CN101048140B - 用于治疗癌症的药物组合物 - Google Patents
用于治疗癌症的药物组合物 Download PDFInfo
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- CN101048140B CN101048140B CN2005800369528A CN200580036952A CN101048140B CN 101048140 B CN101048140 B CN 101048140B CN 2005800369528 A CN2005800369528 A CN 2005800369528A CN 200580036952 A CN200580036952 A CN 200580036952A CN 101048140 B CN101048140 B CN 101048140B
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Abstract
Description
本申请要求2004年8月27日提交的美国临时申请60/604,753的申请日利益，该申请引入本文作为参考。
发明领域
本发明涉及新药物组合物、制备这些新药物组合物的方法和它们作为单一药剂(agent)或与其它治疗组合用于治疗过度增生性疾病如癌症的用途。
发明背景
二芳基脲为本领域已知的一类丝氨酸-苏氨酸激酶抑制剂和酪氨酸激酶抑制剂。下述出版物阐述了它们在用于治疗过度增生性疾病如癌症的药物组合物中作为活性成分的用途：
Smith等人，Bioorg.Med.Chem.Lett.2001，11，2775-2778.
Lowinger等人，Clin.Cancer Res.2000，6(suppl.)，335.
Lyons等人，Endocr.-Relat.Cancer 2001，8，219-225.
Riedl等人，Book of Abstracts，92nd AACR Meeting，New Orleans，LA，USA，abstract 4956.
Khire等人，Book of Abstracts，93rd AACR Meeting，San Francisco，CA，USA，abstract 4211.
Lowinger等人，Curr.Pharm.Design 2002，8，99-110.
Carter等人，Book of Abstracts，92nd AACR Meeting，New Orleans，LA，USA，abstract 4954.
Vincent等人，Book of Abstracts，38th ASCO Meeting，Orlando，FL，USA，abstract 1900.
Hilger等人，Book of Abstracts，38th ASCO Meeting，Orlando，FL，USA，abstract 1916.
Moore等人，Book of Abstracts，38th ASCO Meeting，Orlando，FL，USA，
Strumberg等人，Book of Abstracts，38th ASCO Meeting，Orlando，FL，USA，abstract 121.
在以下文献中公开了ω-羧基芳基二苯基脲类：WO00/42012(2000年7月20日公布)、WO00/41698(2000年7月20日公布)和下述公布的美国申请：
US2002-0165394-A1，2002年11月7日公布，
US2001-003447-A1，2001年10月25日公布，
US2001-0016659-A1，2001年8月23日公布，
US2002-013774-A1，2002年9月26日公布，
以及共同在审美国申请：
09/758,547，2001年1月12日提交，
09/889,227，2001年7月12日提交，
09/993,647，2001年11月27日提交，
10/042,203，2002年1月11日提交，和
10/071,248，2002年2月11日提交。
特别地，已经发现式I的二苯基脲，也称为“BAY 43-9006”或4{4-[3-(4-氯-3-三氟甲基苯基)-脲基]-苯氧基}-吡啶-2-羧酸甲基酰胺，是raf、VEGFR-2、p38和PDGFR激酶的有效抑制剂。这些酶都是对治疗包括癌症在内的过度增生性疾病而言重要的分子靶。因此，式I化合物将用作治疗上述疾病的药物。
优选的给药途径是通过口腔。这一途径提供给药的最大舒适性和便利性。口服给药后获得的生物利用度是药物的口服剂型可能有效性的量度。口服施用后的生物利用度取决于几个因素，如活性物质在水性介质中的溶解度、剂量强度、所述剂型的溶出度、整个胃肠道的吸收和首过效应。
因此，期望的用于口服施用的包含式I化合物的固体药物组合物是这样的，其导致在哺乳动物中改善的溶出、吸收和暴露(exposure)、改善的患者间变异性和全面改善的临床功效。
发明内容
本发明提供包含以下式I化合物的固体分散体的药物组合物。
式I如下：
术语“式I化合物”或“本发明的化合物”不仅指如在式I中描述的4{4-[3-(4-氯-3-三氟甲基苯基)-脲基]-苯氧基}-吡啶-2-羧酸甲基酰胺，也指其溶剂化物、水合物、药学可接受的盐或其组合。
本发明涉及
(i)固体分散体形式的包含式I化合物的新药物组合物，所述固体分散体包括固体溶液、玻璃溶液、玻璃悬浮液、结晶载体中的无定形沉淀、低共熔混合物或偏晶(monotecics)、混合或复合形成物及其组合。
(ii)用于制备这些新药物组合物的方法，和
(iii)这些组合物作为单一药剂或与其它抗癌治疗组合用于治疗过度增生性疾病如癌症的用途。
在下文中，不同类型的固体分散体(固体溶液、玻璃溶液、玻璃悬浮液、结晶载体中的无定形沉淀、低共熔混合物或偏晶、混合或复合形成物及其组合)总称为“固体分散体”。
本发明的药物组合物包含固体分散体，所述固体分散体至少包含式I化合物和药学可接受的基质。
如本文使用的术语“基质”或“基质剂”指能溶解或分散式I化合物的聚合赋形剂、非聚合赋形剂及其组合。
特别重要的本发明的方面为包含固体分散体的药物组合物，其中所述基质包含药学可接受的聚合物，如聚乙烯吡咯烷酮、乙烯基吡硌烷酮/乙酸乙烯酯共聚物、聚亚烷基二醇(即聚乙二醇)、羟烷基纤维素(即羟丙基纤维素)、羟烷基甲基纤维素(即羟丙基甲基纤维素)、羧甲基纤维素、羧甲基纤维素钠、乙基纤维素、聚甲基丙烯酸酯、聚乙烯醇、聚乙酸乙烯酯、乙烯 醇/乙酸乙烯酯共聚物、聚乙二醇化(polyglycolized)甘油酯、黄原胶、角叉菜胶、壳聚糖、壳多糖、聚糊精(polydextrin)、糊精、淀粉、蛋白质或其组合。
本发明的另一方面为包含固体分散体的药物组合物，其中所述基质包含糖和/或糖醇和/或环糊精，例如蔗糖、乳糖、果糖、麦芽糖、棉子糖、山梨糖醇、乳糖醇、甘露糖醇、麦芽糖醇、赤藓糖醇、肌醇、海藻糖、异麦芽糖醇(isomalt)、菊糖、糊精-麦芽糖复合剂、β-环糊精、羟丙基-β-环糊精、磺丁基醚环糊精或其组合。
特别重要的本发明的方面为包含固体分散体的药物组合物，所述固体分散体是式I化合物与聚乙烯吡咯烷酮的无定形共沉淀物。
可用于形成所述固体分散体的基质的其它适宜的赋形剂包括，但不限于醇、有机酸、有机碱、氨基酸、磷脂、蜡、盐、脂肪酸酯、聚氧乙烯脱水山梨醇脂肪酸酯和脲。
所述基质中式I化合物的固体分散体可包含某些另外的药学可接受的成分，如载体、表面活性剂、填充剂、崩解剂、重结晶抑制剂、增塑剂、消泡剂、抗氧剂、防粘剂、pH-调节剂、助流剂和润滑剂。
根据本发明的载体为赋形剂，在所述固体分散体的制备方法过程中，其装载至少包含基质剂和本发明的化合物的混合物，从而成为所述固体分散体的主要部分，所述制备方法例如热熔挤出、热熔融涂装、造粒、冻凝、溶剂蒸发法(例如分层、涂装、制粒)。
在本发明的实施方案中，所述基质包含水溶性聚合物。
在另一个实施方案中，将选自聚乙烯吡咯烷酮、共聚维酮(copovidone)、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇和聚环氧乙烷中的至少一种用做所述固体分散体中的基质剂。
在另一个实施方案中，将聚乙烯吡咯烷酮用作基质剂。
另一个实施方案包含作为基质剂的羟丙基纤维素。
特别重要的本发明的另一方面为包含作为载体或崩解剂的交联羧甲纤维素钠、淀粉乙醇酸钠、交聚维酮、低取代的羟丙基纤维素(L-HPC)、淀粉、微晶纤维素或其组合的固体分散体。
在实施方案中，所述固体分散体包含聚乙烯吡咯烷酮和交联羧甲纤维 素钠。
在另一个实施方案中，所述固体分散体包含聚乙烯吡咯烷酮和淀粉乙醇酸钠。
在另一个实施方案中，所述固体分散体包含聚乙烯吡咯烷酮、交联羧甲纤维素钠和微晶纤维素。
在另一个实施方案中，所述固体分散体包含羟丙基纤维素和交联羧甲纤维素钠。
在再一个实施方案中，所述固体分散体包含羟丙基纤维素和至少一种赋形剂，所述赋形剂为糖、糖醇、环糊精或其组合。
本发明的固体分散体根据本领域已知的制备固体分散体的方法制备，所述方法如熔合/熔融技术、热熔融涂装、造粒、冻凝、溶剂蒸发(例如冷冻干燥、喷雾干燥、真空干燥、粉末、颗粒或小丸的分层和流化床制粒)、共沉淀、超临界流体技术和静电纺丝法。
热熔挤出或溶剂蒸发技术为制备本发明的固体分散体制剂的适宜方法。
适于通过溶剂蒸发方法如喷雾干燥、分层和流化床制粒而制备固体分散体的溶剂可以为在其中式I化合物可被溶解的任意化合物。优选的溶剂包括醇(例如甲醇、乙醇、正丙醇、异丙醇和丁醇)、酮(例如丙酮、甲基乙基酮和甲基异丁基酮)、酯(例如乙酸乙酯和乙酸丙酯)和各种其它溶剂如乙腈、二氯甲烷、氯仿、己烷、甲苯、四氢呋喃、环醚和1，1，1-三氯乙烷。也可以使用较低挥发性溶剂，如二甲基乙酰胺或二甲亚砜。也可以使用溶剂混合物，也可以使用与水的混合物，只要药物和必要时基质剂能充分溶解以使所述方法可行。
特别重要的本发明的方面为其中式I化合物基本上为无定形的药物组合物。
特别重要的本发明的另一方面为式I化合物的固体分散体，其中所述基质为聚乙烯吡咯烷酮聚合物。
特别重要的本发明的另一方面为式I化合物的固体分散体，其中所述基质为羟丙基纤维素聚合物。
特别重要的本发明的另一方面为包含式I化合物与基质的共沉淀物的新药物组合物。
该药物组合物将通过口服给予有此需要的患者来使用以获得期望的药理学作用，并且就在哺乳动物内的药物释放、生物利用度和/或患者间变异而言，其比常规制剂有益。为了本发明的目的，患者为需要治疗特定病症或疾病包括预防性治疗的哺乳动物，包括人。
对于口服给药而言，本文描述的固体分散体可以配制成固体或液体制剂，如散剂、颗粒剂、小丸、片剂、胶囊剂、糖衣药丸、咀嚼片剂、分散片剂、糖锭、锭剂、熔体、溶液剂、混悬剂或乳剂，并可根据本领域已知的用于制备药物组合物的方法来制备。为此目的，所述固体分散体可以与常规赋形剂混合，所述赋形剂例如粘合剂、填充剂、润滑剂、崩解剂、溶剂、表面活性剂、增稠剂和稳定剂、包衣物质以及调味剂、甜味剂、调味剂和着色剂。
相信本领域技术人员利用前述信息可以最大程度地利用本发明。式I化合物的口服制剂指多种剂量，如每日给药1mg、10mg、100mg或者甚至1g和更多。这将通过例如调节所述片剂或胶囊剂的组成和大小，和/或通过每日给予有此需要的患者多个片剂或胶囊剂来实现。或者，所述固体分散体制剂也可以以诸如散剂、颗粒剂、咀嚼片剂或分散片剂的形式服用，或者例如如果最佳服药方案不再与可用片剂或胶囊剂大小一致，则可以通过在使用前将任意合适的固体制剂分散于适宜液体中来服用。
治疗过度增生性疾病的方法
本发明还涉及使用式I化合物的新口服药物组合物治疗包括癌症在内的哺乳动物过度增生性疾病的方法。这一方法包括给予有此需要的包括人在内的哺乳动物有效治疗所述疾病的量的固体分散体形式的药物组合物。术语“过度增生性疾病”和/或“癌症”不仅指实体瘤如乳腺、呼吸道、脑、生殖器官、消化道、泌尿道、眼、肝、皮肤、头和颈、甲状腺、甲状旁腺的癌症和它们的远端转移，也包括淋巴瘤、肉瘤和白血病。
乳癌的实例包括，但不限于浸润性导管癌、浸润性小叶癌、原位导管 癌和原位小叶癌。
呼吸道癌症的实例包括，但不限于小细胞和非小细胞肺癌及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的实例包括，但不限于脑干和hypophtalmic胶质瘤、小脑和大脑星形细胞瘤、髓母细胞瘤、室管膜瘤及神经外胚层瘤和松果体瘤。
雄性生殖器官肿瘤包括，但不限于前列腺癌和睾丸癌。雌性生殖器官肿瘤包括，但不限于子宫内膜癌、子宫颈癌、卵巢癌、阴道癌和外阴癌以及子宫肉瘤。
消化道肿瘤包括，但不限于肛门癌、结肠癌、结肠直肠癌、食管癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
泌尿道肿瘤包括，但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌和尿道癌。
眼部癌症包括，但不限于眼内黑素瘤和视网膜母细胞瘤。
肝癌的实例包括，但不限于肝细胞癌(有或没有纤维层变异的肝细胞癌)、胆管癌(肝内胆管癌)和混合肝细胞胆管癌。
皮肤癌包括，但不限于鳞状细胞癌、卡波西肉瘤、恶性黑色素瘤、梅克尔细胞皮肤癌和非黑素瘤皮肤癌。
头和颈癌包括，但不限于喉部/咽下部/鼻咽/口咽癌症，和唇及口腔癌症。
淋巴瘤包括，但不限于艾滋病相关性淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病和中枢神经系统淋巴瘤。
肉瘤包括，但不限于软组织肉瘤、纤维肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
白血病包括，但不限于急性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性髓性白血病和多毛细胞白血病。
这些疾病在人中已得到良好表征，也在其它哺乳动物中以类似的病因学存在，并可通过给予本发明的药物组合物来治疗。
使用本发明的药物组合物经由口服途径给予的活性成分(式I化合物)的总量通常为每天约0.01mg/kg至约50mg/kg体重。以已知评价用于治疗过 度增生性疾病的化合物的标准实验室技术为基础，通过标准毒性测试和通过确定治疗哺乳动物中上述病症的标准药理学测定法，并通过比较这些结果与治疗这些病症的已知药物的结果，本发明的药物组合物的有效剂量可容易地由本领域技术人员确定。所给予的活性成分的量可根据如下考虑因素在很大程度上改变：所采用的具体化合物和剂量单元、给药方式和时间、治疗期、所治疗的患者的年龄、性别和一般状况、所治疗的病症的性质和程度、药物代谢和排泄的速率、可能的药物组合和药物-药物相互作用等。
本发明的药物组合物可以作为单一药剂或与一种或多种其它治疗组合给予，其中所述组合不引起不能接受的副作用。例如，它们可以与细胞毒性药剂、信号转导抑制剂或与其它抗癌药剂或治疗以及其混合物及组合来组合。
在一个实施方案中，本发明的药物组合物可以与细胞毒性抗癌药剂组合。这些药剂的实例可见于默克索引(1996)第11版中。这些药剂包括，但决不限于门冬酰胺酶、博来霉素、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、左旋门冬酰胺酶、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、柔红霉素、多柔比星(阿霉素)、表柔比星、依托泊苷、5-氟尿嘧啶、六甲蜜胺、羟基脲、异环磷酰胺、依立替康、亚叶酸、环己亚硝脲、氮芥、6-巯嘌呤、巯乙磺酸钠、甲氨蝶呤、丝裂霉素C、米托蒽醌、泼尼松龙、泼尼松、甲基苄肼、雷洛昔芬、链脲霉素、他莫昔芬、硫鸟嘌呤、托泊替康、长春花碱、长春新碱和长春地辛。
适于与本发明的药物组合物一起使用的其它细胞毒性药物包括，但不限于在Goodman and Gilman′s The Pharmacological Basis of Therapeutics(第九版，1996，McGraw-Hill)中确认用于治疗肿瘤疾病的那些化合物。这些药剂包括，但决不限于氨鲁米特、L-天冬酰胺酶、硫唑嘌呤、5-氮杂胞苷、白消安、己烯雌酚、2′2′-二氟脱氧胞苷酸、多西他赛、erythrohydroxynonyladenine、乙炔雌二醇、5-氟尿嘧啶脱氧核苷、5-氟尿嘧啶脱氧核苷单磷酸酯、氟达拉滨磷酸酯、氟烃甲基睾丸素、氟他胺、己酸孕酮、伊达比星、干扰素、醋酸甲羟孕酮、醋酸甲地孕酮、苯丙氨酸氮芥、米托坦、紫杉醇、喷司他丁、N-膦酰乙酰基-L-天冬氨酸(PALA)、普卡霉 素、司莫司汀、表鬼臼毒噻吩糖苷、丙酸睾丸酮、塞替派、三甲蜜胺、尿核甙和长春瑞滨。
适于与本发明的组合物组合使用的其它细胞毒性抗癌药剂还包括新发现的细胞毒性成分，如奥沙利铂、吉西他滨、卡培他滨、埃坡霉素和其天然或合成的衍生物、替莫唑胺(Quinn等人，J.Clin.Oncology 2003，21(4)，646-651)、托西莫单抗(Bexxar)、trabedectin(Vidal等人，Proceedings of theAmerican Society for Clinical Oncology 2004，23，abstract 3181)和驱动蛋白纺锤体蛋白质Eg5的抑制剂(Wood等人，Curr.Opin.Pharmacol.2001，1，370-377)。
在另一个实施方案中，本发明的药物组合物可以与其它信号转导抑制剂组合。特别重要的为靶向于EGFR家族如EGFR、HER-2和HER-4(Raymond等人，Drugs 2000，60(Suppl.1)，15-23；Harari等人，Oncogene2000，19(53)，6102-6114)和它们各自的配体的信号转导抑制剂。这些药剂的实例包括，但决不限于抗体治疗剂如赫赛汀(曲妥单抗)、Erbitux(西妥昔单抗)和pertuzumab。这些治疗剂的实例还包括，但决不限于小分子激酶抑制剂如ZD-1839/Iressa(Baselga等人，Drugs 2000，6O(Suppl.1)，33-40)、OSI-774/Tarceva(Pollack等人，J.Pharm.Exp.Ther.1999，291(2)，739-748)、CI-1033(Bridges，Curr.Med.Chem.1999，6，825-843)、GW-2016(Lackey等人，92nd AACR Meeting，New Orleans，March 24-28，2001 abstract 4582)、CP-724，714(Jani等人，Proceedings of the American Society for ClinicalOncology 2004，23，abstract 3122)、HKI-272(Rabindran等人，Cancer Res.2004，64，3958-3965)和EKB-569(Greenberger等人,11th NCI-EORTC-AACRSymposium on New Drugs in Cancer Therapy，Amsterdam，November 7-10，2000，abstract 388)。
在另一个实施方案中，本发明的药物组合物可以与靶向于分裂激酶功能域(split-kinase domain)家族(VEGFR、FGFR、PDGFR、flt-3、c-kit、c-fms等)的受体激酶和它们各自的配体的其它信号转导抑制剂组合。这些药剂包括，但决不限于抗体如Avastin(贝伐单抗)。这些药剂还包括，但决不限于小分子抑制剂如STI-571/Gleevec(Zvelebil，Curr.Opin.Oncol.，Endocr. Metab.Invest.Drugs 2000，2(1)，74-82)、PTK-787(Wood等人，Cancer Res.2000，60(8)，2178-2189)、SU-11248(Demetri等人，Proceedings of theAmerican Society for Clinical Oncology 2004，23，abstract 3001)、ZD-6474(Hennequin等人，92nd AACR Meeting，New Orleans，March 24-28 2001，abstract 3152)、AG-13736(Herbst等人，Clin.Cancer Res.2003，9，16(suppl.1)，abstract C253)、KRN-951(Taguchi等人，95th AACR Meeting，Orlando，FL，2004，abstract 2575)、CP-547，632(Beebe等人，Cancer Res.2003，63，7301-7309)、CP-673，451(Roberts等人，Proceedings of the AmericanAssociation of Cancer Research 2004，45，abstract 3989)、CHIR-258(Lee等人，Proceedings of the American Association of Cancer Research 2004，45，abstract 2130)、MLN-518(Shen等人，Blood 2003，102，11，abstract 476)和AZD-2171(Hennequin等人，Proceedings of the American Association ofCancer Research 2004，45，abstract 4539)。
在另一个实施方案中，本发明的药物组合物可以与Raf/MEK/ERK转导途径(Avruch等人，Recent Prog.Horm.Res.2001，56，127-155)或PKB(akt)途径(Lawlor等人.J Cell Sci.2001，114，2903-2910)抑制剂组合。这些包括，但决不限于PD-325901(Sebolt-Leopold等人，Proceedings of the AmericanAssociation of Cancer Research 2004，45，abstract 4003)和ARRY-142886(Wallace等人，Proceedings of the American Association of Cancer Research2004，45，abstract 3891)。
在另一个实施方案中，本发明的药物组合物可以与组蛋白脱乙酰酶抑制剂组合。这些药剂的实例包括，但决不限于N-辛二酰苯胺(suberoylanilide)异羟肟酸(SAHA)、LAQ-824(Ottmann等人，Proceedings of the AmericanSociety for Clinical Oncology 2004，23，abstract 3024)、LBH-589(Beck等人，Proceedings of the American Society for Clinical Oncology 2004，23，abstract3025)、MS-275(Ryan等人，Proceedings of the American Association ofCancer Research 2004，45，abstract 2452)和FR-901228(Piekarz等人，Proceedings of the American Society for Clinical Oncology 2004，23，abstract3028)。
在另一个实施方案中，本发明的药物组合物可以与其它抗癌药剂如蛋白酶体抑制剂和m-TOR抑制剂组合。这些包括，但决不限于硼替佐米(bortezomib)(Mackay等人，Proceedings of the American Society for ClinicalOncology 2004，23，Abstract 3109)和CCI-779(Wu等人，Proceedings of theAmerican Association of Cancer Research 2004，45，abstract 3849)。
通常，细胞毒性和/或细胞抑制性抗癌药剂与本发明的药物组合物的组合应用将提供
(1)与单独给予任一药剂相比，在减少肿瘤生长或乃至消除肿瘤方面更好的功效，
(2)给予更少量的所给予的药剂，
(3)化学治疗方案，其具有良好的患者耐受性，且与用单一药剂化疗和某些其它组合治疗所观察到的相比，具有更少的有害药理学并发症，
(4)治疗哺乳动物尤其是人中更广谱的不同癌症类型，
(5)所治疗的患者中的较高响应速率，
(6)与标准化学治疗相比所治疗的患者更长的存活时间，
(7)更长的肿瘤发展时间，和/或
(8)与其中其它癌症药剂组合产生拮抗效应的已知情况相比，至少与单独使用所述药剂同样好的功效和耐受性(tolerability)结果。
相信本领域技术人员使用前述信息和本领域可获得的信息，可以最大程度地利用本发明。
对本领域技术人员应显而易见的是，在不背离如本文阐述的本发明的精神或范围的情况下，可以对本发明进行改变和修饰。
以上和以下引用的所有出版物、申请和专利均引入本文作为参考。
实施例1涉及在本发明中使用的化合物的制备。本发明的化合物的代表性固体分散体制剂描述于实施例2、3和4中。
实施例
实施例1：4{4-[3-(4-氯-3-三氟甲基苯基)-脲基]-苯氧基}-吡啶-2-羧酸甲基酰胺的制备
制备BAY43-9006(4{4-[3-(4-氯-3-三氟甲基苯基)-脲基]-苯氧基}-吡啶-2-羧酸甲基酰胺)的方法描述于Bankston等人，″A Scaleable Synthesis ofBAY 43-9006：A Potent Raf Kinase Inhibitor for the Treatment of Cancer″Org.Proc.Res.Dev.2002，6(6)，777-781中。
实施例2：实施例1的化合物与聚乙烯吡咯烷酮的1∶1、1∶2、1∶3、1∶4和1∶5固体分散体的制备
在开盖的小瓶中，分别将一份游离碱形式的实施例1的化合物与一、二、三、四或五份聚乙烯吡咯烷酮(PVP-25/Kollidon 25)混合。将混合物溶于足量的5∶1丙酮和乙醇混合物中，直到所有粉末都在溶液中。将开盖的小瓶放置在40℃的真空烘箱中，并使其干燥至少24小时。
如以下溶出曲线所示，比较了实施例2的药物组合物与实施例1的游离碱的体外溶出性质。
根据该数据可以设想，与常规制剂相比，口服给予固体分散体形式的本发明的化合物会在人中导致改善的吸收和生物利用度。
溶出曲线
本发明的化合物在各种量的聚乙烯吡咯烷酮(比率为1∶1至1∶5)中的固体分散体的体外溶出曲线
实施例3：实施例1的化合物与羟丙基纤维素的1∶3固体分散体的制备
在耐热容器中，将一份游离碱形式的实施例1的化合物与三份羟丙基纤维素(HPC-L)彻底混合，在＞200℃的温度下一起在加热板上熔融，然后冷却回至室温。
实施例4：实施例1的化合物与淀粉和聚乙二醇的1∶5固体分散体的制备
在耐热容器中，将一份游离碱形式的实施例1的化合物与4份淀粉和一份聚乙二醇(PEG 6000)彻底混合，在＞200℃的温度下一起在加热板上熔融，然后冷却至室温。
相信对于治疗包括癌症在内的过度增生性疾病而言，这一包含式I化合物的固体分散体的新型药物组合物会导致改善的生物利用度、改善的患者间变异性和全面优越的功效。
根据这些发现可以设想，对于治疗包括癌症在内的过度增生性疾病而言，这一包含式I化合物的固体分散体的新型药物组合物会导致改善的吸收和暴露、降低的患者间变异性和全面优越的功效。
Claims (13)
1.组合物，其包含固体分散体，所述固体分散体至少包含式I化合物和/或其盐、水合物或溶剂化物，
以及药学可接受的基质，所述基质由聚乙烯吡咯烷酮组成，并且以不含溶剂的碱计算所述式I化合物与聚乙烯吡咯烷酮的重量比为1∶1至1∶5。
2.权利要求1的组合物，其还包含交联羧甲纤维素钠。
3.权利要求1的组合物，其还包含淀粉乙醇酸钠。
4.权利要求1的组合物，其还包含交联羧甲纤维素钠和微晶纤维素。
5.权利要求1的组合物，其中所述固体分散体为基本上均相的。
6.权利要求1的组合物，其包含基本上为无定形形式的式I化合物。
7.权利要求1的组合物，其为用于口服施用的药物组合物。
8.权利要求1的组合物，其为片剂形式的药物组合物。
9.权利要求1的组合物，其为胶囊剂形式的药物组合物。
10.权利要求1的组合物，其为散剂、颗粒剂或小药囊形式的药物组合物。
11.4{4-[3-(4-氯-3-三氟甲基苯基)-脲基]-苯氧基}-吡啶-2-羧酸甲基酰胺和/或其盐、水合物、溶剂化物作为单一药剂用于制备治疗哺乳动物的过度增生性疾病的权利要求1的组合物的用途。
12.权利要求11的用途，其中所述哺乳动物是人。
13.权利要求11或12的用途，其中所述过度增生性疾病是癌症。
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| CN2005800369528A Expired - Fee Related CN101048140B (zh) | 2004-08-27 | 2005-08-29 | 用于治疗癌症的药物组合物 |
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| EP (1) | EP1796642B1 (zh) |
| JP (1) | JP5128948B2 (zh) |
| CN (1) | CN101048140B (zh) |
| AT (1) | ATE395905T1 (zh) |
| CA (1) | CA2578442A1 (zh) |
| DE (1) | DE602005007048D1 (zh) |
| ES (1) | ES2306216T3 (zh) |
| MX (1) | MX2007002398A (zh) |
| WO (1) | WO2006026501A1 (zh) |
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| US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| JP2002534468A (ja) | 1999-01-13 | 2002-10-15 | バイエル コーポレイション | ｐ３８キナーゼ阻害剤としてのω−カルボキシアリール置換ジフェニル尿素 |
| EP2324825A1 (en) | 2002-02-11 | 2011-05-25 | Bayer Healthcare LLC | Aryl ureas with angiogenesis inhibiting activity |
| DE202004021757U1 (de) * | 2003-02-21 | 2010-09-30 | ResMed Ltd., Bella Vista | Nasale Anordnung |
| UY28213A1 (es) | 2003-02-28 | 2004-09-30 | Bayer Pharmaceuticals Corp | Nuevos derivados de cianopiridina útiles en el tratamiento de cáncer y otros trastornos. |
| JP4860474B2 (ja) * | 2003-05-20 | 2012-01-25 | バイエル、ファーマシューテイカルズ、コーポレイション | Ｐｄｇｆｒによって仲介される病気のためのジアリール尿素 |
| JP4777887B2 (ja) * | 2003-07-23 | 2011-09-21 | バイエル、ファーマシューテイカルズ、コーポレイション | 病気および状態の処置および防止のためのフロロ置換オメガカルボキシアリールジフェニル尿素 |
| MY191349A (en) * | 2004-08-27 | 2022-06-17 | Bayer Pharmaceuticals Corp | New pharmaceutical compositions for the treatment of hyper-proliferative disorders |
| KR101239489B1 (ko) * | 2004-09-29 | 2013-03-06 | 바이엘 파마 악티엔게젤샤프트 | 열역학적으로 안정한 형태의 ｂａｙ 43-9006 토실레이트 |
| CA2601955C (en) | 2005-03-07 | 2012-07-10 | Bayer Healthcare Ag | Pharmaceutical composition comprising an omega-carboxyaryl substituted diphenyl urea for the treatment of cancer |
| CA2652926A1 (en) * | 2006-05-26 | 2007-12-06 | Bayer Healthcare Llc | Drug combinations with substituted diaryl ureas for the treatment of cancer |
| EP2049084A2 (en) * | 2006-07-10 | 2009-04-22 | Elan Pharma International Limited | Nanoparticulate sorafenib formulations |
| EA200970361A1 (ru) | 2006-10-09 | 2010-02-26 | Такеда Фармасьютикал Компани Лимитед | Ингибиторы киназы |
| AR062927A1 (es) * | 2006-10-11 | 2008-12-17 | Bayer Healthcare Ag | 4- [4-( [ [ 4- cloro-3-( trifluorometil) fenil) carbamoil] amino] -3- fluorofenoxi) -n- metilpiridin-2- carboxamida monohidratada |
| CA2667720A1 (en) * | 2006-11-09 | 2008-05-15 | Abbott Gmbh & Co. Kg. | Pharmaceutical dosage form for oral administration of tyrosine kinase inhibitor |
| PT2305263E (pt) * | 2007-06-07 | 2012-10-22 | Novartis Ag | Formas amorfas estabilizadas de mesilato de imatinib |
| TW200922549A (en) * | 2007-10-19 | 2009-06-01 | Abbott Gmbh & Amp Co Kg | Solid dispersion product containing N-aryl urea-based compound |
| CN101220024A (zh) * | 2007-12-11 | 2008-07-16 | 杜晓敏 | 一组抑制激酶的抗癌化合物 |
| US20090203709A1 (en) * | 2008-02-07 | 2009-08-13 | Abbott Laboratories | Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor |
| WO2009106825A1 (en) * | 2008-02-27 | 2009-09-03 | Cipla Limited | Polymorphs of sorafenib and salts thereof |
| WO2010142678A2 (en) * | 2009-06-12 | 2010-12-16 | Ratiopharm Gmbh | Polymorphs of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methyl-pyridine-2-carboxamide |
| WO2011076711A2 (en) | 2009-12-23 | 2011-06-30 | Ratiopharm Gmbh | Polymorphs of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide |
| AR081060A1 (es) | 2010-04-15 | 2012-06-06 | Bayer Schering Pharma Ag | Procedimiento para preparar 4-{4-[({[4-cloro-3-(trifluorometil)fenil]amino}carbonil)amino]-3-fluorofenoxi}-n-metilpiridin-2-carboxamida |
| UA108886C2 (ru) | 2010-06-09 | 2015-06-25 | Еббві Бахамаз Лтд. | Твердые дисперсии, содержащие ингибиторы киназ |
| CA2813510A1 (en) * | 2010-10-14 | 2012-04-19 | Abbott Gmbh & Co. Kg | Curcuminoid solid dispersion formulation |
| UA113500C2 (xx) | 2010-10-29 | 2017-02-10 | Одержані екструзією розплаву тверді дисперсії, що містять індукуючий апоптоз засіб | |
| US20120277210A1 (en) | 2010-10-29 | 2012-11-01 | Abbott Laboratories | Solid dispersions containing an apoptosis-inducing agent |
| US20120129853A1 (en) | 2010-11-23 | 2012-05-24 | Abbott Laboratories | Methods of treatment using selective bcl-2 inhibitors |
| SI2643322T1 (en) | 2010-11-23 | 2018-01-31 | Abbvie Inc. | Salts and crystalline forms of an apoptosis induction agent |
| EP2559431A1 (en) | 2011-08-17 | 2013-02-20 | Ratiopharm GmbH | Pharmaceutical composition comprising 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide |
| CN103301067B (zh) * | 2012-03-15 | 2018-09-11 | 苏州泽璟生物制药有限公司 | 一种改善吸收性能的固体分散体及其制备 |
| CN103301066B (zh) * | 2012-03-15 | 2018-12-07 | 苏州泽璟生物制药有限公司 | 一种改善吸收性能的固体分散体及其制备 |
| US20140275082A1 (en) | 2013-03-14 | 2014-09-18 | Abbvie Inc. | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
| AR096469A1 (es) * | 2013-06-06 | 2015-12-30 | Bayer Pharma AG | Composiciones farmacéuticas que comprenden compuestos del tipo triazolpiridinas |
| CN107661296A (zh) * | 2016-07-27 | 2018-02-06 | 江苏先声药业有限公司 | 一种瑞戈非尼固体分散体及其制备方法 |
| JP2019528279A (ja) * | 2016-08-17 | 2019-10-10 | アイカーン スクール オブ メディシン アット マウント サイナイ | キナーゼ阻害物質化合物、組成物、及びがんの治療方法 |
| CN111991418A (zh) * | 2020-08-29 | 2020-11-27 | 吴国斌 | 一种壳聚糖载体的载药系统及其制备方法 |
| CA3155855A1 (en) * | 2020-12-07 | 2022-06-07 | Tianjin Creatron Biotechnology Co., Ltd. | Sorafenib pharmaceutical composition with high bioavailability and use thereof |
| WO2023155182A1 (zh) * | 2022-02-21 | 2023-08-24 | 北京睿创康泰医药研究院有限公司 | 一种低服用剂量高药物暴露量的索拉非尼或多纳非尼口服制剂及其应用 |
| CN118948847A (zh) * | 2024-10-18 | 2024-11-15 | 杭州华东医药集团新药研究院有限公司 | 一种索拉非尼药物组合物及其制备方法 |
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| WO2003047523A2 (en) * | 2001-12-04 | 2003-06-12 | Onyx Pharmaceuticals, Inc. | Raf-mek-erk pathway inhibitors to treat cancer |
| WO2003068228A1 (en) * | 2002-02-11 | 2003-08-21 | Bayer Pharmaceuticals Corporation | Aryl ureas with angiogenesis inhibiting activity |
| US20030207872A1 (en) * | 2002-01-11 | 2003-11-06 | Bayer Corporation | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7235576B1 (en) * | 2001-01-12 | 2007-06-26 | Bayer Pharmaceuticals Corporation | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
-
2005
- 2005-08-29 ES ES05791660T patent/ES2306216T3/es active Active
- 2005-08-29 US US11/212,907 patent/US20060078617A1/en not_active Abandoned
- 2005-08-29 MX MX2007002398A patent/MX2007002398A/es active IP Right Grant
- 2005-08-29 AT AT05791660T patent/ATE395905T1/de not_active IP Right Cessation
- 2005-08-29 EP EP05791660A patent/EP1796642B1/en not_active Not-in-force
- 2005-08-29 CA CA002578442A patent/CA2578442A1/en not_active Abandoned
- 2005-08-29 JP JP2007533490A patent/JP5128948B2/ja not_active Expired - Fee Related
- 2005-08-29 WO PCT/US2005/030542 patent/WO2006026501A1/en active Application Filing
- 2005-08-29 CN CN2005800369528A patent/CN101048140B/zh not_active Expired - Fee Related
- 2005-08-29 DE DE602005007048T patent/DE602005007048D1/de not_active Expired - Fee Related
-
2011
- 2011-11-23 US US13/303,565 patent/US20120142741A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003047523A2 (en) * | 2001-12-04 | 2003-06-12 | Onyx Pharmaceuticals, Inc. | Raf-mek-erk pathway inhibitors to treat cancer |
| US20030207872A1 (en) * | 2002-01-11 | 2003-11-06 | Bayer Corporation | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| WO2003068228A1 (en) * | 2002-02-11 | 2003-08-21 | Bayer Pharmaceuticals Corporation | Aryl ureas with angiogenesis inhibiting activity |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2007002398A (es) | 2007-05-15 |
| JP5128948B2 (ja) | 2013-01-23 |
| EP1796642A1 (en) | 2007-06-20 |
| ES2306216T3 (es) | 2008-11-01 |
| ATE395905T1 (de) | 2008-06-15 |
| CN101048140A (zh) | 2007-10-03 |
| JP2008511686A (ja) | 2008-04-17 |
| US20060078617A1 (en) | 2006-04-13 |
| US20120142741A1 (en) | 2012-06-07 |
| CA2578442A1 (en) | 2006-03-09 |
| DE602005007048D1 (de) | 2008-07-03 |
| WO2006026501A1 (en) | 2006-03-09 |
| EP1796642B1 (en) | 2008-05-21 |
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