗氧化剂在需要时可增强化学稳定性。
在一些实施方案中,制剂还可包含一种或多种防腐剂以抑制微生物活性。合适的防腐剂包括含汞物质,诸如硼酸苯汞和硫柳汞;稳定的二氧化氯;以及季铵化合物,诸如苯扎氯铵、十六烷基三甲基溴化铵和十六烷基氯化吡啶鎓。
在一些实施方案中,制剂还可包含一种或多种粘合剂。粘合剂赋予内聚性质并且包含例如海藻酸及其盐;纤维素衍生物,诸如羧甲基纤维素、甲基纤维素(例如)、羟丙基甲基纤维素、羟乙基纤维素、羟丙基纤维素(例如)、乙基纤维素(例如)和微晶纤维素(例如);微晶右旋糖;直链淀粉;硅酸镁铝;多糖酸;膨润土;明胶;聚乙烯吡咯烷酮/乙酸乙烯酯共聚物;交联聚维酮;聚维酮;淀粉;预胶化淀粉;黄蓍胶、糊精、麦芽糖糊精、糖(诸如蔗糖(例如)、葡萄糖、右旋糖、糖蜜、甘露糖醇、山梨糖醇、木糖醇(例如)和乳糖);天然或合成树胶,诸如金合欢、黄蓍胶、isapol外壳的茄替树胶粘液、聚乙烯吡咯烷酮(例如CL、CL、XL-10)、落叶松阿拉伯半乳聚糖、聚乙二醇、聚环氧乙烷、蜡、海藻酸钠等。
一般来讲,在粉末填充的明胶胶囊制剂中使用约10%至约70%的粘合剂含量。无论是直接压片、湿法制粒、碾压还是使用其他赋形剂(诸如填料,其本身可作为中等粘合剂),片剂制剂中的粘合剂用量水平可变化。本领域配制人员可确定制剂的粘合剂含量,但是片剂制剂中粘合剂的用量高达约70%是常见的。
在一些实施方案中,制剂还可包含分散剂和/或粘度调节剂。分散剂和/或粘度调节剂包括通过液体介质或制粒方法或共混方法控制药物的扩散和均匀性的物质。在一些实施方案中,这些试剂还有助于包衣或侵蚀基质的有效性。示例性扩散促进剂/分散剂包括例如亲水性聚合物、电解质、20、60或80、PEG、聚乙烯吡咯烷酮(PVP;商业上称为),以及碳水化合物类分散剂,诸如例如羟丙基纤维素(例如HPC、HPC-SL和HPC-L)、羟丙基甲基纤维素(例如HPMC K100、RPMC K4M、HPMC K15M和HPMC K100M)、羧甲基纤维素钠、甲基纤维素、三乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸硬脂酸酯(HPMCAS)、非结晶纤维素、硅酸镁铝、三乙醇胺、聚乙烯醇(PVA)、乙烯基吡咯烷酮/乙酸乙烯酯共聚物(S630)、4-(1,1,3,3-四甲基丁基)-苯酚与环氧乙烷和甲醛的聚合物(也称为泰洛沙泊)、泊洛沙姆(例如F68、F88和F108,它们是环氧乙烷和环氧丙烷的嵌段共聚物);以及泊洛沙胺(例如908,也称为908,它是一种四官能嵌段共聚物,衍生自将环氧丙烷和环氧乙烷顺式加成到乙二胺(BASF Corporation,Parsippany,N.J.))、聚乙烯吡咯烷酮K12、聚乙烯吡咯烷酮K17、聚乙烯吡咯烷酮K25或聚乙烯吡咯烷酮K30、聚乙烯吡咯烷酮/乙酸乙烯酯共聚物(S-630)、聚乙二醇(例如聚乙二醇的分子量可为约300至约6000或约3350至约4000或约7000至5400)、羧甲基纤维素钠、甲基纤维素、聚山梨酸酯-80、海藻酸钠、树胶(诸如例如黄蓍胶和金合欢胶、瓜尔胶、黄原胶类(包括黄原胶))、糖、纤维素(诸如例如羧甲基纤维素钠、甲基纤维素、羧甲基纤维素钠)、聚山梨酸酯-80、海藻酸钠、聚乙氧基化脱水山梨糖醇单月桂酸酯、聚乙氧基化脱水山梨糖醇单月桂酸酯、聚维酮、卡波姆、聚乙烯醇(PVA)、海藻酸盐、壳聚糖以及它们的组合。
在一些实施方案中,制剂还可包含一种或多种“稀释剂”,其是指在递送之前用于稀释目标化合物的化学化合物。稀释剂也可用于稳定化合物,因为它们可提供更稳定的环境。溶解在缓冲溶液(其也可控制或维持pH)中的盐被用作本领域的稀释剂,包括但不限于磷酸盐缓冲盐水溶液。在某些实施方案中,稀释剂增加了组合物的体积以便于压缩或产生足够的体积用于胶囊填充的均匀混合物。这些化合物包括例如乳糖、淀粉、甘露糖醇、山梨糖醇、右旋糖、微晶纤维素诸如磷酸氢钙、二水磷酸二钙;磷酸三钙;磷酸钙;无水乳糖;喷雾干燥的乳糖;预胶化淀粉;可压缩糖,诸如(Amstar);羟丙基甲基纤维素、羟丙基甲基纤维素乙酸硬脂酸酯;蔗糖类稀释剂;糖果用糖;一元硫酸钙一水合物、硫酸钙二水合物;乳酸钙三水合物;葡萄糖结合剂;水解的谷物固体;直链淀粉;粉状纤维素;碳酸钙;甘氨酸;高岭土;甘露糖醇、氯化钠;肌醇;膨润土;等。
在一些实施方案中,制剂可含有长链分子的表面活性试剂或表面活性剂,其可在亲水性/疏水性(水/油)界面处积聚并降低该界面处的表面张力。因此,它们可稳定乳液。在一些实施方案中,表面活性剂可包含:(聚氧乙烯山梨酸酯)系列表面活性剂、(脱水山梨糖醇长链羧酸酯)系列表面活性剂、(环氧乙烷或环氧丙烷嵌段共聚物)系列表面活性剂、和(各种聚乙二醇化甘油酯)系列表面活性剂、油酸酯、硬脂酸酯、月桂酸酯或其他长链羧酸的脱水山梨糖醇酯、泊洛沙姆(聚乙二醇-聚丙二醇嵌段共聚物或)、其他脱水山梨糖醇或蔗糖长链羧酸酯、甘油单酯和甘油二酯、辛酸甘油三酯/癸酸甘油三酯的PEG衍生物及其混合物,或者上述两种或更多种的混合物。在一些实施方案中,表面活性剂相可包含聚氧乙烯(20)脱水山梨糖醇单油酸酯(Tween)和脱水山梨糖醇单油酸酯(Span)的混合物。
在一些实施方案中,制剂还可包含一种或多种“崩解剂”,其包括与胃肠液接触时剂型的溶解和分散。“崩解试剂”或“崩解剂”可促进物质的分解或崩解。崩解试剂的示例包括淀粉(例如天然淀粉诸如玉米淀粉或马铃薯淀粉、预胶化淀粉诸如National 1551或者羟乙酸淀粉钠诸如或)、纤维素(诸如木材产品、甲基结晶纤维素(例如 PH101、PH 102、PH105、P100、和)、甲基纤维素、交联羧甲纤维素或交联纤维素(诸如交联交联羧甲纤维素钠交联羧甲基纤维素或交联的交联羧甲纤维素))、交联淀粉(诸如羟乙酸淀粉钠)、交联聚合物(诸如交联聚维酮、交联聚乙烯吡咯烷酮)、海藻酸盐(诸如海藻酸或海藻酸的盐,诸如海藻酸钠)、粘土(诸如HV(硅酸镁铝))、树胶(诸如琼脂、瓜尔胶、槐豆胶、梧桐胶、果胶或黄蓍胶)、羟乙酸淀粉钠、膨润土、天然海绵、表面活性剂、树脂(诸如阳离子交换树脂)、柑橘渣、月桂基硫酸钠、与淀粉组合的月桂基硫酸钠等。
在一些实施方案中,制剂还可包含侵蚀促进剂。“侵蚀促进剂”包括控制特定物质在胃肠液中的侵蚀的物质。侵蚀促进剂通常是本领域普通技术人员所知的。示例性侵蚀促进剂包括例如亲水性聚合物、电解质、蛋白质、肽和氨基酸。
在一些实施方案中,制剂还可包含一种或多种填充试剂(本文也称为填料),其包括化合物诸如乳糖、碳酸钙、磷酸钙、磷酸氢钙、硫酸钙、微晶纤维素、纤维素粉末、右旋糖、葡聚糖结合剂、右旋糖酐、淀粉、预胶化淀粉、蔗糖、木糖醇、乳糖醇、甘露糖醇、山梨糖醇、氯化钠、聚乙二醇等。
在一些实施方案中,制剂还可包含一种或多种调味剂和/或“甜味剂”,例如金合欢糖浆、乙酰磺胺酸钾、阿力甜、茴香、苹果、阿斯巴甜、香蕉、巴伐利亚奶油浆果、黑醋栗、奶油糖、柠檬酸钙、樟脑、焦糖、樱桃、樱桃奶油巧克力、肉桂、泡泡糖、柑橘、柑橘混合物、柑橘奶油、棉花糖、可可、可乐、冰樱桃、冰柑橘、环磺酸盐、氰酸酯、右旋糖、桉树、丁子香酚、果糖、水果混合物、生姜、甘草次酸、甘草糖浆(甘草汁)、葡萄、葡萄柚、蜂蜜、异麦芽、柠檬、酸橙、柠檬奶油、甘草酸单铵、麦芽酚、甘露醇、枫树、蜀葵糖剂、薄荷醇、薄荷奶油、混合浆果、新橙皮苷DC、纽甜、橙、梨、桃、薄荷、薄荷奶油、粉、覆盆子、沙士、朗姆酒、糖精、黄樟素、山梨糖醇、留兰香、留兰香奶油、草莓、草莓奶油、甜叶菊、三氯蔗糖、蔗糖、糖精钠、糖精、阿斯巴甜、乙酰磺胺酸钾、甘露醇、踝蛋白、木糖醇、三氯蔗糖、山梨糖醇、瑞士奶油、塔格糖、柑桔、非洲甜果素、百果糖、香草、胡桃、西瓜、野樱桃、冬青、木糖醇或这些调味成分的任意组合,例如茴香-薄荷醇、樱桃-茴香、肉桂-橙、樱桃-肉桂、巧克力-薄荷、蜂蜜-柠檬、柠檬-酸橙、柠檬-薄荷、薄荷醇-桉树、橙-奶油、香草-薄荷以及它们的混合物。
在一些实施方案中,制剂还可包含一种或多种润滑剂和/或助流剂,它们是防止、减少或抑制物质的粘附或摩擦的化合物。示例性润滑剂包括例如硬脂酸、氢氧化钙、滑石、硬脂酰富马酸钠、烃(诸如矿物油)或氢化植物油(诸如氢化大豆油)、高级脂肪酸及其碱金属和碱土金属盐(诸如铝、钙、镁、锌)、硬脂酸、硬脂酸钠、甘油、滑石、蜡、硼酸、苯甲酸钠、乙酸钠、氯化钠、亮氨酸、聚乙二醇(例如PEG4000)或甲氧基聚乙二醇(诸如)、油酸钠、苯甲酸钠、山嵛酸甘油酯、聚乙二醇、月桂基硫酸镁或月桂基硫酸钠、胶体二氧化硅(诸如 )、淀粉(诸如玉米淀粉)、硅油、表面活性剂等。
在一些实施方案中,制剂还可包含一种或多种增溶剂,其包括化合物诸如三醋精、柠檬酸三乙酯、油酸乙酯、辛酸乙酯、月桂基硫酸钠、多库酯钠、维生素E TPGS、二甲基乙酰胺、N-甲基吡咯烷酮、N-羟乙基吡咯烷酮、聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基环糊精(例如乙醇、正丁醇、异丙醇、胆固醇、胆盐、聚乙二醇200-600、糖原质、卡必醇、丙二醇、二甲基异山梨醇等。在一个实施方案中,增溶剂是维生素E TPGS和/或
在一些实施方案中,制剂还可包含一种或多种悬浮剂,其包括化合物诸如聚乙烯吡咯烷酮(例如聚乙烯吡咯烷酮K112、聚乙烯吡咯烷酮K17、聚乙烯吡咯烷酮K25或聚乙烯吡咯烷酮K30)、乙烯基吡咯烷酮/乙酸乙烯酯共聚物(S630)、聚乙二醇(例如聚乙二醇的分子量可为约300至约6000或约3350至约4000或约7000至约5400)、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、羟甲基纤维素乙酸硬脂酸酯、聚山梨酸酯-80、羟乙基纤维素、海藻酸钠、树胶(诸如例如黄蓍胶和金合欢胶、瓜尔胶、黄原胶类(包括黄原胶))、糖、纤维素(诸如例如羧甲基纤维素钠、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、羧乙基纤维素)、聚山梨酸酯-80、海藻酸钠、聚乙氧基化脱水山梨糖醇单月桂酸酯、聚乙氧基化脱水山梨糖醇单月桂酸酯、聚维酮等。
在某些实施方案中,制剂还可包含一种或多种表面活性剂,其包括化合物诸如月桂基硫酸钠、多库酯钠、吐温60或80、三醋精、维生素ETPGS、脱水山梨糖醇单油酸酯、聚氧乙烯脱水山梨糖醇单油酸酯、聚山梨酸酯、泊洛沙姆、胆汁盐、单硬脂酸甘油酯、环氧乙烷和环氧丙烷的共聚物(例如(BASF))等。一些其他表面活性剂包括聚氧乙烯脂肪酸甘油酯和植物油,例如聚氧乙烯(60)氢化蓖麻油;以及聚氧乙烯烷基醚和烷基苯基醚,例如辛苯聚醇10、辛苯聚醇40。在一些实施方案中,可包括表面活性剂以增强物理稳定性或用于其他目的。
在某些实施方案中,制剂还可包含一种或多种粘度增强剂,其包括例如甲基纤维素、黄原胶、羧甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素乙酸硬脂酸酯、羟丙基甲基纤维素邻苯二甲酸酯、卡波姆、聚乙烯醇藻酸酯、金合欢、壳聚糖以及它们的组合。
在一些实施方案中,制剂还可包含一种或多种润湿剂,其包括化合物诸如油酸、单硬脂酸甘油酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单月桂酸酯、油酸三乙醇胺、聚氧乙烯脱水山梨糖醇单油酸酯、聚氧乙烯脱水山梨糖醇单月桂酸酯、多库酯钠、油酸钠、月桂基硫酸钠、、多库酯钠、三醋精、吐温80、维生素E TPGS、铵盐等。
应当理解,在本文所述的固体剂型中使用的赋形剂之间存在相当大的重叠。因此,上面列出的添加剂应仅视为可包括在本文所述的固体剂型中的赋形剂的示例性而非限制性类型。根据所需的特定性质,本领域技术人员可容易地确定所述赋形剂的类型和量。
实施例
实施例1
改性释放药物产品的组合物的实施例
化合物(I)片剂是改性释放口服剂型。本公开采用“设计空间”概念来优化片剂药物产品的改性释放(MR)性能。该“设计空间”是三维的,其具有不同的剂量、药物释放调节剂百分比和聚合物包衣百分比来控制药物释放区域,因此延迟药物释放时间。
该设计空间限制为:
1.不同剂量范围:30mg(低剂量;DL(D=剂量;L=低))至100mg(高剂量;DH(H=高));
2.药物释放调节剂(溶解助剂):在胃排空后0.5小时至1.5小时范围内控制药物释放。药物释放调节剂为羟丙甲纤维素K100Premium LV并且将在0%(溶解模式为AF;F=快速;无药物释放调节剂)和35%(溶解模式为AS;S=缓慢;35%药物释放调节剂)之间变化;以及
3.肠溶聚合物包衣(例如Eudragit L30 D-55)百分比:在7%(PF;F=快速)和16%(Ps;S=缓慢)之间,在胃排空后控制药物释放。
可将化合物(I)片剂制造成选自“设计空间”内的单位剂量。如果需要高于100mg的剂量,则可施用多个剂量单位。
设计空间在图2中示出。
在“设计空间”极端的组成细节下,可改变表1和表2中所示的化合物(I)药物物质质量、羟丙甲纤维素K100 Premium LV和Eudragit L30 D55。可制造“设计空间”内的任何中间制剂。制剂的所有其他组分将保持恒定或将其调节成保持片剂的重量。
表1:化合物(I)MR片剂的角1、角2、角3和角4的组成
角1-制剂1低剂量,快速释放核心,快速包衣
角2-制剂2低剂量,缓慢释放核心,快速包衣
角3-制剂3低剂量,缓慢释放核心,缓慢包衣
角4-制剂4低剂量,快速释放核心,缓慢包衣
表2:化合物(I)MR片剂的角5、角6、角7和角8的组成
角5-制剂5高剂量,快速释放核心,缓慢包衣
角6-制剂6高剂量,快速释放核心,快速包衣
角7-制剂7高剂量,缓慢释放核心,快速包衣
角8-制剂8高剂量,缓慢释放核心,缓慢包衣
实施例2
药物溶解和pH变化的一般程序:将片剂置于酸性介质(pH 2)中并在其中保持两(2)小时。然后加入磷酸盐缓冲液,将pH变为6.0。使片剂包衣在该pH值下溶解;片剂破裂并释放药物。在pH变化之前,即在酸性介质中,释放小于约10%的药物。使用HPLC获得溶解曲线。
实施例3
角1制剂(30mg,低剂量片剂,快速释放核心,快速包衣,DLAsPF)的溶解曲线。在pH转换(从pH2转换为pH6)后需要约30分钟至约45分钟来释放约80%的药物。
实施例4
角2制剂(30mg,低剂量片剂,缓慢释放核心,快速包衣,DLAFPF)的溶解曲线。在pH转换后需要约1小时来释放约80%的药物。
实施例5
角3制剂(30mg,低剂量片剂,缓慢释放核心,缓慢包衣,DLASPS)的溶解曲线。在pH转换后需要约1.5小时来释放约80%的药物。
实施例6
角4制剂(30mg,低剂量片剂,快速释放核心,缓慢包衣,DLAFPS)的溶解曲线。在pH转换后需要约1.5小时来释放约80%的药物。
实施例7
角5制剂(100mg,高剂量片剂,快速释放核心,缓慢包衣,DHAFPs)的溶解曲线。在pH转换后需要约45分钟来释放约80%的药物。
实施例8
角6制剂(100mg,高剂量片剂,快速释放核心,快速包衣,DHAFPF)的溶解曲线。在pH转换后需要约少于30分钟来释放约80%的药物。
实施例9
角7制剂(100mg,高剂量片剂,缓慢释放核心,快速包衣,DHASPF)的溶解曲线。在pH转换后需要少于2小时来释放约80%的药物。
实施例10
角8制剂(100mg,高剂量片剂,缓慢释放核心,缓慢包衣,DHASPS)的溶解曲线。在pH转换后需要约2小时来释放约80%的药物。
实施例11
图3示出了化合物(I)的“设计空间”改性释放片剂制剂的所有八个角(在实施例3至实施例10中详细描述)的溶解曲线。
实施例12
用于制备化合物(I)核心片剂的方案:对化合物(I)药物物质、微晶纤维素PH 101、甘露糖醇100SD和羟丙甲纤维素K100 Premium LV(如果需要)进行称重并通过大小合适的筛子进行筛分。将所需量的每一种物质转移到大小合适的共混器中并机械混合。
对交联聚维酮CL进行称重并通过大小合适的筛子进行筛分。将所需量的交联聚维酮转移到上述大小合适的容器中。
对硬脂酰富马酸钠进行称重并通过大小合适的筛子进行筛分。将所需量转移到上述大小合适的容器中并机械混合。这提供了用于压制的化合物(I)改性释放片剂共混物。
将上述用于压制的化合物(I)改性释放片剂共混物进行单独称重并转移到片剂模具中,使用合适的压片机进行压制。这提供了化合物(I)改性释放核心片剂。
将该核心片剂置于容器闭合系统中。
实施例13
用于制备化合物(I)改性释放原型片剂的方案:将所需量的Opadry II黄的无菌水溶液分散用于冲洗。将其搅拌直至均匀。这提供了底部包衣悬浮液。通过将底部包衣悬浮液置于多孔包衣锅中,将底部包衣施加在化合物(I)核心片剂上。
将聚山梨酸酯80溶解在无菌水中用于冲洗。将Eudragit L30 D-55和PlasACRYL分散在聚山梨酸酯溶液中。搅拌混合物直至均匀。这提供了肠溶包衣悬浮液。
在多孔包衣锅中将肠溶包衣施加在底部包衣化合物(I)改性释放片剂上。将包衣片剂固化。这提供了肠溶包衣化合物(I)改性释放片剂。将所有可接受的片剂置于最终容器封闭件中并进行标记。
出于清楚和理解的目的,已经通过说明和示例的方式相当详细地描述了前述公开内容。因此,应当理解,以上描述旨在是说明性的而非限制性的。因此,本公开的范围不应参考以上描述来确定,而应参考以下所附权利要求以及这些权利要求所赋予的等同物的全部范围来确定。
Claims (14)
1.改性的释放固体口服剂型在制备治疗对其有需要的哺乳动物中的由布鲁顿酪氨酸激酶(BTK)介导的疾病的药物中的用途,其中所述用途包括向所述哺乳动物施用治疗有效量的改性的释放固体口服剂型的化合物(I)和/或其药学上可接受的盐,所述改性的释放固体口服剂型包含
(a)核心组合物,其包含以下物质的(E)异构体、(Z)异构体、或者(E)异构体和(Z)异构体的混合物和/或其药学上可接受的盐:(R)-2-
[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈、
(S)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈、或者2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈的(R)异构体和(S)异构体的混合物,2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-
[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈(化合物(I))具有以下结构:
其中*C是立体化学中心;
其中所述核心组合物包含以重量计的以下物质:
约6%至约20%的化合物(I)和/或其药学上可接受的盐;
约34%至约72%的微晶纤维素;
约5%至约25%的甘露糖醇;
0%至约20%的羟丙基甲基纤维素;
约0.5%至约1.5%的N-乙烯基-2-吡咯烷酮的交联均聚物;以及
约0.5%至约1.5%的硬脂酰富马酸钠;
(b)包覆所述核心组合物的底部包衣层,所述底部包衣层包含聚乙烯醇和任选地羟丙基甲基纤维素;以及
(c)包封所述底部包衣层和所述核心组合物的肠溶包衣层,所述肠溶包衣层包含聚(甲基丙烯酸-共-丙烯酸乙酯)共聚物,和任选地至少一种选自纤维素衍生物和聚乙烯吡咯烷酮的聚合物;
其中所述疾病选自特应性皮炎和特发性血小板减少性紫癜,并且其中术语“约”用于将数值修改为所述值以上和以下5%的变化。
2.根据权利要求1所述的改性的释放固体口服剂型的用途,其中所述纤维素衍生物选自纤维素乙酸邻苯二甲酸酯、纤维素乙酸三苯甲酸酯、甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、羟丙基甲基纤维素琥珀酸酯(HPMCS)和羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)。
3.根据权利要求1所述的改性的释放固体口服剂型的用途,其中所述聚乙烯醇是有色聚乙烯醇。
4.根据权利要求1所述的改性的释放固体口服剂型的用途,其中:
所述改性的释放固体口服剂型在小于或等于约2.0的pH下在少于两小时内释放小于约10重量%的化合物(I)和/或其药学上可接受的盐;在等于或大于约6.0的pH下在约15分钟至约两小时内释放至少约80重量%的化合物(I)和/或其药学上可接受的盐;并且在等于或大于约6.0的pH下在约7.5小时之前释放任何未释放量的化合物(I)。
5.根据权利要求1所述的改性的释放固体口服剂型的用途,其中所述核心组合物包含化合物(I)。
6.根据权利要求1所述的改性的释放固体口服剂型的用途,其中:
(a)化合物(I)和/或其药学上可接受的盐为2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈的(R)异构体和(S)异构体的混合物的(E)和(Z)混合物;或
(b)化合物(I)和/或其药学上可接受的盐为(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶1-基]哌啶-1-羰基)-4-甲基-4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]戊-2-烯腈的(E)和(Z)混合物。
7.根据权利要求6所述的改性的释放固体口服剂型的用途,其中至少约85重量%的化合物(I)和/或所述其药学上可接受的盐为(E)异构体。
8.根据权利要求6所述的改性的释放固体口服剂型的用途,其中至少约90重量%的化合物(I)和/或所述其药学上可接受的盐为(E)异构体。
9.根据权利要求1所述的改性的释放固体口服剂型的用途,其中化合物(I)和/或其药学上可接受的盐为基本上纯的无定形形式,其中所述“基本上纯的无定形形式”是指化合物(I)和/或其药学上可接受的盐的固态形式,其中超过约70重量%的化合物(I)和/或其药学上可接受的盐是无定形形式,其余的以结晶形式存在。
10.根据权利要求1所述的改性的释放固体口服剂型的用途,其中所述核心组合物包含约30mg至约100mg的化合物(I)和/或其药学上可接受的盐。
11.根据权利要求1所述的改性的释放固体口服剂型的用途,其中:
(a)所述核心组合物占所述改性的释放固体口服剂型的总重量的约80%至约91%;
(b)所述底部包衣层占所述改性的释放固体口服剂型的重量的约2%至约4%;
(c)所述肠溶包衣层还包含增溶剂和增塑剂/抗粘剂;
(d)所述肠溶包衣层占所述改性的释放固体口服剂型的总重量的约6%至约20%;和/或
(e)所述肠溶包衣层包含按所述改性的释放固体口服剂型的总重量计:
约5%至约16%的L 30D-55或L 100-55;
约1%至约3%的PlasACRYLTMT20;以及
约0.3%至约0.8%的聚山梨酸酯80,
其中所述改性的释放固体口服剂型的各组分的含量总和在每种情况下为100%。
12.根据权利要求11所述的改性的释放固体口服剂型的用途,其中所述核心组合物占所述改性的释放固体口服剂型的总重量的约83%至约91%。
13.根据权利要求1至12中任一项所述的改性的释放固体口服剂型的用途,其中所述用途包括向所述哺乳动物施用治疗有效量的所述改性的释放固体口服剂型的化合物(I)和/或其药学上可接受的盐。
14.根据权利要求1至13中任一项所述的改性的释放固体口服剂型的用途,其中所述用途包括将所述化合物(I)和/或其药学上可接受的盐与一种或多种抗癌剂或抗炎剂组合施用。
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IL263815B (en) | 2022-07-01 |
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US20190231784A1 (en) | 2019-08-01 |
AU2017290354C1 (en) | 2023-07-06 |
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KR102391693B1 (ko) | 2022-04-29 |
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