CN116392598A - 含有瑞戈非尼的包衣的药物组合物 - Google Patents
含有瑞戈非尼的包衣的药物组合物 Download PDFInfo
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- CN116392598A CN116392598A CN202310406916.6A CN202310406916A CN116392598A CN 116392598 A CN116392598 A CN 116392598A CN 202310406916 A CN202310406916 A CN 202310406916A CN 116392598 A CN116392598 A CN 116392598A
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- regorafenib
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- polyvinyl alcohol
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Abstract
本发明涉及含有瑞戈非尼的包衣的药物组合物。具体地,本发明涉及一种包衣药物组合物,包含:瑞戈非尼,其水合物、溶剂合物、代谢物或其药学上可接受的盐,或其晶型物;以及它的制备方法和其用于治疗疾病的用途。
Description
本发明申请是PCT专利申请PCT/US2013/058257,国际申请日为2013年09月05日、发明名称为“含有瑞戈非尼的包衣的药物组合物”的发明专利申请的分案申请,母案进入中国的申请号为201380049461.1。
技术领域
本发明涉及一种包衣的药物组合物、其制备方法及其用于治疗疾病的用途,所述包衣的药物组合物包含:瑞戈非尼(regorafenib),其水合物、溶剂合物、代谢物或药学上可接受的盐或其多晶型物。
背景技术
瑞戈非尼为4{4-[3-(4-氯-3-三氟甲基苯基)-脲基]-3-氟苯氧基}-吡啶-2-羧酸甲酰胺,即式(I)的化合物,
瑞戈非尼是一种有效的抗癌和抗血管生成剂,其具有各种活性,包括对VEGFR、PDGFR、raf、p38和/或flt-3激酶信号分子的抑制活性,并且其可用于治疗各种疾病和病症,如过度增殖疾病,例如癌症、肿瘤、淋巴癌、肉瘤和白血病,如WO 2005/009961中所描述。此外,WO 2005/009961中提及了式(I)的化合物的盐,如其盐酸盐、甲磺酸盐和苯磺酸盐。WO2008/043446中提到了式(1)的化合物的一水合物。WO 2011/128261中描述了一种制备高纯度瑞戈非尼的改进的方法。由于瑞戈非尼一水合物的有限的溶解度(参见表1),含有瑞戈非尼的可应用的药物组合物以固体分散剂的形式存在,如WO 2006/026500所描述。
表1:瑞戈非尼一水合物在不同溶剂中的热力学溶解度
溶剂 | 溶解度(mg/ml) |
水 | <0.1 |
轻质液体石蜡 | <0.1 |
乙醇 | 6.4 |
聚乙二醇(PEG)400 | 67.3 |
HPβ-环糊精/水(10∶90) | <0.1 |
PEG 400/水(30∶70) | 0.27 |
油酰基聚乙二醇甘油酯 | 3.6 |
优选的给药途径是通过口腔。该途径提供了给药的最大舒适性和便利性。对于口服给药而言,片剂是药物组合物的优选形式。为了方便地给予固体制剂,通常需要包衣。包衣的目的可以是提供均匀的外表、掩盖储存期间的变色、添加颜色以识别产品、掩盖不良味道、防止处理时沾灰、阻止片剂的磨损或摩擦、增加机械稳定性、吞下片剂时(特别是当片剂尺寸较大时)促进并给予更方便的感觉、为药物提供光保护或保护药物免于潮湿。常用片剂包衣剂为羟乙基纤维素、羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、蔗糖、液体葡萄糖、乙基纤维素、乙酸邻苯二甲酸纤维素和虫胶。包衣剂可与其他适用的包衣赋形剂混合或可使用市售可得的即用型包衣混合物,如OpadryTM II 85G35294粉、OpadryTMII 85G25457红、OpadryTMII 85G23665橙。包衣的温度通常取决于所使用的包衣剂和溶剂的类型。基于聚乙烯醇的包衣通常是在45-48℃的床温(进风温度60-65℃)下进行处理。对于其他包衣材料常使用甚至更高的温度。在包衣过程(例如排风温度)中使用水性溶剂时,包衣通常在更高温度下进行。
发明内容
本发明解决的问题是提供特别是直接包衣后和/或储存后含有高纯度的瑞戈非尼的包衣的药物组合物。
令人惊讶地,本发明的药物组合物表现出降低的活性剂降解。
本发明涉及一种药物组合物,其包含:瑞戈非尼(其为式(I)的化合物),瑞戈非尼的水合物、溶剂合物、代谢物或药学上可接受的盐,或其多晶型物,和至少一种药学上可接受的赋形剂,其中药物组合物被含有基于聚乙烯醇的聚合物和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆,
本发明的药物组合物能够通过向需要它的患者给药而得以利用,从而达到所需的药理作用。为了本发明的目的,患者为需要治疗具体的病症或疾病的哺乳动物,包括人。因此,本发明包括由药学上可接受的赋形剂和药学有效量的本发明化合物组成的药物组合物。药学上可接受的赋形剂为任何赋形剂,其在与活性成分的有效活性一致时的浓度下对患者相对无毒且无害,从而使得归因于载体的任何副作用不会削弱活性成分的有益效果。化合物的药学有效量是指对正在治疗的特殊病症产生效果或施加影响的量。
术语“式(I)的化合物”或“瑞戈非尼”指的是如式(I)所描述的4{4-[({[4-氯-3-(三氟甲基)苯基]氨基}羰基)氨基]-3-氟苯氧基}-N-甲基吡啶-2-甲酰胺。
术语“本发明的化合物”或“活性剂”或“活性成分”指的是瑞戈非尼,瑞戈非尼的水合物、溶剂合物、代谢物或药学上可接受的盐,或其多晶型物。
为了本发明的目的,溶剂合物为化合物或其盐的下述形式:其中溶剂分子形成化学计量的固态复合物,所述溶剂分子包括但不限于例如水、乙醇和甲醇。
水合物为溶剂合物的特殊形式,其中溶剂分子为水。本发明化合物或其盐的水合物为该化合物或盐与水的化学计量的组合物,例如,半水合物、一水合物或二水合物。优选瑞戈非尼的一水合物。
为了本发明的目的,盐优选为本发明化合物的药学上可接受的盐。合适的药学上可接受的盐为本领域技术人员公知的并且包括无机酸和有机酸的盐,所述无机酸和有机酸包括如盐酸、氢溴酸、硫酸、磷酸、甲基磺酸、三氟甲基磺酸、苯磺酸、对甲苯磺酸(甲苯磺酸盐)、1-萘磺酸、2-萘磺酸、乙酸、三氟乙酸、苹果酸、酒石酸、柠檬酸、乳酸、乙二酸、琥珀酸、富马酸、马来酸、苯甲酸、水杨酸、苯乙酸和扁桃酸。另外,药学上可接受的盐包括无机碱的盐,如含有碱阳离子(例如,Li+、Na+或K+)、碱土阳离子(例如,Mg2+、Ca2+或Ba2+)、铵阳离子的盐;以及有机碱的酸式盐,包括脂族和芳族取代的铵,以及季铵阳离子,如由三乙胺、N,N-二乙胺、N,N-二环己胺、赖氨酸、吡啶、N,N-二甲氨基吡啶(DMPA)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)、1,5-二氮杂二环[4.3.0]壬-5-烯(DBN)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)的质子化或过烷基化(peralkylation)产生的季铵阳离子。优选瑞戈非尼的盐酸盐、甲磺酸盐或苯磺酸盐。
为了本发明的目的,瑞戈非尼的代谢物包括4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺1-氧化物、4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-(羟甲基)吡啶-2-甲酰胺、4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]吡啶-2-甲酰胺和4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]吡啶-2-甲酰胺1-氧化物。
优选瑞戈非尼和瑞戈非尼的一水合物作为本发明的化合物。
利用本发明的药物组合物优选通过口服途径给药的活性成分(本发明的化合物)的总量通常为每天约0.1mg/kg体重至约50mg/kg体重。基于已知用于评估对治疗过度增殖疾病有效的化合物的标准实验室技术,通过用于在哺乳动物中确定上述病症的治疗方法的标准毒性实验和标准药理实验,以及通过比较这些结果与用于治疗这些病症的已知药物的结果,本领域技术人员可容易地确定本发明的药物组合物的有效剂量。给予的活性成分的量可根据如下考虑因素广泛变化:所使用的具体的化合物和剂量单位,给药方式和时间,治疗期,治疗的患者的年龄、性别和总体病情,治疗的病症的性质和程度,药物代谢和排泄的速度,潜在的药物结合和药物-药物相互作用等。
优选药物组合物中本发明化合物的量为4至400mg,优选10至200mg,更优选10至100mg。
本发明令人特别感兴趣的一方面是药物组合物中含有的瑞戈非尼的量为4至400mg,优选10至200mg,更优选10至100mg。
本发明化合物(具体而言瑞戈非尼)的日剂量为10至1000mg,优选40至500mg,更优选80至320mg,例如160mg。
每天给予本发明的药物组合物一次以上,优选最高达3次,更优选最高达2次。优选通过口服途径给药。
然而,在某些情况下,根据体重、对于有效成分的个体行为、制剂类型和影响给药的时间或间隔,偏离规定的量是有利的。例如,在某些情况下,小于上述的最低量的给药量可能是足够的,然而,在其他情况下,给药量不得不超过规定的上限。在给药量较大的情况下,建议在一天内将这些药物分成若干单独的剂量。
本发明的药物组合物优选通过向需要它的患者口服给药而实现所需的药理作用,并且在药物释放、生物利用度和/或哺乳动物依从性方面具有有利的特性。为了本发明的目的,患者为需要治疗具体的病症或疾病的哺乳动物,包括人。
优选的药物组合物为速释片剂。
本发明的药物组合物优选为固体药物组合物且为口服或直肠给药,优选口服给药。
本发明的药物组合物包括任何适于包衣的固体制剂。
本发明的药物组合物包括但不限于颗粒剂、丸粒(pellet)、片剂、糖衣药丸、丸剂(pill)、熔化剂(melts)或固体分散剂,且可根据本领域已知的用于制备药物组合物的方法制备。优选片剂、固体分散剂、丸粒和颗粒剂。本发明的药物组合物最优选为片剂。
本发明令人特别感兴趣的一方面是固体分散剂形式的药物组合物或含有固体分散剂的药物组合物。所述固体分散剂可为固态溶液、玻璃溶液(glass solution)、玻璃混悬液(glass suspension)、透明载体中的无定形沉淀、共晶或偏晶的、复合的或络合的形成物或其结合。
本发明的固体分散剂包括至少一种本发明的化合物和药学上可接受的基质。
本文中所用的术语“基质”或“基质剂”指的是能够溶解或分散本发明化合物的聚合的赋形剂、非聚合的赋形剂及其结合。
本发明令人特别感兴趣的一方面是含有固体分散剂的药物组合物,其中基质包括药学上可接受的聚合物,如聚乙烯基吡咯烷酮、乙烯基吡咯烷酮/乙酸乙烯酯共聚物、聚烷二醇(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、聚乙二醇化的甘油酯(polyglycolized glycerides)、黄原胶、角叉菜胶、壳聚糖、甲壳质、聚糊精、糊精、淀粉、蛋白质或其混合物。
本发明的另一方面是包括固体分散剂的药物组合物,其中基质包括糖和/或糖醇和/或环糊精,例如,蔗糖、乳糖、果糖、麦芽糖、棉子糖、山梨醇、乳糖醇、甘露醇、麦芽糖醇、赤藓糖醇、肌醇、海藻糖、益寿糖(isomalt)、菊糖、麦芽糖糊精、β-环糊精、羟丙基-β-环糊精或磺丁基醚环糊精或其混合物。
在一个优选的实施方案中,固体分散剂中使用选自聚乙烯基吡咯烷酮、共聚维酮、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作为基质剂。更优选使用聚乙烯基吡咯烷酮和/或羟丙基纤维素作为基质剂。最优选使用聚乙烯基吡咯烷酮作为基质剂。
在令人特别感兴趣的一个实施方案中,固体分散剂包括本发明的组合物(以无溶剂的式(I)的化合物的瑞戈非尼基体计算)和基质剂,重量比为1:0.5至1:20,优选1:1至1:10,最优选1:1至1∶5。
在固体分散剂的基质的形成中可用的其他合适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、聚氧乙烯山梨聚糖脂肪酸酯和脲。
固体分散剂可包括某些其他药学上可接受的成分,如表面活性剂、填料、崩解剂、再结晶抑制剂、增塑剂、消泡剂、抗氧化剂、防黏剂、pH调节剂、助流剂和润滑剂。
本发明令人特别感兴趣的另一方面是含有作为载体或崩解剂的交联羧甲基纤维素钠、羟乙酸淀粉钠、交聚维酮、低取代的羟丙基纤维素(L-HPC)、淀粉、微晶纤维素或其结合的固体分散剂。优选固体分散剂包括微晶纤维素和/或交联羧甲基纤维素钠。
在另一优选的实施方案中,固体分散剂包括聚乙烯基吡咯烷酮、交联羧甲基纤维素钠和任选的微晶纤维素。
在令人特别感兴趣的一个实施方案中,固体分散剂包括本发明组合物(以无溶剂的式(I)的化合物的瑞戈非尼基体计算)和载体与崩解剂的总量的重量比为1∶0.5至1∶20,优选1∶1至1∶10,最优选1∶1至1∶6。
本发明的固体分散剂可根据本领域已知的用于制备固体分散剂的方法制备,例如WO 2006/026500中记载的如融合/熔化技术、热熔挤出、溶剂蒸发(如冷冻干燥、喷雾干燥或颗粒剂的粉状物质的分层(layering of powders of granules))、共沉淀、超临界流体技术和静电纺丝法(electrostatic spinning method)。
用于制备本发明的固体分散制剂的优选方法为热熔挤出和溶剂蒸发技术。
适于通过溶剂蒸发法(如喷雾干燥、分层或流化床造粒)制备固体分散剂的溶剂可为任何化合物,本发明的化合物可溶解于其中。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;和各种其他溶剂,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。也可使用挥发性较低的溶剂,如二甲基乙酰胺或二甲亚砜。还可以使用溶剂混合物,如20%乙醇和80%丙酮,也可使用与水的混合物,只要药物和(如果需要)基质剂可充分溶解以使工艺可行即可。
在一个优选的实施方案中,用于制备固体分散剂的溶剂为甲醇、乙醇、正丙醇、异丙醇、丙酮或其混合物。更优选使用乙醇和丙酮的混合物作为溶剂。
本发明令人特别感兴趣的一方面是组合物,其中固体分散剂基本上均匀。
本发明令人特别感兴趣的一方面是药物组合物,其中本发明的化合物基本上是无定形的。
本发明的药物组合物的包衣包含作为成膜剂的基于聚乙烯醇的聚合物。本发明的基于聚乙烯醇的聚合物包括但不限于完全水解的聚乙烯醇聚合物、部分水解的聚乙烯醇聚合物(包括游离醇基团和酯化醇基团即如乙酸酯)、酯化的聚乙烯醇聚合物(例如,聚乙酸乙烯酯聚合物)、前述物质与聚乙二醇的共聚物(例如,聚乙烯醇-聚乙二醇共聚物)或前述物质的混合物。优选部分水解的聚乙烯醇聚合物。
包衣中存在的基于聚乙烯醇的聚合物的量为全部包衣的30至70重量%,优选35至60重量%,更优选35至50重量%。
此外,本发明的药物组合物的包衣任选地包含一种以上其他的药学上可接受的赋形剂,如增塑剂、着色剂、遮光剂(opacifier)、防粘剂(anti-tacking agent)、分散剂和悬浮剂。
可在包衣中使用的增塑剂包括但不限于聚乙二醇、丙二醇、山梨醇、丙三醇、麦芽糖醇、木糖醇、甘露醇、赤藓糖醇、三油酸甘油酯、柠檬酸三丁酯、柠檬酸三乙酯、乙酰柠檬酸三乙酯、三乙酸甘油酯、硬脂酸、中链甘油三酯或其混合物。优选聚乙二醇、中链甘油三酯和/或硬脂酸。
可存在于包衣中的增塑剂的量为全部包衣的5至30重量%,优选8至25重量%,更优选10至20重量%。
包衣中可使用的着色剂包括但不限于氧化铁红、氧化铁黄、氧化铁黑、二氧化钛、靛蓝、日落黄FCF、柠檬黄、赤藓红、喹啉黄、炭黑、花色苷、核黄素、胭脂红、姜黄素、叶绿素、胡萝卜素或其混合物。优选氧化铁类和二氧化钛。
包衣中存在的着色剂的总量为全部包衣的5至40重量%,优选8至30重量%,更优选10至20重量%。
包衣中可使用的防粘剂包括但不限于滑石、硬脂酸镁、硬脂酸、卵磷脂、大豆卵磷脂、矿物油、巴西棕榈蜡、乙酰化的单酸甘油酯、聚山梨醇酯或其混合物。优选滑石、卵磷脂、大豆卵磷脂和聚山梨醇酯。
包衣中的防粘剂的总量为全部包衣的3至30重量%,优选5至25重量%,更优选10至20重量%。
包衣中可使用的遮光剂包括但不限于滑石和二氧化钛。包衣中存在的遮光剂的总量为全部包衣的10至45重量%,优选15至35重量%,更优选15至25重量%。
包衣材料可由前面提及的各成分制备。或者,可使用即用型混合物,其包括但不限于例如OpadryTM II 85G35294粉、OpadryTM II 85G25457红、OpadryTM II 85G23665橙(由Colorcon提供)、KollicoatTM IR白(由BASF提供)、SepifilmTM IR(由SEPPIC提供)。优选OpadryTM II 85G35294粉、OpadryTM II 85G25457红、OpadryTM II 85G23665橙。
本发明令人特别感兴趣的一方面是一种药物组合物,其为片剂,包含:瑞戈非尼,瑞戈非尼的水合物、溶剂合物、代谢物或药学上可接受的盐,或其多晶形物,优选瑞戈非尼,和至少一种药学上可接受的赋形剂,其中所述药物组合物被包含基于聚乙烯醇的聚合物和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆。
本发明令人特别感兴趣的一方面是一种包含固体分散剂的药物组合物,所述固体分散剂包含瑞戈非尼和至少一种药学上可接受的赋形剂,其中药物组合物被包含基于聚乙烯醇的聚合物和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆。
优选如下的药物组合物,其为包含固体分散剂的片剂,所述固体分散剂包含瑞戈非尼和至少一种药学上可接受的赋形剂,其中药物组合物被包含基于聚乙烯醇的聚合物和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆。
更优选本发明的药物组合物为包含固体分散剂的片剂,所述固体分散剂包含瑞戈非尼和至少一种药学上可接受的基质剂,所述基质剂选自聚乙烯基吡咯烷酮、乙烯基吡咯烷酮/乙酸乙烯酯共聚物、聚烷二醇(如聚乙二醇)、羟烷基纤维素(如羟丙基纤维素)、羟烷基甲基纤维素(如羟丙基甲基纤维素)、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、聚乙二醇化的甘油酯、黄原胶、角叉菜胶、壳聚糖、甲壳质、聚糊精、糊精、淀粉、蛋白质或其混合物,优选聚乙烯基吡咯烷酮,其中所述药物组合物被含有基于聚乙烯醇的聚合物和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆。
最优选本发明的药物组合物为如下的包含固体分散剂的片剂,所述固体分散剂包含瑞戈非尼、作为药学上可接受的基质剂的聚乙烯基吡咯烷酮和作为其他药学上可接受的赋形剂的微晶纤维素和/或交联羧甲基纤维素钠,其中所述药物组合物被含有基于聚乙烯醇的聚合物(特别是部分水解的聚乙烯醇聚合物)和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆。
在这一点上,本发明的药物组合物-当进行释放测试研究时-包含4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(IIPAC:4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺)(AFP-PMA)的量基于式(I)的化合物的量计为等于或小于0.050重量%,意指0.001重量%至最大为0.050重量%;优选为等于或小于0.025重量%,意指0.001重量%至最大为0.025重量%;最优选为等于或小于0.015重量%,意指0.001重量%至最大为0.015重量%。应理解,释放测试在已完成一批产品的制备后无不当延误地进行。在各产品批次在上市前也会对释放测试做出正式要求。
此外,本发明的药物组合物-在产品保质期的末期进行研究时-含有4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(IUPAC:4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺)(AFP-PMA)的量基于式(I)的化合物的量计为等于或小于0.10重量%,意指0.001重量%至最大为0.10重量%;优选为等于或小于0.08重量%,意指0.001重量%至最大为0.08重量%;最优选为等于或小于0.05%,意指0.001重量%至最大为0.05重量%。
本发明的另一方面是薄膜包衣的药物组合物,优选片剂,其包含瑞戈非尼和-当进行释放测试研究时-4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(IUPAC:4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺)(AFP-PMA)的量基于瑞戈非尼和至少一种药学上可接受的赋形剂的量计为等于或小于0.050重量%,意指0.001重量%至最大为0.050重量%;优选为等于或小于0.025重量%,意指0.001重量%至最大为0.025重量%;最优选为等于或小于0.015重量%,意指0.001重量%至最大为0.015重量%。
优选一种片剂,其包含瑞戈非尼和-当进行释放测试研究时-4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(IUPAC:4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺)(AFP-PMA)的量基于瑞戈非尼和至少一种药学上可接受的赋形剂的量计为等于或小于0.050重量%,意指0.001重量%至最大为0.050重量%;优选为等于或小于0.025重量%,意指0.001重量%至最大为0.025重量%;最优选为等于或小于0.015重量%,意指0.001重量%至最大为0.015重量%,其中所述片剂被含有基于聚乙烯醇的聚合物(特别是部分水解的聚乙烯醇聚合物)和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆。
本发明的另一方面是薄膜包衣的药物组合物,优选一种片剂,其包含瑞戈非尼和-在产品保质期的末期进行研究时—4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(IUPAC:4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺)(AFP-PMA)的量基于瑞戈非尼和至少一种药学上可接受的赋形剂的量计为等于或小于0.10重量%,意指0.001重量%至最大为0.10重量%;优选为等于或小于0.08重量%,意指0.001重量%至最大为0.08重量%;最优选为等于或小于0.05重量%,意指0.001重量%至最大为0.05重量%。。
优选一种片剂,其包含瑞戈非尼和-在产品保质期的末期进行研究时-4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(IUPAC:4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺)(AFP-PMA)的量基于瑞戈非尼和至少一种药学上可接受的赋形剂的量计为等于或小于0.10重量%,意指0.001重量%至最大为0.10重量%;优选为等于小于0.08重量%,意指0.001重量%至最大为0.08重量%;最优选为等于或小于0.05重量%,意指0.001重量%至最大为0.05重量%,其中所述片剂被含有基于聚乙烯醇的聚合物(特别是部分水解的聚乙烯醇聚合物)和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆。
可将本发明的药物组合物和干燥剂如分子筛一起包装于包装系统(像瓶或容器)。优选将本发明的药物组合物和分子筛一起包装于瓶中。更优选地,将任选地被包含聚乙烯醇的包衣包覆且为含有瑞戈非尼的片剂的药物组合物和分子筛一起包装于瓶中。最优选地,将任选地被包含基于聚乙烯醇的聚合物的包衣包覆且为含有瑞戈非尼的固体分散剂的片剂的药物组合物和分子筛一起包装于瓶中。
通常,分子筛为含有精确和均一尺寸的微孔的材料。可进入分子筛材料的孔中的分子或离子的最大尺寸由通道的尺寸的控制,例如0.4nm(埃)。小分子可进入孔中并被吸附,而大分子却不能。例如,水分子足够小且强行进入孔中,该孔可对渗透的水分子起截留作用,从而使水分子保留在孔中。
广泛使用的分子筛材料为铝硅酸盐矿物,例如沸石。
对于药品,使用孔径为或/>的分子筛,因为尺寸为约/>的水分子被有效截留,而较大的分子却不能。优选孔径为/>的分子筛。所使用的分子筛非常有效,其在25℃下甚至在80%的高相对湿度下具有至少16%(重量/重量)的吸附容量。
分子筛为市售可得的,如购于Süd-Chemie的CAN TRI-SORBTM 4A。
例如在气候带1至2、优选在气候带1至4b中储存的过程中,本发明的药物组合物在大于18个月、优选大于24个月、最优选大于36个月的时间内是化学稳定的。
例如在气候带1至2、优选在气候带1至4b中储存的过程中,本发明的药物组合物在至少18个月、优选至少24个月、最优选至少36个月的时间内是化学稳定的,且本发明的药物组合物包含4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(AFP-PMA)的量为小于0.100重量%,意指0.001重量%至最大为0.100重量%;优选为等于或小于0.08重量%,意指0.001重量%至最大为0.08重量%;最优选为等于或小于0.050重量%,意指0.001重量%至最大为0.050重量%,基于组合物中的瑞戈非尼的量计。为了确定药品的保质期,气候带为公知概念,其限定了用于长期稳定性研究的储存条件,从而确定药品的保质期。例如,由在25℃和60%相对湿度下储存得到的数据用于证实气候带1至2的保质期,而由在40℃和75%相对湿度下储存得到的数据用于证实气候带1至4b的保质期。
在25℃/60%相对湿度下储存的过程中,本发明药物组合物中AFP-PMA的量的月增长率为每月等于或小于0.0015重量%,意指0.0001重量%至最大为0.0015重量%;优选为等于或小于0.001重量%,意指0.0001%至最大为0.001重量%,基于组合物中瑞戈非尼的量计。
在30℃/75%相对湿度下储存的过程中,本发明药物组合物中AFP-PMA的量的月增长率为每月等于或小于0.0030重量%,意指0.0001重量%至最大为0.0030重量%;优选为等于或小于0.0025重量%,意指0.0001重量%至最大为0.0025重量%,基于组合物中瑞戈非尼的量计。
令人惊讶地,在本发明的药物组合物的储存过程中,本发明药物组合物与分子筛一起包装时比与其他干燥剂如硅胶一起包装时产生更少的副产物,所述副产物优选为4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺。
制备方法(包衣)
本发明的药物组合物包括但不限于颗粒剂、丸粒、片剂、糖衣药丸、丸剂、熔化剂或固体分散剂,优选片剂、固体分散剂、丸粒和颗粒剂,最优选片剂,且可根据本领域用于制备药物组合物的已知方法制备,其例如记载于WO 2006/026500中。
本发明的药物组合物——优选含有瑞戈非尼的片剂——根据本领域已知方法包衣,所述方法如在包衣锅或有孔滚筒包衣机(perforated drum coater)中喷洒包衣液体至药物组合物上,条件是排风温度为等于或低于42℃,例如20℃至42℃;优选等于或低于40℃,例如30℃至40℃;最优选等于或低于38℃,例如32℃至38℃。在包衣步骤中所使用的用于溶解或分散包衣材料的溶剂/媒介物为水性溶剂/媒介物,优选为水。
本发明的另一主题是一种药物组合物,其包含:瑞戈非尼,瑞戈非尼的水合物、溶剂合物、代谢物或药学上可接受的盐,或其多晶型物,优选瑞戈非尼,其中药物组合物被包衣包覆,其中包衣可通过包衣过程获得或通过包衣过程获得,其中所述包衣过程中排风温度为等于或低于42℃,例如20℃至42℃;优选等于或低于40℃,例如30℃至40℃;最优选等于或低于38℃,例如32℃至38℃,且在包衣步骤中所使用的溶剂/媒介物为水性溶剂/媒介物,优选为水。
使用含有基于聚乙烯醇的聚合物的包衣材料的包衣步骤可通过将包衣材料均匀地溶解或分散在溶剂/媒介物(例如水)中而进行,所述包衣材料例如OpadryTM II 85G35294粉、OpadryTM II 85G25457红、OpadryTM II 85G23665橙。或者,包衣材料可由单独的组分制备。然后在有孔滚筒包衣机中将包衣液体喷洒至本发明的药物组合物(如片剂)上。
令人惊讶地,可在低包衣温度下得到良好的包衣结果,即,排风温度等于或低于42℃,例如20℃至42℃;优选等于或低于40℃,例如30℃至40℃;最优选等于或低于38℃,例如32℃至38℃。
令人惊讶地,4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(IUPAC:4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺)(AFP-PMA)的量在由未包衣到最终包衣的本发明的药物组合物中仅增加0.0005重量%至0.0030重量%,优选增加0.0005重量%至0.0020重量%,基于瑞戈非尼的量计。
因此,本发明的另一方面是制备包含瑞戈非尼的包衣的药物组合物的方法,所述药物组合物优选为片剂,其中4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(IUPAC:4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺)(AFP-PMA)的量在由未包衣的药物组合物到最终包衣的药物组合物中仅增加0.0005重量%至0.0030重量%,优选0.0005重量%至0.0020重量%,基于瑞戈非尼的量计。
治疗方法
本发明还涉及一种使用本发明的化合物及其组合物治疗哺乳动物过度增殖疾病的方法。该方法包括向有需要的哺乳动物包括人给予治疗所述疾病有效量的本发明的化合物或其组合物。过度增殖疾病包括但不限于实体瘤,如乳腺癌、呼吸道癌、脑癌、生殖器癌、消化道癌、尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌及其远端转移。那些疾病还包括淋巴癌、肉瘤和白血病。
乳腺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、原位小叶癌。
呼吸道癌的实例包括但不限于小细胞和非小细胞肺癌,以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下丘脑胶质瘤、小脑和大脑星形细胞瘤、髓母细胞瘤、室管膜瘤、以及神经外胚层肿瘤和松果体瘤。
男性生殖器的肿瘤包括但不限于前列腺癌和睾丸癌。女性生殖器的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、大肠癌、食管癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
优选大肠癌。
还优选胃肠道间质瘤(GIST)。
尿道肿瘤包括但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、尿管癌和尿道癌。
眼癌包括但不限于眼内黑色素瘤和视网膜母细胞瘤。
肝癌包括但不限于肝细胞癌(有或无纤维板层变体的肝细胞癌)、胆管细胞型肝癌(肝内胆管癌)和混合型肝细胞-胆管细胞型肝癌。
优选肝细胞癌。
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色素皮肤癌。
头颈癌包括但不限于喉癌/下咽癌/鼻咽癌/口咽癌以及嘴唇和口腔癌。
淋巴瘤包括但不限于艾滋病相关淋巴瘤、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、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髓性白血病、急性淋巴母细胞白血病、慢性淋巴细胞白血病、慢性髓性白血病和多毛细胞白血病。
这些疾病在人类中已得到充分表征,而且在其他哺乳动物中也具有类似的病原学,且可通过给予本发明的药物组合物治疗。
基于已知用于评估对治疗过度增殖疾病有效的化合物的标准实验室技术,通过用于在哺乳动物中确定上述病症的治疗方法的标准毒性实验和标准药理实验,以及通过比较这些结果与用于治疗这些病症的已知药物的结果,可容易地确定用于治疗各个目标适应症的本发明化合物的有效剂量。在这些病症之一的治疗中给予的活性成分的量可根据如下考虑因素广泛变化:所使用的具体化合物和剂量单位、给药方式、治疗期、治疗的患者的年龄和性别、治疗的病情的性质和程度。
本发明还提供本发明的化合物在制备用于治疗上述疾病的药物组合物中的用途。
与其他药剂结合
本发明的化合物可作为单一药剂给药或与一种以上其他药剂结合给药,其中所述结合不会引起不可接受的副作用。例如,本发明的化合物可与已知的抗过度增殖的药剂或其他适应症药剂等结合,以及与所述抗过度增殖的药剂或其他适应症药剂的混合物或结合物结合。
可添加到该组合物中的任选的抗过度增殖的药剂包括但不限于Merck Index的第11版(1996)中的癌症化疗用药法中所列出的化合物,其以引用的方式纳入本说明书,如天冬酰胺酶、博来霉素、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、门冬酰胺酶(colaspase)、环磷酰胺、阿糖胞苷、达卡巴嗪、更生霉素、柔红霉素、多柔比星(阿霉素)、表柔比星、依托泊苷、5-氟尿嘧啶、六甲嘧胺、羟基脲、异环磷酰胺、伊立替康、甲酰四氢叶酸、环己亚硝脲、氮芥、6-巯基嘌呤、美司钠、甲氨蝶呤、丝裂霉素C、米托蒽醌、泼尼松龙、强的松、丙卡巴肼、雷洛昔芬、链脲菌素、三苯氧胺、硫鸟嘌呤、托泊替康、长春碱、长春新碱和长春地辛。
适合于与本发明组合物结合使用的其他抗过度增殖的药剂包括但不限于在Goodman and Gilman′s The Pharmacological Basis of Therapeutics(第九版),主编Molinoff等,由McGraw-Hill出版,第1225-1287页,(1996)中公知的在肿瘤性疾病的治疗中使用的那些化合物,其以引用的方式纳入本说明书,如氨鲁米特、L-天冬酰胺酶、硫唑嘌呤、5-氮杂胞苷克拉屈滨、白消安、己烯雌酚、2′,2′-二氟脱氧胞苷、多西紫杉醇、赤式羟基壬基腺嘌呤(erythrohydroxynonyladenine)、炔雌醇、5-氟脱氧尿苷、5-氟脱氧尿苷一磷酸盐、氟达拉滨磷酸酯、氟甲睾酮、氟他胺、己酸羟孕酮、伊达比星、干扰素、醋酸甲羟孕酮、醋酸甲地孕酮、美法仑、米托坦、紫杉醇、喷司他丁、N-膦酰基乙酰基-天冬氨酸盐(PALA)、普卡霉素、司莫司汀、替尼泊苷、丙酸睾酮、噻替哌、三甲基三聚氰胺、尿苷和长春瑞滨。
适于与本发明组合物结合使用的其他抗过度增殖的药剂包括但不限于其他抗癌药剂,如埃博霉素类及其衍生物、伊立替康、雷洛昔芬和托泊替康。
通常,使用上述的本发明的结合将有助于:
(1)与单独给予任一药剂相比在减少肿瘤的生长或甚至消除肿瘤方面产生更好的功效,
(2)提供所给予的化疗药剂的更少量的给药,
(3)提供在患者中具有良好耐受的化疗治疗,与单一药剂化疗和某些其他结合治疗所观察到的相比,其不良药理学并发症更少,
(4)提供治疗哺乳动物尤其是人中更广范围的不同癌症类型,
(5)提供在所治疗患者之中的更高响应速率,
(6)提供相比于标准的化疗治疗而言所治疗患者的更长的存活时间,
(7)提供更长时间的肿瘤进展,和/或
(8)与其他癌症药剂结合产生拮抗作用的已知情况相比较,产生与单独使用的那些药剂至少一样好的功效和耐受性。
为了本发明的目的,“结合”不仅指包含所有组分的剂型(所谓的固定结合)以及含有彼此分开的组分的结合包装,还指同时或依次给药的组分,只要它们被用于相同疾病的预防或治疗即可。
本领域普通技术人员应理解,在不脱离本文所述的本发明的精神或范围的情况下,可对本发明进行变化和修改。
上文和下文所引用的所有出版物、申请和专利以引用的方式纳入本说明书。
除非另有说明,否则重量数据为重量百分数且份数为重量份。
项目1.一种药物组合物,其包含:瑞戈非尼,瑞戈非尼的水合物、溶剂合物、代谢物或药学上可接受的盐,或其多晶型物,和至少一种药学上可接受的赋形剂,其中所述药物组合物被含有基于聚乙烯醇的聚合物和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆。
项目2.项目1的组合物,其为片剂。
项目3.项目1至2中任一项的组合物,其为速释片剂。
项目4.项目1至3中任一项的组合物,其中基于聚乙烯醇的聚合物为水解的聚乙烯醇聚合物、部分水解的聚乙烯醇聚合物、酯化的聚乙烯醇聚合物、其与聚乙二醇的共聚物,或其混合物。
项目5.项目4的组合物,其中基于聚乙烯醇的聚合物为部分水解的聚乙烯醇聚合物。
项目6.项目1至5中任一项的组合物,其中基于聚乙烯醇的聚合物的存在量为全部包衣的30至70重量%。
项目7.项目1至6中任一项的组合物,其中所述包衣包含作为增塑剂的聚乙二醇、丙二醇、山梨醇、丙三醇、麦芽糖醇、木糖醇、甘露醇、赤藓糖醇、三油酸甘油酯、柠檬酸三丁酯、柠檬酸三乙酯、乙酰柠檬酸三乙酯、三乙酸甘油酯、硬脂酸、中链甘油三酯或其混合物。
项目8.项目7的组合物,其中增塑剂为聚乙二醇。
项目9.项目7至8中任一项的组合物,其中增塑剂的量为全部包衣的5至30重量%。
项目10.项目1至9中任一项的组合物,其包含固体分散剂,所述固体分散剂包含瑞戈非尼。
项目11.项目10的组合物,其包含无定形态的瑞戈非尼和药学上可接受的基质,其中所述基质包括聚乙烯基吡咯烷酮、乙烯基吡咯烷酮/乙酸乙烯酯共聚物、聚烷二醇、羟烷基纤维素、羟烷基甲基纤维素、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、聚乙二醇化的甘油酯、黄原胶、角叉菜胶、壳聚糖、甲壳质、聚糊精、糊精、淀粉、蛋白质、蔗糖、乳糖、果糖、麦芽糖、棉子糖、山梨醇、乳糖醇、甘露醇、麦芽糖醇、赤藓糖醇、肌醇、海藻糖、益寿糖、菊糖、麦芽糖糊精、β-环糊精、羟丙基-β-环糊精或磺丁基醚环糊精或其混合物。
项目12.项目10至11中任一项的组合物,其包含的瑞戈非尼和基质剂的重量比为1:0.5至1:20。
项目13.项目10至12中任一项的组合物,其包含瑞戈非尼和聚乙烯基吡咯烷酮、交联羧甲基纤维素钠和/或微晶纤维素。
项目14.项目13的组合物,其包含的瑞戈非尼与交联羧甲基纤维素钠和/或微晶纤维素的总和的重量比为1:0.5至1:20。
项目15.薄膜包衣的药物组合物,其含有瑞戈非尼,其中4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺的量为等于或小于0.100重量%,基于瑞戈非尼的量计。
项目16.容器,其装有分子筛和含有瑞戈非尼的药物组合物。
项目17.药物组合物,其包含:瑞戈非尼,瑞戈非尼的水合物、溶剂合物、代谢物或药学上可接受的盐,或其多晶型物,优选瑞戈非尼,其中所述药物组合物被包衣包覆,其中所述包衣通过包衣过程得到,其中在包衣过程中排风温度等于或低于42℃。
项目18.用于制备含有瑞戈非尼的薄膜包衣的药物组合物的方法,其中在包衣锅或有孔滚筒包衣机中将包衣液体喷洒至药物组合物上,且在包衣过程中排风温度等于或低于42℃。
具体实施方式
实施例
实施例1:含有瑞戈非尼的包衣片剂
a)固体分散剂
制备0.415kg的瑞戈非尼一水合物(对应于0.40kg瑞戈非尼)和1.60kg的聚乙烯基吡咯烷酮(PVP 25)于4.8kg丙酮和1.20kg 乙醇的混合物中的溶液。使用流化床真空制粒机在60至70℃的温度下将该溶液喷洒在1.00kg交联羧甲基纤维素钠和1.00kg微晶纤维素的粉末层上。
b)制片
步骤a)的颗粒被滚筒压紧并筛出3.15mm和1.0mm的颗粒。随后压紧的颗粒与0.54kg交联羧甲基纤维素钠、0.0240kg胶态无水二氧化硅和0.0360kg硬脂酸镁混合。在旋转压片机中将该预压混合物压制成含有20mg和40mg的瑞戈非尼的片剂。
c)薄膜包衣
对于20mg片剂的包衣,将0.160kg的OpadryTM II 85G35294粉均匀地分散于0.640kg水中。对于40mg片剂的包衣,将0.120kg的OpadryTM II 85G35294粉均匀地分散于0.480kg水中。在35℃的排风温度下,在有孔滚筒包衣机中将这些包衣混悬液喷洒在分别为20mg和40mg的步骤b)的片剂上。包衣过程产生具有光滑表面的均匀包衣片。不能观察到包衣缺陷。
市售可得的OpadryTM II 85G35294粉包含聚乙烯醇(部分水解)[全部混合物的44重量%]、聚乙二醇(PEG 3350)[全部混合物的12.4重量%]、卵磷脂(大豆)、氧化铁、二氧化钛和滑石。
表2:含有瑞戈非尼的片剂的组成
实施例1的制剂也以不同(即更大)规模制备。配料比和设备的操作原理相同。
实施例A:基于HPMC包衣的含有瑞戈非尼的片剂用于对比
在60℃的排风温度下,将与如实施例1(a-b)所述制备的未包衣片剂相同的片剂芯用基于羟丙基甲基纤维素(HMPC)的包衣混悬液(HMPC 15cp 720g,PEG 335024.0g,二氧化钛23.3g,氧化铁红0.72g,水1480g)包衣。
实验结果:
实施例1与实施例A之间的比较
在步骤b)之后在实施例1的未包衣片剂中检测到的降解产物4-(4-氨基-3-氟苯氧基)吡啶-2-羧酸甲酰胺(IUPAC:4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺)(AFP-PMA)的量为0.0042重量%,基于瑞戈非尼的量计。在实施例1的最后的步骤c)之后,在实施例1的包衣片剂中检测到AFP-PMA的量为0.0050重量%,基于瑞戈非尼的量计。AFP-PMA的量仅增加0.0008%。
在研究以更大规模制备的实施例1的片剂和包衣片剂时,观察到类似的增长率。
在对比实施A中使用的未包衣片剂中检测到AFP-PMA的量为0.0024重量%,基于瑞戈非尼的量计。在包衣(基于HMPC的包衣)之后,在实施例A的包衣片中检测到AFP-PMA的量为0.0078重量%,基于瑞戈非尼计。AFP-PMA的量增加0.0054%。
实施例1的储存稳定性
在a)25℃和60%相对湿度,以及b)30℃和75%相对湿度下,将实施例1的包衣片剂连同分子筛(CAN TRI-SORBTM 4A,3g,Süd-Chemie)一起包装于HDPC(高密度聚乙烯)瓶中。
类似地,在a)25℃和60%相对湿度,以及b)30℃和75%相对湿度下,将实施例1的包衣片剂连同硅胶(CAN SORB-ITTM3g,Süd-Chemie)一起包装于HDPC瓶中。
两个稳定性研究的结果如表3所示。在所有的研究中发现AFP-PMA的量近似线性增加。因此,稳定性结果以在最高达30个月的时间内在若干批次上测定的平均月增长率表示。
在各批次的保质期的末期存在于含有瑞戈非尼的包衣片剂中的AFP-PMA的实际量可通过在释放测试时向存在于包衣片剂中的起始量加上各月增量来估算。同样地,可推算与干燥剂一起包装于瓶中的产品在气候带的保质期。
表3:含有瑞戈非尼的片剂的稳定性结果
Claims (10)
1.一种药物组合物,其包含:瑞戈非尼,瑞戈非尼的水合物、溶剂合物、代谢物或药学上可接受的盐,或其多晶型物,和至少一种药学上可接受的赋形剂,其中所述药物组合物被含有基于聚乙烯醇的聚合物和任选地一种以上其他的药学上可接受的赋形剂的包衣包覆。
2.权利要求1的组合物,其为片剂。
3.权利要求1至2中任一项的组合物,其为速释片剂。
4.权利要求1至3中任一项的组合物,其中基于聚乙烯醇的聚合物为水解的聚乙烯醇聚合物、部分水解的聚乙烯醇聚合物、酯化的聚乙烯醇聚合物、其与聚乙二醇的共聚物,或其混合物。
5.权利要求4的组合物,其中基于聚乙烯醇的聚合物为部分水解的聚乙烯醇聚合物。
6.权利要求1至5中任一项的组合物,其中基于聚乙烯醇的聚合物的存在量为全部包衣的30至70重量%。
7.权利要求1至6中任一项的组合物,其中所述包衣包含作为增塑剂的聚乙二醇、丙二醇、山梨醇、丙三醇、麦芽糖醇、木糖醇、甘露醇、赤藓糖醇、三油酸甘油酯、柠檬酸三丁酯、柠檬酸三乙酯、乙酰柠檬酸三乙酯、三乙酸甘油酯、硬脂酸、中链甘油三酯或其混合物。
8.权利要求7的组合物,其中增塑剂为聚乙二醇。
9.权利要求7至8中任一项的组合物,其中增塑剂的量为全部包衣的5至30重量%。
10.权利要求1至9中任一项的组合物,其包含固体分散剂,所述固体分散剂包含瑞戈非尼。
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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 |
JP2016531151A (ja) * | 2013-09-13 | 2016-10-06 | バイエル ファーマ アクチエンゲゼルシャフト | レファメチニブを含有する医薬組成物 |
CN104586808B (zh) * | 2014-12-27 | 2017-08-18 | 北京元延医药科技股份有限公司 | 抗肿瘤药物组合物 |
CN105136956A (zh) * | 2015-09-11 | 2015-12-09 | 江苏嘉逸医药有限公司 | 一种快速测定瑞戈非尼含量的方法 |
CN105267167A (zh) * | 2015-09-11 | 2016-01-27 | 江苏嘉逸医药有限公司 | 一种瑞戈非尼口服固体药物组合物的制备方法 |
CN106880615A (zh) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | 一种瑞戈非尼的口服固体制剂及其制备方法 |
CN106880607A (zh) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | 一种含有瑞戈非尼的口腔崩解片及其制备方法 |
CN105496975B (zh) * | 2015-12-17 | 2019-01-04 | 河南润弘制药股份有限公司 | 一种瑞戈非尼片剂及其制备方法 |
CN106913527A (zh) * | 2015-12-28 | 2017-07-04 | 江苏先声药业有限公司 | 一种瑞戈非尼速释微丸及其制备方法 |
CN105879049B (zh) * | 2016-05-13 | 2019-03-26 | 浙江大学 | 一种瑞戈非尼与β-环糊精的包合物及其制备方法 |
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 |
BR112019025478A8 (pt) * | 2017-06-02 | 2022-12-06 | Bayer Ag | Combinação de regorafenib e inibidores de pd-1/pd-l1(2) para tratamento de câncer |
MX2021000068A (es) * | 2018-07-06 | 2021-03-25 | Agios Pharmaceuticals Inc | Formas y composiciones farmaceuticas de ivosidenib. |
CN111053751A (zh) * | 2018-10-16 | 2020-04-24 | 正大天晴药业集团股份有限公司 | 瑞戈非尼的缓释片剂及其制备方法 |
TWI799599B (zh) * | 2019-06-06 | 2023-04-21 | 華納國際生物科技股份有限公司 | 醫藥或保健品自乳化固體分散組成物 |
EP3861989A1 (en) | 2020-02-07 | 2021-08-11 | Bayer Aktiengesellschaft | Pharmaceutical composition containing regorafenib and a stabilizing agent |
CN112587485A (zh) * | 2021-01-08 | 2021-04-02 | 湖南南新制药股份有限公司 | 一种药物固体分散体及其制备方法 |
CN113018274A (zh) * | 2021-03-10 | 2021-06-25 | 药源生物科技(启东)有限公司 | 一种含羟丙甲纤维素的药物组合物及其制备方法 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101363679B1 (ko) * | 2002-09-20 | 2014-02-14 | 안드렉스 랩스 엘엘씨 | 약제학적 정제 |
CN1265793C (zh) * | 2002-11-18 | 2006-07-26 | 杭州容立医药科技有限公司 | 左西替利嗪伪麻黄碱复方口服制剂及制备方法 |
NZ580384A (en) | 2003-07-23 | 2011-03-31 | Bayer Pharmaceuticals Corp | 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide and metabolites for the treatment and prevention of diseases and conditions |
MY191349A (en) * | 2004-08-27 | 2022-06-17 | Bayer Pharmaceuticals Corp | New pharmaceutical compositions for the treatment of hyper-proliferative disorders |
CA2633411A1 (en) * | 2005-12-15 | 2007-06-21 | Bayer Healthcare Ag | Diaryl ureas for treating inflammatory skin, eye and/or ear diseases |
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 |
WO2008044111A1 (en) * | 2006-10-13 | 2008-04-17 | Pfizer Products Inc. | Pharmaceutical formulation tablet |
AU2007333302A1 (en) * | 2006-12-07 | 2008-06-19 | Eli Lilly And Company | An article comprising prasugrel |
US20100316711A1 (en) * | 2007-10-25 | 2010-12-16 | Bayer Yakuhin ,Ltd. | Nifedipine containing opress coated tablet and method of preparing same |
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 |
AU2012260605B2 (en) * | 2011-05-20 | 2015-02-19 | Astrazeneca Uk Limited | Pharmaceutical composition of rosuvastatin calcium |
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