CN110831582B - 药物组合物 - Google Patents
药物组合物 Download PDFInfo
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- CN110831582B CN110831582B CN201880044687.5A CN201880044687A CN110831582B CN 110831582 B CN110831582 B CN 110831582B CN 201880044687 A CN201880044687 A CN 201880044687A CN 110831582 B CN110831582 B CN 110831582B
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Abstract
本发明涉及包含作为活性成分的N‑{3‑[5‑(2‑氨基‑4‑嘧啶基)‑2‑(1,1‑二甲基乙基)‑1,3‑噻唑‑4‑基]‑2‑氟苯基}‑2,6‑二氟苯磺酰胺甲磺酸盐的分散片、所述分散片的制备方法、及所述分散片的使用方法。
Description
技术领域
本发明涉及口服混悬剂的分散片,所述口服混悬剂的分散片包含N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸盐,其由以下式(I)表示、称为达拉菲尼甲磺酸盐或并且在下文称为化合物A:
背景技术
N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺(以下称为化合物B)是如下文献中披露和要求保护的化合物,其呈游离碱、以及药学上可接受的盐及其溶剂化物,作为BRAF活性的抑制剂有用,特别是用于治疗癌症:国际提交日期为2009年5月4日的国际申请号PCT/US 2009/042682;国际公开号WO/2009/137391且国际公开日期为2009年11月12日,将其全部披露内容通过引用并入本文。化合物B是实例58a的化合物。
可以如国际申请号PCT/US 2009/042682中所述制备化合物B。可以如于2011年7月14日公开的美国专利公开号US 2011/0172215(将其全部披露通过引用并入本文)中所述制备化合物B。
合适地,以甲磺酸盐、或者如本文所定义的化合物A或达拉菲尼甲磺酸盐的形式制备化合物B。化合物B的其他合适的药学上可接受的盐形式包括硫酸盐、盐酸盐和钠盐形式。盐形式可以通过本领域技术人员例如从国际申请号PCT/US 2009/042682或美国专利公开号US 2011/0172215中的描述进行制备。化合物A在美国专利公开号US 2011/0172215的实例58d-e中进行制备。
固体口服药物剂型是用于施用药物活性化合物的流行且有用的药物形式。多种这样的形式是已知的,包括片剂、胶囊、丸剂、锭剂、和粉末。
然而,以商业规模配制可接受的固体口服药物剂型并不简单。当在体内施用时,药物活性化合物的药代动力学特性可以取决于配制品而显著变化。配制品必须能够递送足以达到所希望的治疗药物水平的特定量的药物活性化合物,同时还使与次优治疗药物水平相关的不良作用(例如毒性)最小化。而且,配制品和制造方法必须如提供直至使用时保持其完整性的完整剂型。该剂型还必须具有可接受的崩解和溶解特性,以便在使用中提供所希望的特性。
药物活性化合物(如化合物A)在制备高质量剂型方面提出了特殊的挑战。虽然已发现甲磺酸盐形式可增强化合物A的生物利用度,但化合物A是高渗透性和低溶解度的化合物,所述化合物在强酸性水性介质中极难溶,而在弱酸性、中性pH和碱性介质中几乎不溶。配制人员必须在药物的独特化学性质与每种赋形剂的特性之间取得平衡,以为了制备安全、有效和易于使用的固体口服药物剂型。
化合物A的固体剂型(如片剂和胶囊)披露在国际申请号PCT/US 2009/042682中。FDA批准了化合物A(以50mg和75mg胶囊的形式)作为单一疗法或与曲美替尼组合用于治疗BRAF V600E突变阳性转移性黑色素瘤。FDA还批准了化合物A与曲美替尼的组合用于治疗BRAF V600E突变阳性转移性非小细胞肺癌。在最近的I期研究中,目前正在评估化合物A在BRAF突变阳性实体瘤的儿科治疗中的安全性和有效性。但是,化合物A针对儿科患者群体的目标剂量可以大幅低于由当前胶囊配制品所提供的剂量。
虽然片剂和胶囊剂对于成人来说是可接受的,但是此类配制品对于不易吞咽片剂和胶囊的儿童或个体可能是不希望的或不切实际的。在儿科群体中,通常更希望提供用于口服施用的分散组合物,例如粉末或片剂,其在被患者食用之前首先可以分散在可摄取的水性介质中。不同于口服混悬剂的粉末,分散片配制品通常为水性介质中的混悬剂提供较短的重构时间,而不会浪费药物。
期望以商业规模提供分散固体组合物中的化合物A,特别是用于口服施用的药学上分散片作为混悬剂(在本文中也称为“用于口服混悬剂的分散片”),其便于向儿童施用并提供化合物A的每日剂量。
发明内容
本发明涉及化合物A的用于口服混悬剂的药物分散片,其适于用水重构。另外,本发明涉及制备所述分散片的方法以及使用所述分散片的方法。
具体实施方式
在一个实施例中,本发明针对含有化合物A的口服药物剂型,优选地剂型是分散片形式,优选地以商业规模生产此剂型。
如本文所用,术语“分散片”意指以片剂形式的药物配制品,其可分散于水性相(优选为水)中,以水混悬液形式口服施用。
在一个实施例中,本发明针对包含化合物A的分散片,化合物A以基于片剂的总重量的按重量计从5%至40%的量存在。
在一个实施例中,本发明针对包含治疗有效量的化合物A的分散片,化合物A以基于片剂的总重量的按重量计从5%至40%的量存在。
如本文所用,术语“改善的特性”及其衍生物考虑了当与不利用本发明的那个方面的配制品相比,利用本发明的方面的分散片体内释放化合物A的药代动力学特征的若干个优势,合适地,该配制品以商业规模生产。当分散片与水性媒介物混合时,改善的特性的实例包括:增加的口服生物利用度、改善的物理和化学稳定性、改善的光稳定性、稳定的药代动力学特征、改善的药代动力学特征、稳定的溶出速率和稳定的口服药物配制品。
已知化合物A具有高渗透性和差的水溶性。在水中,化合物A形成过饱和溶液,并倾向于快速,溶液介导的转化或沉淀成达拉菲尼游离碱。延迟化合物A的沉淀并在延长的时间段内保持过饱和溶液特别重要,以允许在体内更大的吸收,并导致化合物A的更高的生物利用度。
已经发现化合物A的相对生物利用度取决于配制品的溶解特征。特别地,已经发现化合物A的胶囊配制品的离解速率受羟丙甲纤维素(HPMC)聚合物胶囊壳材料的存在的影响(Ouellet等人,J.Pharm.Sci.[药物科学杂志],102(9):3100-3109)。比较化合物A的明胶和羟丙甲纤维素胶囊配制品的体外溶解研究显示与明胶胶囊相比,羟丙甲纤维素(占胶囊总重量的超过20%)胶囊的溶解百比分更高,从而延迟了达拉菲尼的沉淀、维持了过饱和溶液经延长的时间段、导致更高的口服生物利用度(Ouellet等人,J.Pharm.Sci.[药物科学杂志],102(9):3105-3107)。
在一个实施例中,本发明还针对包含以下的分散片:
(a)化合物A,
(b)羟丙甲纤维素,以及
(c)适合于制备分散片至少一种药学上可接受的赋形剂,其中化合物A或其药学上可接受的盐的量计算为基于分散片的总重量的活性部分的重量含量的百分比,是基于分散片的总重量的从约5%至40%、优选地约15%重量;基于分散片的总重量,羟丙甲纤维素的量可以是按重量计从约1%至25%、优选地从约5%至10%变化。
配制化合物A的分散片的一个特别困难是使用高水平的羟丙甲纤维素。高水平的羟丙甲纤维素可能通过延长片剂的崩解和分散时间而不利地影响化合物A的分散片配制品中的溶出曲线,使得剂型对于在施用至专利之前制备充分分散的水性介质制剂而言,不便且费时。除了优化羟丙甲纤维素的水平外,崩解剂的选择对于在水性介质存在下促进片剂崩解成精细颗粒至关重要。
在分散片中可以存在一种或多种药学上可接受的赋形剂,例如常规使用的哪些,例如至少一种填充剂(例如乳糖、乙基纤维素、微晶纤维素)、至少一种崩解剂(例如交联的聚乙烯吡咯烷酮,例如交聚维酮)、至少一种助流剂(例如二氧化硅胶体)、至少一种润滑剂(例如硬脂酸镁)。
对于本文提及的这些和其他药学上可接受的赋形剂和程序,参考了有关该主题的大量文献,尤其参见Handbook of Pharmaceutical Excipients[药物赋形剂手册],第八版,由Paul J.Sheskey编辑,American Pharmaceutical Association[美国药学会],美国华盛顿和Pharmaceutical Press[英国医药出版社],伦敦;和Lexikon der Hilfsstoffe für Pharmazie[药学用辅料词汇],Kosmetik and angrenzende Gebiete[化妆品及邻近区域]由H.P.Fiedler编辑,第4版,Edito Cantor,Aulendorf和较早版本,将其通过引用并入本文。
配制化合物A的分散片的另一个特别困难是选择用于增加产品表面积并软化将片剂的固体颗粒保持在一起的结合物的崩解剂。崩解开始时,羟丙甲纤维素可使用游离水进行其水合以形成凝胶,并抑制崩解剂对水分的摄取,以使其芯吸(wicking)(毛细作用)或膨胀,从而延长片剂的崩解时间。配制品中羟丙甲纤维素含量较高时,这种现象更加明显,导致片剂崩解时间更长。
根据本发明的合适的崩解剂包括但不限于淀粉、纤维素、交联的聚合物、和泡腾剂,如玉米淀粉、马铃薯淀粉、预胶化的淀粉、改性的玉米淀粉、交联羧甲基纤维素钠、交聚维酮、羟基乙酸淀粉钠、甲基纤维素、羧甲基纤维素、及其盐如钙盐和钠盐。在本发明的一个实施例中,崩解剂是交联羧甲基纤维素钠或交聚维酮、优选为交聚维酮。已经发现高浓度的交联羧甲基纤维素钠能胶凝并因此增加崩解时间。
本发明提供了如使用崩解时间设备,根据欧洲药典2.9.1的崩解测试(即片剂在水中在15℃至25℃的崩解时间)测量的,例如,在水性介质中(在水中)具有不超过3分钟、优选地3分钟或更少的崩解时间的分散片。因此,分散片提供了快速的重构时间,并因此便于例如向儿童施用。这导致更好的患者依从性
通过“崩解时间”意指在崩解时间装置中需要分散片在15℃至25℃在水中崩解的时间。
本发明的分散片在水相(优选地水)中可分散。
可以目视观察分散。当没有残留物残留在屏幕上时、或者如果有残留物(残留物由柔软的物质组成的(所述物质不是明显坚固的、未润湿的核))、或者仅在屏幕上残留有涂层(片剂)的碎片,则认为完成崩解。
已知,随着分散片的片剂硬度增加,崩解时间增加、并且脆性降低。因此,通常由潜在缺乏机械强度(即,高脆性值)的相对较软的片剂证明崩解时间较短。但是,硬度不足的片剂在需要之前(即在包装、运输、储存过程中或在将片剂添加到可摄取的水性介质中食用之前的任何时间)容易粉碎、碎裂或崩解。
本发明旨在提供化合物A的分散片,所述分散片具有高水平的羟丙甲纤维素、较短的崩解时间以方便混悬剂重构、以及低的脆性以具有承受常规的散装产品处理和初级包装的能力。令人惊奇地,发现包含化合物A和基于分散片的总重量的按重量计约1%至13%的总重量的羟丙甲纤维素的配制品可以产生快速分散组合物,所述快速分散组合物具有不超过3分钟的崩解时间(如使用崩解时间装置,根据欧洲药典2.9.1的崩解测试(即片剂在水中在15℃至25℃的崩解时间))、以及在100次翻转后小于1%的低的脆性。
如本文所用,术语“药物”或“活性成分”及其衍生物,除非另外定义,意指化合物A或N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸盐。
如本文所用,术语“化合物B”意指N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺,呈游离或未盐化和未溶剂化的化合物。化合物B也指化合物A中游离或未盐化和未溶剂化的化合物的量。
如本文所用,通过术语“商业规模”及其衍生物意指制备大于约20kg的直接压制混合物(适当地大于50kg、适当地大于75kg),或适合于制备至少约50,000个片剂、合适地至少75,000个片剂、合适地至少100,000个片剂的批次规模。
术语“约”意指大约、在其范围内、概略地、或周围。当术语“约”与数字范围结合使用时,它通过扩展以上示出的数值的上下边界来修改该范围。一般而言,术语“约”在本文中用于将数值在所述值之上和之下修改10%的变化。
术语“有效量”及其衍生词意指引起由研究人员或临床医生所寻求的组织、系统、动物或人的生物学或医学反应的药物或活性成分的量。此外,术语“治疗有效量”意指与没有接受该量的相应受试者相比,导致改善的治疗、治愈、预防、或改善疾病、病症或副作用,或降低疾病或病症的进展速度的量。所述术语在其范围内还包括有效增强正常生理功能的量。
因此,含有化合物A的分散片可以用于治疗哺乳动物的赘生物、特别是易感赘生物(癌症或肿瘤)。本发明还提供了在有需要的哺乳动物中治疗赘生物,特别是易感赘生物的方法,所述方法包括向哺乳动物施用治疗有效量的本发明的以分散片的化合物A。
如本文所用,“易感赘生物”是指易于通过激酶抑制剂治疗的赘生物,尤其是易受Raf抑制剂治疗的赘生物。与一种或多种Raf家族激酶的异常活性有关的赘生物,尤其是表现出Raf家族激酶的突变、Raf家族激酶的过表达、或Raf家族激酶的上游激活剂的突变、或Raf家族激酶的上游激活剂的过表达的赘生物,因此易于用本领域已知的Raf抑制剂治疗,并且包括原发性和转移性肿瘤和癌症。参见,Catalogue of Somatic Mutations inCancer(COSMIC)[癌症中的体细胞突变目录],Wellcome Trust Sanger Institute[韦尔科姆基金会桑格学院],http://www.sanger.ac.uk/genetics/CGP/cosmic/以及背景中引用的那些参考文献。
在本发明范围内的易感赘生物的具体实例包括但不限于:
巴雷特腺癌的腺癌;
胆道癌;
乳腺癌;
宫颈癌;
胆管癌;
中枢神经系统肿瘤,包括原发性CNS肿瘤(如胶质母细胞瘤、星型细胞瘤(包括多形性胶质母细胞瘤)和室管膜瘤)、和继发性CNS肿瘤(即,源自中枢神经系统外的肿瘤转移至中枢神经系统);
结肠直肠癌,包括大肠结肠癌;
胃部癌症;
头和颈的癌,包括头和颈的鳞状细胞癌;
血液性癌症,包括白血病和淋巴瘤,如急性淋巴细胞白血病、急性骨髓性白血病(AML)、骨髓增生异常综合征、慢性髓细胞性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、巨核细胞白血病、多发性骨髓瘤和红白血病;
肝细胞癌;
肺癌,包括小细胞肺癌和非小细胞肺癌;
卵巢癌;
子宫内膜癌;
胰腺癌;
垂体腺瘤;
前列腺癌;
肾癌;
肉瘤;
皮肤癌,包括黑素瘤;以及
甲状腺癌。
前述列表旨在单独披地露每个所列举的赘生物。在一个特定的实施例中,易感赘生物是在B-Raf中表现出突变的赘生物。
在另一个实施例中,提供了化合物A的分散片在需要治疗的哺乳动物(例如,人)中用于治疗易感赘生物(例如,巴雷特腺癌的腺癌;胆道癌;乳腺癌;宫颈癌;胆管癌;中枢神经系统肿瘤,包括原发性CNS肿瘤(如胶质母细胞瘤、星型细胞瘤(例如,多形性胶质母细胞瘤)和室管膜瘤)、和继发性CNS肿瘤(即,源自中枢神经系统外的肿瘤转移至中枢神经系统);结肠直肠癌,包括大肠结肠癌;胃部癌症;头和颈的癌,包括头和颈的鳞状细胞癌;血液性癌症,包括白血病和淋巴瘤,如急性淋巴细胞白血病、急性骨髓性白血病(AML)、骨髓增生异常综合征、慢性髓细胞性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、巨核细胞白血病、多发性骨髓瘤和红白血病;肝细胞癌;肺癌,包括小细胞肺癌和非小细胞肺癌;卵巢癌;子宫内膜癌;胰腺癌;垂体腺瘤;前列腺癌;肾癌;肉瘤;皮肤癌,包括黑素瘤;和甲状腺癌)。
如本文所用,通过术语“共同施用”意指同时施用或以任何方式分开地依次施用含有化合物A和一种或多种已知可用于治疗癌症的另外的活性剂的分散片,包括化学疗法和放射治疗。如本文所用,术语一种或多种另外的活性剂包括当施用于需要治疗癌症的患者时已知或表现出有利性质的任何化合物或治疗剂。如本文所用,“其他活性剂”与另外的抗肿瘤剂互换使用。优选地,如果施用不是同时的,则在彼此接近的时间内施用化合物。此外,是否将化合物以相同的剂型施用并不重要,例如,可以将一种化合物通过注射施用,而另一种化合物可以口服施用。合适地,“共同施用”将基本上由含有化合物A的分散片和含有另外的活性剂的第二药物剂型组成。合适地,“共同施用”将基本上由含有化合物A的分散片、含有另外的活性剂的第二药物剂型、和含有另一种活性剂的第三药物剂型组成。
通常,在本发明中可以在治疗癌症中共同施用对所治疗的易感肿瘤具有活性的任何抗肿瘤剂。此类药剂的实例可以在以下中发现:Cancer Principles and Practice ofOncology[肿瘤学原理与实践],由V.T.Devita和S.Hellman(编辑),第6版(2001年2月15日),Lippincott Williams&Wilkins Publishers[利平科特威廉姆斯&威尔金斯出版公司]。基于药物的特定特征和所涉及的癌症,本领域普通技术人员将能够辨别哪种药剂组合将是有用的。可用于本发明的典型抗肿瘤剂包括但不限于抗微管剂,如双萜类和长春花生物碱;铂配位复合物;烷基化剂,如氮芥、氧杂氮杂磷杂苯(氧杂氮杂磷杂苯)、烷基磺酸盐、亚硝基脲、和三氮烯(triazene);抗生素,如蒽环(anthracyclin)、放线菌素和博来霉素;拓扑异构酶II抑制剂,如表鬼臼毒素;抗代谢物,如嘌呤和嘧啶类似物和抗叶酸化合物;拓扑异构酶I抑制剂,如喜树碱;激素和激素类似物;信号传导通路抑制剂;非受体酪氨酸激酶血管生成抑制剂;免疫治疗剂;促凋亡剂;细胞周期信号传导抑制剂;蛋白酶体抑制剂;癌症新陈代谢的抑制剂。
用于与本发明的药物剂型组合或共同施用的另外的一种或多种活性剂(抗肿瘤剂)的实例是化学治疗剂。
抗微管或抗有丝分裂剂是在M周期或细胞周期的有丝分裂期对肿瘤细胞的微管有活性的相特异性药剂。抗微管剂的实例包括但不限于双萜类和长春花生物碱。
源自天然来源的双萜类是在细胞周期的G2/M期起作用的相特异性抗癌药。据信,双萜类通过与此蛋白结合而稳定了微管的β-微管蛋白亚基。然后,蛋白质的分解似乎受到抑制,阻止了有丝分裂,随后细胞死亡。双萜类的实例包括但不限于紫杉醇及其类似物多西他赛。
紫杉醇(5β,20-环氧-1,2α,4,7β,10β,13α-六-羟基紫杉-11-烯-9-酮4,10-二乙酸酯2-苯甲酸13-酯与(2R,3S)-N-苯酰基-3-苯基异丝氨酸)是从短叶紫杉树短叶红豆杉(Taxus brevifolia)中分离得到的天然双萜产品,并且作为可注射溶液是可商购的。它是萜烯的紫杉烷类的成员。在美国,已经批准紫杉醇用于临床使用以治疗难治性卵巢癌和乳腺癌。
多西他赛((2R,3S)-N-羧基-3-苯基异丝氨酸、N-叔丁基酯、13-酯与5β-20-环氧-l,2α,4,7β,10β,13α-六羟基紫杉-11-烯-9-酮4-二乙酸酯2-苯甲酸酯三水合物)作为作为可注射溶液是可商购的。多西他赛被指定用于疗乳腺癌。多西他赛是紫杉醇的半合成衍生物,参见(q.v.),使用从欧洲紫杉树的针中提取的天然前体10-去乙酰基浆果赤霉素III制备。多西他赛的剂量限制性毒性为中性粒细胞减少症。
长春花生物碱是源自长春花植物的相特异性抗肿瘤剂。长春花生物碱通过特异性结合至微管蛋白而作用于细胞周期的M期(有丝分裂)。因此,结合的微管蛋白分子不能聚合成微管。据信有丝分裂在中期被阻止,随后细胞死亡。长春花生物碱的实例包括但不限于长春花碱、长春新碱、和长春瑞滨。
长春花碱(长春质碱硫酸盐(vincaleukoblastine sulfate))作为可注射溶液作为是可商购的。尽管有可能作为各种实体瘤的二线治疗指征,但它主要用于治疗睾丸癌和各种淋巴瘤(包括霍奇金病);以及淋巴细胞和组织细胞淋巴瘤。骨髓抑制是长春花碱的剂量限制副作用。
长春新碱(长春质碱(vincaleukoblastine),22-氧代-,硫酸盐)作为可注射溶液作为是可商购的。长春新碱被指定用于治疗急性白血病,并且还发现已经用于霍奇金和非霍奇金恶性淋巴瘤的治疗方案中。脱发和神经系统影响是长春新碱最常见的副作用,并且在较小程度上发生了骨髓抑制和胃肠道粘膜炎作用。
长春瑞滨(3’,4’-二脱氧-4’-脱氧基-C’-非长春质碱(norvincaleukoblastine)[R-(R*,R*)-2,3-二羟基丁二酸酯(1:2)(盐)]作为长春瑞滨酒石酸盐的可注射溶液可商购的)是半合成长春花生物碱(vinca alkaloid)。长春瑞滨在各种实体瘤(特别是非小细胞肺癌、晚期乳腺癌和激素难治性前列腺癌)的治疗中,可作为单一药剂或与其他化学治疗剂(如顺铂)组合使用。骨髓抑制是长春瑞滨最常见的剂量限制副作用。
铂配位复合物是非相特异性抗癌剂,其与DNA相互作用。铂络合物进入肿瘤细胞,经过水合作用并与DNA形成链内和链间交联,从而对肿瘤产生不利的生物学影响。铂配位复合物的实例包括但不限于顺铂和卡铂。
顺铂(cisplatin(顺双氯双氨络铂(cis-diamminedichloroplatinum)))作为可注射溶液以是可商购的。顺铂主要用于治疗转移性睾丸癌和卵巢癌以及晚期膀胱癌。顺铂的主要剂量限制性副作用是肾毒性(其可以通过水合作用和利尿作用来控制)、以及耳毒性。
卡铂(铂(platinum)、二氨[1,1-环丁烷-二甲酸酯(2-)-O,O’])作为作为可注射溶液是可商购的。卡铂主要用于晚期卵巢癌的一线和二线治疗。骨髓抑制是卡铂的剂量限制性毒性。
烷基化剂是非相抗癌特异性药剂和强亲电药剂。通常,烷基化剂通过烷基化通过DNA分子的亲核部分例如磷酸、氨基、巯基、羟基、羧基和咪唑基团形成与DNA的共价键。这种烷基化破坏了核酸功能,导致细胞死亡。烷基化剂的实例包括但不限于氮芥,如环磷酰胺、美法仑、和苯丁酸氮芥;烷基磺酸酯,如白消安;亚硝基脲,如卡莫司汀;和三氮烯,如达卡巴嗪。
环磷酰胺(2-[双(2-氯乙基)氨基]四氢-2H-1,3,2-氧杂氮杂磷杂苯2-氧化物一水合物)作为可注射溶液和片剂作为是可商购的。在治疗恶性淋巴瘤、多发性骨髓瘤和白血病中,环磷酰胺被指定为单一药剂或与其他化学治疗剂组合使用。脱发、恶心、呕吐和白细胞减少是环磷酰胺最常见的剂量限制副作用。
美法仑(4-[双(2-氯乙基)氨基]-L-苯丙氨酸)作为可注射溶液或片剂作为是可商购的。美法仑被指定用于多发性骨髓瘤和不可切除的卵巢上皮癌的姑息治疗。骨髓抑制是美法仑最常见的剂量限制副作用。
苯丁酸氮芥(4-[双(2-氯乙基)氨基]苯丁酸)作为片剂是可商购的。苯丁酸氮芥被指定用于慢性淋巴白血病和恶性淋巴瘤(如淋巴肉瘤、巨大滤泡性淋巴瘤和霍奇金病)的姑息治疗。骨髓抑制是苯丁酸氮芥最常见的剂量限制副作用。
白消安(1,4-丁二醇二甲磺酸酯)作为片剂是可商购的。白消安被指定用于慢性髓细胞性白血病的姑息治疗。骨髓抑制是白消安最常见的剂量限制副作用。
卡莫司汀(1,3-[双(2-氯乙基)-1-亚硝基脲)作为冻干的材料的单个小瓶作为是可商购的。卡莫司汀被指定用于作为单一药剂或与用于脑肿瘤、多发性骨髓瘤、霍奇金病、和霍奇金淋巴瘤的其他药剂组合的姑息治疗。延迟的骨髓抑制是卡莫司汀最常见的剂量限制副作用。
达卡巴嗪(5-(3,3-二甲基-1-三氮烯基(triazeno))-咪唑-4-甲酰胺)作为材料的单个小瓶作为是可商购的。达卡巴嗪被指定用于治疗转移性恶性黑素瘤,并与其他药剂组合用于霍奇金病的二线治疗。达卡巴嗪最常见的剂量限制副作用是恶心、呕吐和厌食。
抗生素抗肿瘤剂是非相特异性药剂,其与DNA结合或嵌入DNA。通常,这种作用导致稳定的DNA复合物或链断裂,这破坏了核酸的正常功能,导致细胞死亡。抗生素抗肿瘤剂的实例包括但不限于放线菌素(如更生霉素);蒽环类(anthrocyclin)(如柔红霉素和阿霉素);和博来霉素。
更生霉素(也称为放线菌素D)以可注射形式作为是可商购的。更生霉素被指定用于治疗肾母细胞瘤(Wilm’s tumor)和横纹肌肉瘤。更生霉素最常见的剂量限制副作用是恶心、呕吐和厌食。
柔红霉素((8S-顺式-)-8-乙酰基-10-[(3-氨基-2,3,6-三脱氧基-α-L-来苏-吡喃己糖苷)氧基]-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12并四苯二酮盐酸盐)作为脂质体可注射形式作为或作为可注射作为是可商购的。柔红霉素被指定用于急性非淋巴细胞性白血病和晚期HIV相关的卡波西氏肉瘤的治疗中缓解诱导。骨髓抑制是柔红霉素最常见的剂量限制副作用。
阿霉素((8S,10S)-10-[(3-氨基-2,3,6-三脱氧基-□-L-来苏-六吡喃基)氧基]-8-乙醇酰(glycoloyl),7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12并四苯二酮盐酸盐)作为可注射形式作为或 是可商购的。阿霉素主要被指定用于治疗急性淋巴细胞白血病和急性粒细胞白血病,但也是治疗一些实体瘤和淋巴瘤的有用组分。骨髓抑制是阿霉素最常见的剂量限制副作用。
博来霉素(从轮状链霉菌菌株中分离的细胞毒性糖肽抗生素的混合物)作为是可商购的。博来霉素被指定为作为单一药剂或与鳞状细胞癌、淋巴瘤、和睾丸癌的其他药剂组合的姑息治疗。肺和皮肤毒性是博来霉素最常见的剂量限制副作用。
拓扑异构酶II抑制剂包括但不限于表鬼臼毒素。
表鬼臼毒素是源自曼德拉草(mandrake)植物的相特异性抗肿瘤剂。表鬼臼毒素通常通过与拓扑异构酶II和DNA形成三元复合物而引起DNA链断裂,从而影响细胞周期S和G2期的细胞。链断裂积累,随后细胞死亡。表鬼臼毒素的实例包括但不限于依托泊苷和替尼泊苷。
依托泊苷(4’-去甲基-表鬼臼毒素9[4,6-0-(R)-亚乙基-β-D-吡喃葡萄糖苷])作为可注射溶液或胶囊作为是可商购的,并且通常称为VP-16。依托泊苷在治疗睾丸癌和非小细胞肺癌中被指定为单一药物或与其他化疗剂组合。骨髓抑制是依托泊苷最常见的剂量限制副作用。白细胞减少的发生往往比血小板减少更为严重。
替尼泊苷(4’-去甲基-表鬼臼毒素9[4,6-0-(R)-噻吩亚甲基-β-D-吡喃葡萄糖苷])作为可注射溶液作为是可商购的,并且通常称为VM-26。替尼泊苷在治疗儿童急性白血病中被指定为单一药剂或与其他化疗剂组合。骨髓抑制是替尼泊苷最常见的剂量限制副作用。替尼泊苷可以包括白细胞减少和血小板减少。
抗代谢物肿瘤剂是阶段特异性抗肿瘤剂,所述抗肿瘤剂通过抑制DNA合成或抑制嘌呤或嘧啶碱合成从而限制DNA合成而在细胞周期的S期(DNA合成)起作用。因此,S期不会继续进行,随后细胞死亡。抗代谢物抗肿瘤剂的实例包括但不限于氟尿嘧啶、氨甲蝶呤、阿糖孢苷、巯嘌呤、硫鸟嘌呤、和吉西他滨。
5-氟尿嘧啶(5-氟-2,4-(1H,3H)嘧啶二酮)作为氟尿嘧啶是可商购的。5-氟尿嘧啶的施用导致胸苷酸合成的抑制,并且还被并入RNA和DNA中。结果通常是细胞死亡。5-氟尿嘧啶在乳腺癌、结肠癌、直肠癌、胃癌和胰腺癌的治疗中被指定为单一药剂或与其他化疗剂组合。骨髓抑制和黏膜炎是5-氟尿嘧啶剂量限制副作用。其他氟尿嘧啶类似物包括5-氟脱氧尿苷(氟尿苷)和5-氟脱氧尿苷单磷酸盐。
阿糖孢苷(4-氨基-1-β-D-阿拉伯呋喃糖基-2(1H)-嘧啶酮)作为是可商购的,并且通常称为Ara-C。据信阿糖胞苷通过将阿糖胞苷末端并入到生长的DNA链中而抑制DNA链延长,从而在S期表现出细胞相特异性。阿糖孢苷在治疗急性白血病中被指定为单一药剂或与其他化疗剂组合。其他胞苷类似物包括5-氮杂胞苷和2’,2’-二氟脱氧胞苷(吉西他滨)。阿糖孢苷诱导白细胞减少、血小板减少、和黏膜炎。
巯基嘌呤(1,7-二氢-6H-嘌呤-6-硫酮一水合物)作为是可商购的。巯基嘌呤通过尚不清楚的机制抑制DNA合成,从而在S期表现出细胞期特异性。巯基嘌呤在治疗急性白血病中被指定为单一药剂或与其他化疗剂组合。骨髓抑制和胃肠道黏膜炎是高剂量巯基嘌呤的预期副作用。有用的巯基嘌呤类似物是硫唑嘌呤。
硫鸟嘌呤(2-氨基-1,7-二氢-6H-嘌呤-6-硫酮)作为是可商购的。硫鸟嘌呤通过尚不清楚的机制抑制DNA合成,从而在S期表现出细胞期特异性。硫鸟嘌呤在治疗急性白血病中被指定为单一药剂或与其他化疗剂组合。骨髓抑制(包括白细胞减少、血小板减少、和贫血)是硫鸟嘌呤施用最常见的剂量限制副作用。但是,出现胃肠道副作用,并且可以是剂量限制的。其他嘌呤类似物包括喷司他丁、赤羟基壬基腺嘌呤(erythrohydroxynonyladenine)、磷酸氟达拉滨、和克拉屈滨。
吉西他滨(2’-脱氧基-2’,2’-二氟胞苷单盐酸盐(β-异构体))作为是可商购的。吉西他滨在S期和通过阻断细胞通过G1/S边界的进程表现出细胞相特异性。吉西他滨与顺铂组合用于治疗局部晚期非小细胞肺癌,并单独用于治疗局部晚期胰腺癌。骨髓抑制(包括白细胞减少、血小板减少、和贫血)是吉西他滨施用最常见的剂量限制副作用。
氨甲蝶呤(N-[4[[(2,4-二氨基-6-蝶啶基)甲基]甲基氨基]苯酰基]-L-谷氨酸)作为氨甲蝶呤钠是可商购的。氨甲蝶呤通过抑制嘌呤核苷酸和胸苷酸合成所需的二氢叶酸还原酶来抑制DNA的合成、修复和/或复制,从而在S期表现出细胞期效应。氨甲蝶呤在治疗绒毛膜癌、脑膜白血病、非霍奇金淋巴瘤以及乳腺癌、头癌、颈癌、卵巢癌和膀胱癌时,被指定为单一药剂或与其他化疗剂组合使用。骨髓抑制(白细胞减少、血小板减少、和贫血)和黏膜炎是氨甲蝶呤施用的预期副作用。
喜树碱(包括喜树碱和喜树碱衍生物)作为拓扑异构酶I抑制剂获得或正在开发中。喜树碱的细胞毒性活性被认为与其拓扑异构酶I抑制活性有关。喜树碱的实例包括但不限于伊立替康、拓扑替康、以及以下描述的7-(4-甲基哌嗪代-亚甲基)-10,11-亚乙基二氧基-20-喜树碱的各种光学形式。
伊立替康HCl((4S)-4,11-二乙基-4-羟基-9-[(4-哌啶代哌啶代)羧基氧]-1H-吡喃并[3’,4’,6,7]吲哚啉唑(indolizino)[1,2-b]喹啉-3,14(4H,12H)-二酮盐酸盐)作为可注射溶液是可商购的。
伊立替康是喜树碱的衍生物,它与它的活性代谢产物SN-38结合到拓扑异构酶I-DNA复合物中。据信,由于拓扑异构酶I:DNA:伊立替康或SN-38三元复合物与复制酶的相互作用所引起的不可修复的双链断裂而产生细胞毒性。伊立替康被指定用于治疗结肠或直肠的转移性癌症。伊立替康HCl的剂量限制副作用是骨髓抑制(包括中性粒细胞减少症)和GI作用(包括腹泻)。
拓扑替康HCl((S)-10-[(二甲基氨基)甲基]-4-乙基-4,9-二羟基-1H-吡喃并[3’,4’,6,7]吲哚啉唑[1,2-b]喹啉-3,14-(4H,12H)-二酮单盐酸盐)作为可注射溶液是可商购的。拓扑替康是喜树碱的衍生物,其结合拓扑异构酶I-DNA复合物并防止由拓扑异构酶I引起的单链断裂的再连接,以响应DNA分子的扭转应变。拓扑替康被指定用于卵巢癌和小细胞肺癌的转移性癌的二线治疗。拓扑替康HCl的剂量限制副作用是骨髓抑制,主要是中性粒细胞减少症。
同样令人感兴趣的是以下式A的喜树碱衍生物,包括外消旋混合物(R,S)形式以及R和S对映异构体:
通过化学名称“7-(4-甲基哌嗪代-亚甲基)-10,11-亚乙基二氧基-20(R,S)-喜树碱(外消旋混合物)或“7-(4-甲基哌嗪代-亚甲基)-10,11-亚乙基二氧基-20(R)-喜树碱(R对映异构体)或“7-(4-甲基哌嗪代-亚甲基)-10,11-亚乙基二氧基-20(S)-喜树碱(S对映异构体)已知。在以下中描述了此类化合物以及相关化合物,包括制备的方法,美国专利号6,063,923;5,342,947;5,559,235;和5,491,237。
激素和激素类似物是用于治疗癌症有用的化合物,其中一种或多种激素与癌症的生长和/或缺乏生长之间存在关系。可用于癌症治疗的激素和激素类似物的实例包括但不限于:肾上腺皮质类固醇(如强的松和泼尼松龙),其可用于治疗儿童中的恶性淋巴瘤和急性白血病;氨鲁米特和其他芳香化酶抑制剂,如阿那曲唑(anastrozole)、来曲唑(letrazole)、伏拉唑(vorazole)和依西美坦(exemestane),可用于治疗肾上腺皮质癌和激素依赖性乳腺癌(含有雌激素受体);孕激素(如甲地孕酮)可用于治疗激素依赖性乳腺癌和子宫内膜癌;雌激素、雄激素和抗雄激素,例如氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、醋酸环丙孕酮(cyproterone acetate)和5□-还原酶(如非那雄胺(finasteride)和度他雄胺(dutasteride)),可用于治疗前列腺癌和良性前列腺肥大;抗雌激素(如它莫西芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、吲哚昔芬(iodoxyfene))、以及选择性雌激素受体调节剂(SERMS)(如美国专利号5,681,835;5,877,219;和6,207,716中描述的那些)可用于治疗激素依赖性乳腺癌和其他易感癌症;和促性腺激素释放激素(GnRH)及其类似物,它们刺激亮氨酸激素(LH)和/或促卵泡激素(FSH)释放用于治疗前列腺癌,例如LHRH激动剂和拮抗剂,例如醋酸戈舍瑞林(goserelin acetate)和路普瑞德(luprolide)。
信号传导通路抑制剂是阻断或抑制引起细胞内变化的化学过程的抑制剂。如本文所用,这种改变是细胞增殖或分化。可用于本发明的信号转导抑制剂包括受体酪氨酸激酶、非受体酪氨酸激酶、SH2/SH3结构域阻断剂、丝氨酸/苏氨酸激酶、磷脂酰肌醇-3激酶、肌醇信号传导、和Ras癌基因的抑制剂。
若干种蛋白质酪氨酸激酶催化涉及细胞生长调节的各种蛋白质中特定酪氨酸残基的磷酸化。此类蛋白酪氨酸激酶可以广泛地分为受体或非受体激酶。
受体酪氨酸激酶是具有细胞外配体结合结构域、跨膜结构域、和酪氨酸激酶结构域的跨膜蛋白。受体酪氨酸激酶涉及细胞生长的调节,并通常称为生长因子受体。已经证明许多这些激酶的不适当或失控的活化(即异常的激酶生长因子受体活性,例如通过过度表达或突变),导致细胞失控的生长。因此,此类激酶的异常活性已经与恶性组织生长有关。因此,此类激酶的抑制剂可提供癌症治疗方法。生长因子受体包括例如表皮生长因子受体(EGFr)、血小板衍生的生长因子受体(PDGFr)、erbB2、erbB4、血管内皮生长因子受体(VEGFr)、具有免疫球蛋白样的酪氨酸激酶和表皮生长因子同源结构域(TIE-2)、胰岛素生长因子I(IGFI)受体、巨噬细胞集落刺激因子(cfms)、BTK、ckit、cmet、成纤维细胞生长因子(FGF)受体、Trk受体(TrkA、TrkB和TrkC)、肝配蛋(ephrin)(eph)受体、和RET原癌基因。若干种生长受体的抑制剂正在开发中,并包括配体拮抗剂、抗体、酪氨酸激酶抑制剂、和反义寡核苷酸。生长因子受体和抑制生长因子受体功能的药剂描述于例如Kath,John C.,Exp.Opin.Ther.Patents[治疗专利专家评论](2000)10(6):803-818;Shawver等人DDT第2卷,第2期1997年2月;和Lofts,F.J.等人,“Growth factor receptors as targets[生长因子受体作为靶标]”,New Molecular Targets for Cancer Chemotherapy[癌症化疗的新分子靶标],编辑Workman,Paul和Kerr,David,CRC出版社(CRC press)1994,伦敦。
不是生长因子受体激酶的酪氨酸激酶被称为非受体酪氨酸激酶。本发明中使用的非受体酪氨酸激酶是抗癌药物的靶标或潜在靶标,包括cSrc、Lck、Fyn、Yes、Jak、cAbl、FAK(Focal粘附激酶)、Brutons酪氨酸激酶和Bcr-Abl。此类非受体激酶和抑制非受体酪氨酸激酶功能的药剂描述于Sinh,S.和Corey,S.J.,(1999)Journal of Hematotherapy and StemCell Research[血液疗法和干细胞研究杂志]8(5):465-80;和Bolen,J.B.,Brugge,J.S.,(1997)Annual review of Immunology.[免疫学年度评论]15:371-404。
SH2/SH3结构域阻断剂是破坏各种酶或衔接蛋白(包括PI3-K p85亚基、Src家族激酶、衔接分子(Shc、Crk、Nck、Grb2)和Ras-GAP)中SH2或SH3域结合的药剂。SH2/SH3结构域作为抗癌药物的靶标已在Smithgall,T.E.(1995),Journal of Pharmacological andToxicological Methods.[药理和毒理学方法杂志]34(3)125-32中讨论。
丝氨酸/苏氨酸激酶的抑制剂(包括MAP激酶级联阻断剂,包括丝裂原或细胞外调节激酶(MEK)和细胞外调节激酶(ERK)的阻断剂);和蛋白激酶C家族成员阻断剂(包括PKC阻断剂(α、β、γ、ε、μ、λ、ι、ζ)。IkB激酶家族(IKKa、IKKb)、PKB家族激酶、akt激酶家族成员、PDK1和TGFβ受体激酶。此类丝氨酸/苏氨酸激酶及其抑制剂描述于Yamamoto,T.,Taya,S.,Kaibuchi,K.,(1999),Journal of Biochemistry.[生物化学杂志]126(5)799-803;Brodt,P,Samani,A.,和Navab,R.(2000),Biochemical Pharmacology[生化药理学],60.1101-1107;Massague,J.,Weis-Garcia,F.(1996)Cancer Surveys.[癌症调查]27:41-64;Philip,P.A.,和Harris,A.L.(1995),Cancer Treatment and Research.[癌症治疗与研究]78:3-27,Lackey,K.等人Bioorganic and Medicinal Chemistry Letters[生物有机和药物化学],(10),2000,223-226;美国专利号6,268,391;Pearce,L.R等人Nature ReviewsMolecular Cell Biology[自然综述分子细胞生物学](2010)11,9-22.和Martinez-lacaci,L.等人,Int.J.Cancer[国际癌症杂志](2000),88(1),44-52。
合适地,本发明的药物活性化合物与MEK抑制剂组合使用。合适地,N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基-2,4,7-三氧-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲酰胺、或者其药学上可接受的盐或溶剂化物在具有国际提交日期为2005年6月10日的国际申请号PCT/JP 2005/011082(其全部披露通过引用并入本文)中披露和要求保护。N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基-2,4,7-三氧-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲酰胺可以如国际申请号PCT/JP2005/011082中所述进行制备
合适地,本发明的药物活性化合物与Akt抑制剂组合使用。合适地,N-{(1S)-2-氨基-1-[(3-氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-噻吩甲酰胺或其药学上可接受的盐,其在具有国际提交日期为2008年2月7日的国际申请号PCT/US 2008/053269;国际公开号WO/2008/098104以及2008年8月14日的国际公开日期的(将其全部披露通过引用并入本文)中披露和要求保护。N-{(1S)-2-氨基-1-[(3-氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-噻吩甲酰胺是实例96的化合物,并且可以如国际申请号PCT/US 2008/053269中所述进行制备。合适地,N-{(1S)-2-氨基-1-[(3-氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-噻吩甲酰胺是以盐酸盐的形式。可以由本领域技术人员以国际提交日期为2010年1月28日的国际申请号PCT/US 2010/022323的描述来制备盐形式。
磷脂酰肌醇-3激酶家族成员的抑制剂(包括PI3-激酶、ATM、DNA-PK、和Ku的阻断剂)也可用于本发明。此类激酶在以下中讨论:Abraham,R.T.(1996),Current Opinion inImmunology.[免疫学新见]8(3)412-8;Canman,C.E.,Lim,D.S.(1998),Oncogene[癌基因]17(25)3301-3308;Jackson,S.P.(1997),International Journal of Biochemistry andCell Biology.[国际生物化学和细胞生物学杂志]29(7):935-8;和Zhong,H.等人,Cancerres[癌症研究],(2000)60(6),1541-1545。
本发明中还感兴趣的是肌醇信号传导抑制剂,例如磷脂酶C阻断剂和肌醇类似物。在Powis,G.,和Kozikowski A.,(1994)New Molecular Targets for CancerChemotherapy[癌症化疗的新分子靶标]编辑Paul Workman和David Kerr,CRC出版社(CRCpress)1994,伦敦,London中描述此类信号传导抑制剂。
信号传导通路抑制剂的另一组是Ras癌基因的抑制剂。此类抑制剂包括法呢基转移酶、香叶基-香叶基转移酶、和CAAX蛋白酶的抑制剂,以及反义寡核苷酸、核酶和免疫疗法。已经显示出此类抑制剂在含有野生型突变ras的细胞中阻断了ras的活化,从而起着抗增殖剂的作用。Ras癌基因抑制剂在以下中讨论:Scharovsky,O.G.,Rozados,V.R.,Gervasoni,S.I.Matar,P.(2000),Journal of Biomedical Science[生物医学科学杂志]7(4)292-8;Ashby,M.N.(1998),Current Opinion in Lipidology.[脂类学新见]9(2)99-102;和BioChim.Biophys.Acta[生物化学与生物物理学学报],(19899)1423(3):19-30。
如上所述,受体激酶配体结合的抗体拮抗剂也可以用作信号转导抑制剂。这组信号传导通路抑制剂包括使用针对受体酪氨酸激酶的细胞外配体结合结构域的人源化抗体。例如Imclone C225 EGFR特异性抗体(参见Green,M.C.等人,Monoclonal AntibodyTherapy for Solid Tumors[实体瘤的单克隆抗体疗法],Cancer Treat.Rev.[癌症疗法研究],(2000),26(4),269-286);erbB2抗体;和2CB VEGFR2特异性抗体(参见Brekken,R.A.等人,Selective Inhibition of VEGFR2 Activity by a monoclonalAnti-VEGF antibody blocks tumor growth in mice[单克隆抗VEGF抗体选择性抑制VEGFR2活性阻断小鼠肿瘤生长],Cancer Res.[癌症研究](2000)60,5117-5124)。
非受体激酶血管生成抑制剂也可用于本发明。上文关于信号转导抑制剂(两种受体均为受体酪氨酸激酶)讨论了与血管生成相关的VEGFR和TIE2的抑制剂。血管生成通常与erbB2/EGFR信号传导相关,因为已显示erbB2和EGFR的抑制剂可以抑制血管生成(主要是VEGF表达)。因此,非受体酪氨酸激酶抑制剂可以与本发明的化合物组合使用。例如,抗VEGF抗体不识别VEGFR(受体酪氨酸激酶),但与配体结合;整合蛋白的小分子抑制剂(αvβ3),将抑制血管生成;内皮抑素和血管抑制素(非RTK)也可以与所披露的化合物组合使用。
免疫治疗方案中使用的药剂也可以与具有式(I)的化合物组合使用。有许多产生免疫反应的免疫策略。这些策略通常在肿瘤疫苗的领域。通过使用小分子抑制剂共同抑制信号传导通路,可以大大提高免疫学方法的效力。在以下中发现针对erbB2/EGFR的免疫/肿瘤疫苗方法的讨论:Reilly RT等人(2000),Cancer Res.[癌症研究]60:3569-3576;以及Chen Y,Hu D,Eling DJ,Robbins J,和Kipps TJ.(1998),Cancer Res.[癌症研究]58:1965-1971。
促凋亡方案中使用的试剂(例如bcl-2反义寡核苷酸)也可以用于本发明的组合中。蛋白的Bcl-2家族的成员阻断细胞凋亡。因此,bcl-2的上调与化学抗性有关。研究表明,表皮生长因子(EGF)刺激bcl-2家族的抗凋亡成员(即mcl-1)。因此,设计为下调肿瘤中bcl-2表达的策略已证明具有临床益处,即Genta的G3139 bcl-2反义寡核苷酸。在以下中讨论了使用针对bcl-2的反义寡核苷酸策略的此类凋亡策略:Water JS等人(2000),J.Clin.Oncol.[临床肿瘤学杂志]18:1812-1823;和Kitada S等人(1994),AntisenseRes.Dev.[反义研究与开发]4:71-79。
细胞周期信号转导抑制剂抑制了涉及控制细胞周期的分子。称为细胞周期素依赖性激酶(CDK)的蛋白激酶家族及其与称为细胞周期素的蛋白家族的相互作用控制着整个真核细胞周期的进程。不同细胞周期素/CDK复合物的坐标活化和失活对于整个细胞周期的正常进展是必需的。细胞周期信号转导的若干种抑制剂正在开发中。例如,细胞周期素依赖性激酶的实例(包括CDK2、CDK4、和CDK6)、以及例如以下中描述的其的抑制剂:Rosania等人,Exp.Opin.Ther.Patents[治疗专利专家评论](2000)10(2):215-230。此外,p21 WAF1/CIP1已被描述为细胞周期素依赖性激酶(Cdk)的有效且通用的抑制剂(Ball等人,Progress inCell Cycle Res.[细胞周期研究进展],3:125(1997))。已知诱导p21 WAF1/CIP1表达的化合物与细胞增殖的抑制有关,并具有肿瘤抑制活性(Richon等人,Proc.NatAcad.Sci.U.S.A.[美国国家科学院院刊]97(18):10014-10019(2000)),并作为细胞周期信号传导抑制剂包括在内。组蛋白脱乙酰基酶(HDAC)抑制剂与p21 WAF1/CIP1的转录活化有关(Vigushin等人,Anticancer Drugs[抗癌药物],13(1):1-13(2002年1月)),并且是适用于本文的细胞周期信号传导抑制剂。
此类HDAC抑制剂的实例包括:
1.伏立诺他(vorinostat),包括其药学上可接受的盐。Marks等人,NatureBiotechnology[自然生物技术]25,84至90(2007);Stenger,Community Oncology[社区肿瘤]4,384-386(2007)。
伏立诺他具有以下化学结构和名称:
2.罗米地辛(romidepsin),包括其药学上可接受的盐。Vinodhkumar等人,Biomedicine&Pharmacotherapy[生物医学和药物治疗]62(2008)85-93。
罗米地辛具有以下化学结构和名称:
(1S,4S,7Z,10S,16E,21R)-7-亚乙基-4,21-二(丙-2-基)-2-氧杂-12,13-二硫-5,8,20,23-四氮杂二环[8.7.6]二十三(tricos)-16-烯-3,6,9,19,22-戊酮
3.帕比司他(panobinostat),包括其药学上可接受的盐。Drugs of the Future[药物的未来]32(4):315-322(2007)。
帕比司他具有以下化学结构和名称:
(2E)-N-羟基-3-[4-({[2-(2-甲基-1H-吲哚-3-基)乙基]氨基}甲基)苯基]丙烯酰胺
4.丙戊酸(valproic acid),包括其药学上可接受的盐。Gottlicher,等人,EMBOJ.[欧洲分子生物学学会杂志]20(24):6969-6978(2001)。
丙戊酸具有以下化学结构和名称:
5.莫诺司他(mocetinostat)(MGCD0103),包括其药学上可接受的盐。Balasubramanian等人,Cancer Letters[癌症快报]280:211-221(2009)。
莫诺司他具有以下化学结构和名称:
N-(2-氨基苯基)-4-[[(4-吡啶-3-基嘧啶-2-基)氨基]甲基]苯甲酰胺
此类HDAC抑制剂的另外的实例包括在Bertrand European Journal ofMedicinal Chemistry[伯特兰欧洲药物化学杂志]45,(2010)2095-2116中,特别是如下所示的下表中的化合物。
蛋白酶体抑制剂是阻断蛋白酶体作用的药物、破坏蛋白质(例如p53蛋白)的细胞复合物。若干种蛋白酶体抑制剂已上市销售或正在研究中以治疗癌症。适用于本文的蛋白酶体抑制剂包括:
1.硼替佐米(bortezomib)包括其药学上可接受的盐。Adams J,Kauffman M(2004),Cancer Invest[癌症调查]22(2):304-11。
硼替佐米具有以下化学结构和名称:
[(1R)-3-甲基-1-({(2S)-3-苯基-2-[(吡嗪-2-基羰基)氨基]丙酰基}氨基)丁基]硼酸
2.双硫仑(Disulfiram),包括其药学上可接受的盐。
Bouma等人(1998).J.Antimicrob.Chemother.[抗微生物化学疗法杂志]42(6):817-20。
双硫仑具有以下化学结构和名称:
1,1’,1”,1”’-[二硫烷二基双(羰硫基硝基)]四乙烷(1,1’,1”,1”’-[disulfanediylbis(carbonothioylnitrilo)]tetraethane)
3.表没食子儿茶素没食子酸酯(epigallocatechin gallate,EGCG),包括其药学上可接受的盐。Williamson等人,(2006年12月),The Journal of Allergy and ClinicalImmunology[过敏与临床免疫学杂志]118(6):1369-74。
表没食子儿茶素没食子酸酯具有以下化学结构和名称:
[(2R,3R)-5,7-二羟基-2-(3,4,5-三羟基苯基)色满-3-基]3,4,5-三羟基苯甲酸酯
4.盐孢菌酰胺A(salinosporamide A),包括其药学上可接受的盐。Feling等人,(2003),Angew.Chem.Int.Ed.Engl.[应用化学英文国际版]42(3):355-7。
盐孢菌酰胺A具有以下化学结构和名称:
(4R,5S)-4-(2-氯乙基)-1-((1S)-环己-2-烯基(羟基)甲基)-5-甲基-6-氧杂-2-氮杂二环3.2.0庚烷-3,7-二酮
癌症新陈代谢的抑制剂-许多肿瘤细胞显示出与正常组织明显不同的新陈代谢。例如,增加了糖酵解(即将葡萄糖转化为丙酮酸的代谢过程)的速度,并且将生成的丙酮酸还原为乳酸,而不是通过三羧酸(TCA)循环在线粒体中进一步氧化。即使在有氧条件下也经常看到这种效应,并且被称为沃堡效应(Warburg Effect)。
乳酸脱氢酶A(LDH-A)(在肌肉细胞中表达的乳酸脱氢酶的同种型)通过将丙酮酸还原为乳酸盐而在肿瘤细胞代谢中起关键作用,其然后可以将丙酮酸脱氢酶输出到细胞外。该酶已显示在许多肿瘤类型中上调。沃堡效应中描述的葡萄糖代谢的改变对于癌细胞的生长和增殖至关重要,并且使用RNA-i敲低LDH-A已显示导致异种移植模型中细胞增殖和肿瘤生长的减少。
D.A.Tennant等人,Nature Reviews[自然综述],2010,267。
P.Leder,等人,Cancer Cell[癌细胞],2006,9,425。
癌症新陈代谢的抑制剂(包括LDH-A的抑制剂)适合与本发明的配制品组合使用。
根据本发明的合适的填充剂包括但不限于磷酸钙(例如,二盐基和三盐基、水合或无水)、硫酸钙、碳酸钙、碳酸镁,高岭土、喷雾干燥的或无水乳糖、纤维素(例如微晶纤维素、粉末的纤维素)、预胶化的淀粉、淀粉、乳糖醇、甘露醇、山梨醇、麦芽糖糊精、粉末的糖、可压缩糖、蔗糖、右旋糖和肌醇。含水很少或不含水的填充剂适用于本发明的片剂。在本发明的一个实施例中,填充剂包括甘露醇和微晶纤维素中的一种或两种。
根据本发明的合适的助流剂包括但不限于二氧化硅;二氧化硅胶体,例如,无水二氧化硅胶体,例如,和滑石粉,例如Luzenac在本发明的一个实施例中,助流剂是二氧化硅胶体。
根据本发明的合适的润滑剂包括但不限于硬脂酸镁(Mg)、硬脂酸铝(Al)或硬脂酸钙(Ca)、PEG 4000-8000、苯甲酸钠、甘油单脂肪酸(例如具有从200至800道尔顿的分子量,例如甘油单硬脂酸酯(例如英国丹尼斯克公司(Danisco))、二山嵛酸甘油酯(glyceryldibehenate)(例如CompritolAT0888TM,法国Gattefossé)、棕榈硬脂酸甘油酯(例如PrecirolTM,法国Gattefosse)、聚乙二醇(PEG,BASF)、氢化棉籽油(Lubitrab,爱德华门德尔公司(Edward Mendell Co Inc.))、蓖麻籽油(Cutina HR,汉高公司(Henkel))。在本发明的一个实施例中,润滑剂是硬脂酸镁。
根据本发明,填充剂的量可以在基于分散片的总重量的按重量计从约35%至70%、特别地约65%的范围内变化。崩解剂的量可以在基于分散片的总重量的按重量计从约2.5%至13%、特别地从约5%至10%的范围内变化。羟丙甲纤维素的量可以在基于分散片的总重量的按重量计从约1%至13%、特别地从约5%至10%的范围内变化。助流剂的量可以在基于分散片的总重量的按重量计从约0.1%至2.5%、特别地从约0.1%至0.5%的范围内变化。润滑剂的量可以在基于分散片的总重量的按重量计从约0.1%至2%、优选地从约0.1%至1.5%的范围内变化。
在本发明的一个实施例中,分散片包含以下药学上可接受的赋形剂:一种或多种填充剂以基于分散片的总重量的按重量计约65%的总量、羟丙甲纤维素以基于分散片的总重量的按重量计约5%至10%的总量、一种或多种崩解剂以基于分散片的总重量的按重量计约5%至10%的总量、一种或多种助流剂以基于分散片的总重量的按重量计约0.1%至0.5%的总量、和/或一种或多种润滑剂以基于分散片的总重量的按重量计从约0.1%至1.5%的总量。
根据本发明,制备分散片的方法包括内相制粒,将其与一种或多种药学上可接受的赋形剂混合在一起并压制所获得的混合物。
内相包含化合物A。优选地,内相包含化合物A和一种或多种药学上可接受的赋形剂。优选地,内相的药学上可接受的赋形剂是一种或多种填充剂、一种或多种崩解剂、羟丙甲纤维素、和一种或多种助流剂。优选地,基于分散片的总重量,内相中的一种或多种填充剂的量是按重量计从约5%至30%、更优选地从约10%至25%范围、以及最优选地约20%。根据本发明的填充剂优选地是甘露醇和微晶纤维素。崩解剂优选地是交聚维酮。基于分散片的总重量,内相中存在的崩解剂的量按重量计优选地小于10%、更优选地小于7%。基于分散片的总重量,内相中存在的羟丙甲纤维素的量按重量计优选地小于10%、更优选地小于3%。优选的助流剂是二氧化硅胶体。基于分散片的总重量,内相中存在的助流剂的量按重量计优选地从约0.1%至1%范围、优选地小于0.5%。
在搅拌机中,将化合物A和羟丙甲纤维素、一种或多种填充剂、一种或多种崩解剂、和一种或多种助流剂混合在一起。用硬脂酸镁润滑后,将混合物进行干法制粒,例如使用辊压和研磨机。
外相包含一种或多种药学上可接受的赋形剂,并使用例如扩散混合器与内相混合。优选地,添加羟丙甲纤维素、一种或多种填充剂、和一种或多种崩解剂。最优选地,将甘露醇和微晶纤维素作为填充剂添加至外相中。甚至优选地,将甘露醇以基于分散片的总重量的按重量计约12%至45%的范围添加至外相,并且将微晶纤维素以基于分散片的总重量的按重量计约8%至20%添加至外相。最优选地,交联聚维酮作为崩解剂添加至外相中。甚至优选地,将交联聚维酮以基于分散片的总重量的按重量计约1%至5%、更优选地小于5%的范围添加至外相中。
使用例如扩散混合器将包含羟丙甲纤维素、一种或多种填充剂、和一种或多种崩解剂的外相与来自内相的颗粒混合在一起。用硬脂酸镁润滑后,使用合适的旋转压力机将最终混合物压制成分散片。
在本发明的一个实施例中,制备分散片的方法包括
(a)形成内相包括
(i)将化合物A与药学上可接受的赋形剂混合,
(ii)干法制粒,
(b)形成外相包括
(i)向内相中添加另外的药学上可接受的赋形剂并混合;
(c)通过以下方式形成分散片:
(i)压制步骤b(i)中获得的混合物。
更具体地,在一个方面,本发明提供了方法,该方法包括:
(i)在扩散混合器中,将化合物A、羟丙甲纤维素和药学上可接受的赋形剂(例如,一种或多种填充剂,例如,甘露醇和微晶纤维素)与一种或多种崩解剂(例如,交聚维酮)、和一种或多种助流剂(例如,二氧化硅胶体)混合;
(ii)向混合物中添加一种或多种润滑剂(例如,硬脂酸镁),将混合物进行干法制粒,例如使用辊压和研磨机;
(iii)添加羟丙甲纤维素和药学上可接受的赋形剂,例如,筛分的赋形剂,如一种或多种填充剂(例如,甘露醇和微晶纤维素)、一种或多种崩解剂(例如,交联聚维酮),并混合(例如,在扩散混合器中);
(iv)用硬脂酸镁润滑混合物;
(v)通过压制将步骤(iv)中获得的混合物压片,例如在常规压片机中,优选在旋转机器中。
通过“内相”意指颗粒相(步骤(i)和(ii)),所述颗粒相包括活性成分化合物A和一种或多种药学上可接受的赋形剂。
通过“外相”意指添加至内相(颗粒)一种或多种药学上可接受的赋形剂(步骤(iii)和(iv))。
通过“分散片的总重量”意指为内相和外相的片剂的重量。
能以任何常规方式测试物理和化学稳定性,例如,可通过测量溶解度、脆性、崩解时间、分散液的细度、化合物A的测定、降解产物和外观等来测试分散片,例如在室温(即25℃/60%RH)和/或在40℃/75%RH的下储存后。
分散片的形状可以变化,并且可以是例如圆形、椭圆形、长方形、圆柱形或任何其他合适的形状。在本发明的实施例中,通过上述压制方法获得的分散片是圆形或椭圆形的。分散片的边缘可以是有斜面的或圆形的并且可以划痕。最优选地,分散片是具有双凸斜面边缘的圆形。
在本发明的实施例中,分散片包含从10mg至25mg剂量的化合物A作为活性成分、优选地10mg剂量的化合物A作为活性成分。
根据本发明的分散片优选地是圆形的、具有斜边的双凸面。分散片具有在5mm与10mm之间、优选地5mm与7mm之间范围、以及更优选地6mm的直径。
根据本公开的片剂的硬度或抗压碎性可以通过标准测试来确定。片剂硬度优选地根据欧洲药典2.9.8中指定的标准测试来确定。可以使用如3S片剂测试装置的装置。此测试确定了片剂的抗压碎性,通过压碎其所需的力来衡量。
包含约10mg剂量的化合物A作为活性部分的本发明的散片可以进一步具有从约25至75N、优选地不超过55N的平均值的硬度。
发现包含化合物A、约5%至10%w/w交聚维酮、约5%至10%w/w羟丙甲纤维素(其中,羟丙甲纤维素具有在4mPa s至6mPa s之间、优选地5mPa s的标称黏度(如在水中在20℃对于2%按重量计测量的),以及28%至30%甲氧基取代,或在80mPa s至120mPa s之间、优选地100mPa s的黏度(如在水中在20℃对于2%按重量计测量的),以及19%至24%甲氧基取代)、和填充剂(约2.5:1至2:1的重量比存在的甘露醇和微晶纤维素)的配制品可以用于产生分散片,所述分散片具有低的脆性值和短的崩解时间,这符合欧洲药典规范。
本发明的分散片还可以被着色和/或标记,以赋予个人外观并使其立即被识别。染料或色淀颜料(lake pigment)的使用可以改善外观并鉴定分散片。可以使用压印代码标记本发明的分散片。
本发明的分散片可用于治疗BRAF-突变阳性实体瘤。
本发明的分散片的活性和特征可以在标准临床试验和/或动物试验中指出。
此外,获得的本发明的分散片在生产过程中和在储存期间均是稳定的,例如在常规包装例如密封铝泡罩包装中保存2年或甚至3年。如常规测试中所确定的,在这段时间内,小于约5%(例如,2%或3%或更少的)化合物A作为活性成分可以降解。例如,在HDPE装满的瓶子或泡罩中,小于1%的化合物A作为活性成分会在一年内降解。
本发明还涉及以分散片的形式向需要这种治疗的哺乳动物,优选人受试者施用化合物A的方法。本发明还涉及以分散片形式的化合物A在治疗哺乳动物(优选人受试者)中用于上述疾病或病症之一的用途。本发明尤其涉及这样的方法,其中向患者施用每日剂量为4.5mg/kg至5.25mg/kg的体重/天的化合物A作为活性成分。应当理解,任何特定患者的特定剂量水平将取决于多种因素,这些因素包括年龄、体重、总体健康、与一种或多种活性药物的药物组合、疾病的类型和严重性。
该药物包装包含根据本发明的分散片和指示一种或多种化合物A的分散片的口服施用的印刷说明。
在本发明的另一个实施例中,提供了化合物A的分散片,其用于疗法中。
在另一方面,本发明提供了向需要这种治疗的患者施用本发明的药物组合物的方法,所述方法包括(i)将所述组合物与水性介质组合、(ii)使所述组合物分散在水性介质中以形成分散体、和(iii)摄取分散体。
实例
如本文所用,这些方法、方案和实例中使用的符号和惯例与当代科学文献(例如Journal of the American Chemical Society[美国化学学会杂志]或Journal ofBiological Chemistry[生物化学杂志]中使用的那些符号和惯例一致。除非另有说明,否则所有温度均以℃(摄氏度)表示。
实例1
表1-分散片组合物的实例
如表1所示,化合物A的分散片提供了快速分散的组合物,其在100次翻转后具有不超过3分钟的崩解时间和小于0.5%的低脆性。已经测试了各种交聚维酮与羟丙甲纤维素的比例。具有较低黏度羟丙甲纤维素等级的配制品导致更长的崩解时间。具有相同羟丙甲纤维素水平(7.5%w/w)和交聚维酮水平(7.5%w/w)但是就标称黏度而言不同羟丙甲纤维素等级和甲氧基取代的配制品(形式2a和形式5a)导致崩解时间更短于更高黏度羟丙甲纤维素等级配制品(形式5a)。具有更低羟丙甲纤维素水平(5%w/w)和更高交聚维酮水平(10%w/w)的配制品表现出相似的崩解时间(NMT 1min),与使用的羟丙甲纤维素等级的黏度和甲氧基取代百分比(形式1a和形式4a)无关。当化合物A的分散片配制品中使用更高羟丙甲纤维素水平时,羟丙甲纤维素标称黏度对崩解时间的影响显得更明显。
实例2
碾压,制备包含化合物A和表1中的成分的片剂。
表2a-颗粒内和颗粒外分散片组成
表2b-颗粒内和颗粒外分散片组成
制造片剂的方法
共混-筛分-共混
制备片剂内相的组分用于碾压。在适当大小的共混机中将化合物A、微晶纤维素、乙酰磺胺酸钾、交聚维酮、二氧化硅胶体、调味剂、羟丙甲纤维素、和甘露醇混合,并共混。将共混的材料在合适尺寸的筛子中进行筛分,然后转移到合适尺寸的共混机中并进行共混。
在合适尺寸的筛子中筛分硬脂酸镁,然后将其转移到含有共混材料的合适尺寸的搅拌机中,然后再共混另外的时间
碾压和研磨
使用碾压机将润滑的共混物干燥成粒。使压实的带穿过筛网以产生合适尺寸的颗粒。
共混-筛分-共混
制备片剂外相的组分用于压片。在适当大小的共混机中混合另外量的微晶纤维素、甘露醇、羟丙甲纤维素和交聚维酮,并共混。在合适尺寸的筛子中筛分混合的材料,并将其与内相的颗粒一起转移到合适尺寸的混合器中并进行混合。将共混物混合以结合内相和外相材料。
在合适尺寸的筛子中筛分硬脂酸镁,然后将其转移到含有共混材料的合适尺寸的搅拌机中,然后再共混另外的时间
压制
将润滑的共混物在配有6mm圆角、斜边工具的旋转压片机上压制至目标重量80mg,并制备10mg分散片。对压制的片剂取样以进行过程中的单个重量变化,外观、硬度、厚度、脆性、和崩解时间的监测。
将片剂装入含有干燥剂的HDPE容器中,或装在装有10片片剂的泡罩(PVC/PVDC,背面涂有可热封的漆铝箔)中。
实例3
10mg分散片的特性
尽管上面通过举例说明了本发明的优选实施例,但是应该理解,本发明不限于本文披露的精确说明,并且保留在所附权利要求的范围内的所有修改的权利。
Claims (16)
1.一种分散片,所述分散片包含内相和外相,
其中所述内相由内相成分组成,所述内相成分包含(a)基于片剂的总重量的按重量计从5%至40%的量的N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸盐、(b)羟丙甲纤维素、(c)甘露醇和微晶纤维素和(d)交聚维酮;
其中所述外相由外相成分组成,所述外相成分包含(b)羟丙甲纤维素、(c)甘露醇和微晶纤维素和(d)交聚维酮;
其中所述分散片包含基于片剂的总重量的按重量计1%至13%的量的羟丙甲纤维素;基于片剂的总重量的按重量计2.5%至13%的交聚维酮;和基于片剂的总重量的按重量计35%至70%的量的甘露醇和微晶纤维素,
其中甘露醇和微晶纤维素以按重量计2.5:1至2:1的重量比存在,
其中根据欧洲药典2.9.1,在水中在15℃至25℃片剂的崩解时间的崩解测试测量的,所述片剂具有3分钟或更少的崩解时间。
2.根据权利要求1所述的分散片,其中羟丙甲纤维素以基于片剂的总重量的按重量计5%至10%存在。
3.根据权利要求2所述的分散片,其中在20℃对于2%重量水溶液、以及28%至30%甲氧基取代的测试条件下测量,羟丙甲纤维素具有在4mPa s至6mPa s之间的标称黏度。
4.根据权利要求3所述的分散片,其中在20℃对于2%重量水溶液、以及28%至30%甲氧基取代的测试条件下测量,羟丙甲纤维素具有在80mPa s至120mPa s之间的黏度。
5.根据权利要求1所述的分散片,其中根据欧洲药典2.9.8的片剂的抗压碎性测试,所述片剂具有平均值不超过55N的硬度。
6.根据权利要求1所述的分散片,其还包含:
(i)基于片剂的总重量的按重量计0.1%至2%的总量的作为内相和外相成分的至少一种润滑剂,以及
(ii)基于片剂的总重量的按重量计0.1%至2.5%的总量的作为内相成分的至少一种助流剂。
7.根据权利要求1所述的分散片,其中交聚维酮以基于片剂的总重量的按重量计5%至10%存在。
8.根据权利要求6至7中任一项所述的分散片,其中所述助流剂是二氧化硅胶体。
9.根据权利要求6至7中任一项所述的分散片,其中所述润滑剂是硬脂酸镁。
10.根据权利要求8所述的分散片,其中所述润滑剂是硬脂酸镁。
11.根据权利要求1所述的分散片在制备用于治疗具有BRAF V600E或V600K突变的实体瘤的药物中的用途。
12.根据权利要求11所述的分散片在制备用于治疗实体瘤的药物中的用途,其中所述实体瘤是黑素瘤、非小细胞肺癌或甲状腺癌。
13.一种制备根据权利要求1至10所述的分散片的方法,所述方法包括
(i)将内相成分混合;
(ii)对(i)中获得的混合物进行制粒;
(iii)将(ii)中获得的颗粒与外相成分混合以形成混合物;以及
(iv)压制步骤(iii)中获得的混合物以形成片剂。
14.根据权利要求13所述的方法,其中所述制粒步骤(ii)是干法制粒。
15.根据权利要求14所述的方法,其中干法制粒是用制粒机进行碾压。
16.一种分散片,其包含内部相和外部相,其中
(a)所述内部相包含
(i)N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸盐;
(ii)微晶纤维素;
(iii)甘露醇;
(iv)羟丙甲纤维素;
(v)乙酰磺胺酸钾;
(vi)交聚维酮;
(vii)二氧化硅胶体;
(viii)硬脂酸镁;和
(b)所述外部相包含
(i)微晶纤维素;
(ii)甘露醇;
(iii)羟丙甲纤维素;
(iv)交聚维酮;
(v)硬脂酸镁;且
其中
(a)N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸盐以基于片剂的总重量的按重量计从5%至40%的量存在,(b)羟丙甲纤维素以基于片剂的总重量的按重量计1%至13%的量存在,和(c)甘露醇和微晶纤维素以基于片剂的总重量的按重量计35%至70%的量存在,其中甘露醇和微晶纤维素以按重量计2.5:1至2:1的重量比存在。
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JP (1) | JP2019529343A (zh) |
KR (1) | KR20200024890A (zh) |
CN (1) | CN110831582B (zh) |
AU (3) | AU2018297656B2 (zh) |
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WO2022076563A1 (en) * | 2020-10-07 | 2022-04-14 | University Of Florida Research Foundation, Incorporated | Macrocyclic compounds and methods of treatment |
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- 2018-06-29 KR KR1020207003033A patent/KR20200024890A/ko not_active IP Right Cessation
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US11504333B2 (en) | 2022-11-22 |
AU2021221451B2 (en) | 2023-08-17 |
AU2021221451A1 (en) | 2021-09-16 |
CN110831582A (zh) | 2020-02-21 |
KR20200024890A (ko) | 2020-03-09 |
US20200121607A1 (en) | 2020-04-23 |
WO2019008487A1 (en) | 2019-01-10 |
JP2019529343A (ja) | 2019-10-17 |
EP3648744A1 (en) | 2020-05-13 |
US20230105887A1 (en) | 2023-04-06 |
CA3068936A1 (en) | 2019-01-10 |
RU2020104742A (ru) | 2021-08-05 |
RU2020104742A3 (zh) | 2021-11-15 |
AU2018297656A1 (en) | 2020-01-16 |
AU2023266278A1 (en) | 2023-12-07 |
AU2018297656B2 (en) | 2021-09-16 |
IL271513A (en) | 2020-02-27 |
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