CN102076330A - 替卡格泮钾的固体剂量制剂 - Google Patents
替卡格泮钾的固体剂量制剂 Download PDFInfo
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- CN102076330A CN102076330A CN2009801252261A CN200980125226A CN102076330A CN 102076330 A CN102076330 A CN 102076330A CN 2009801252261 A CN2009801252261 A CN 2009801252261A CN 200980125226 A CN200980125226 A CN 200980125226A CN 102076330 A CN102076330 A CN 102076330A
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- oxo
- potassium
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
一种固体剂量药学制剂,其包含作为活性成分的N-[(3R,6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺(替卡格泮)的钾盐、精氨酸和药学上可接受的表面活性剂。本发明还涉及替卡格泮钾盐的无定形形式。
Description
发明领域
本发明的领域为固体剂量药学制剂。更具体地,本发明的领域为口服固体剂型的活性成分制剂。
发明背景
CGRP (降钙素基因相关肽) 是一种天然存在的37个氨基酸的肽,其通过降钙素信使RNA的组织特异性交替加工而产生,并且广泛地分布于中枢神经系统和外周神经系统。CGRP主要位于感觉传入神经元和中枢神经元,并且调节包括血管舒张在内的多种生物作用。当从细胞释放时,CGRP 通过与特定的细胞表面受体结合而启动其生物应答,该特定的细胞表面受体主要与腺苷酸环化酶的激活相关联。已经在多种组织和细胞中鉴定CGRP受体并进行了药理学评价,所述组织和细胞包括大脑、心血管、内皮和平滑肌来源的那些组织和细胞。
CGRP是一种强效的神经调节剂,其参与诸如偏头痛和丛集性头痛的脑血管疾患的病理。在临床研究中,发现在偏头痛发作期间出现颈静脉CGRP 水平的升高 (Goadsby等, Ann. Neurol., 1990, 28,
183-187),并且显示在偏头痛受治疗者的发作之间CGRP的唾液水平升高 (Bellamy等, Headache, 2006, 46, 24-33)。已经显示CGRP自身触发偏头痛性头痛 (Lassen等, Cephalalgia, 2002, 22,
54-61)。在临床试验中,已经证明CGRP拮抗剂BIBN4096BS在治疗偏头痛的急性发作中有效 (Olesen等, New Engl. J. Med., 2004,
350, 1104-1110 ),并且能够预防对照组中由CGRP输注所诱导的头痛 (Petersen等, Clin. Pharmacol Ther., 2005, 77, 202-213)。
三叉神经脉管系统的CGRP介导的激活可能在偏头痛病理中起到关键作用。另外,CGRP 激活颅内血管平滑肌上的受体,导致增加的血管舒张,这被认为造成了偏头痛发作期间的头痛性疼痛 (Lance, Headache
Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide,
Lippincott-Raven Publishers, 1997, 3-9)。脑膜中动脉,即硬膜中的主动脉,受来自三叉神经节的感觉纤维神经支配,该三叉神经节包含若干神经肽,包括CGRP。在猫中三叉神经节的刺激导致CGRP水平增加,并且在人类中,三叉神经系统的激活造成面部潮红以及外颈静脉中CGRP水平的增加 (Goadsby等, Ann. Neurol., 1988, 23,
193-196)。由此,CGRP的血管效应可通过CGRP拮抗剂来衰减、预防或者逆转。
CGRP拮抗剂化合物作为人类和动物中牵涉CGRP的疾患的药理剂是有用的,但是在人类中尤其有用。除头痛之外,此类疾患包括疼痛、非胰岛素依赖型糖尿病、血管疾患、炎症、关节炎、支气管高反应性、哮喘、休克、败血病、阿片戒断综合征、吗啡耐受、男性和女性潮热、变应性皮炎、银屑病、脑炎、脑外伤、局部缺血、中风、癫痫、神经退化性疾病、皮肤疾病、神经源性皮肤发红、皮肤玫瑰色和红斑、耳鸣、炎性肠病、肠易激综合征以及膀胱炎。其中尤为重要的是头痛的急性或预防性治疗,所述头痛包括偏头痛和丛集性头痛。
2004年10月28日公布的国际专利申请WO 2004/092166公开了可用于治疗人类或其他物种的疾病或病症的化合物,所述疾病可用CGRP受体功能抑制剂、调节剂或促进剂治疗。此类疾病或病症包括在参考申请中所提及的那些,并且特别包括偏头痛和丛集性头痛。
WO '166的实施例86 N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺(替卡格泮(telcagepant)或化合物1)是一种特别强效的CGRP调节剂:
WO '166中描述了化合物1的实验室制备。
国际专利申请公布WO 2007/120592公开了化合物1的钾盐(“替卡格泮”或化合物1A)、该钾盐的水合物(化合物1B或“替卡格泮钾水合物”)、以及该钾盐的乙醇化物(化合物1C或“替卡格泮钾乙醇化物”):
国际专利申请公布WO 2008/030524描述了化合物1的液体制剂,及其盐和溶剂化物形式。
替卡格泮目前处于治疗偏头痛的临床开发阶段。
发明概述
本发明涉及固体剂量药学制剂,其包含作为活性成分的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺(替卡格泮)的钾盐、精氨酸和药学上可接受的表面活性剂。在特定的实施方案中,该活性成分是替卡格泮钾的乙醇化物或水合物、或无定形形式。当该活性成分为乙醇化物时,本发明的组合物包含I型或II型替卡格泮钾乙醇化物或其混合物。
本发明还涉及替卡格泮钾盐的新的无定形形式。
发明附图
图1A和1B是由喷雾干燥法制备的粉末无定形形式的替卡格泮钾盐的照片;
图2A和2B是由沉淀法制备的粉末无定形形式的替卡格泮钾盐的照片;
图3是I型替卡格泮钾乙醇化物的X-射线衍射图;
图4是II型替卡格泮钾乙醇化物的X-射线衍射图;
图5是替卡格泮钾水合物的X-射线衍射图;
图6是无定形形式的替卡格泮钾的调制式DSC曲线;
图7是替卡格泮的结晶替卡格泮钾乙醇化物(I型)的碳-13交叉极化魔角自旋(CPMAS)核磁共振(NMR)谱;
图8是结晶替卡格泮钾水合物的碳-13交叉极化魔角自旋(CPMAS)核磁共振(NMR)谱;
图9是无定形替卡格泮钾的碳-13交叉极化魔角自旋(CPMAS)核磁共振(NMR)谱;
图10是I型替卡格泮钾乙醇化物的拉曼光谱;
图11是替卡格泮钾水合物的拉曼光谱;
图12是无定形形式的替卡格泮钾的拉曼光谱;
图13描绘了施用300 mg单一口服剂量的替卡格泮钾乙醇化物之后的初步平均血浆浓度-时间曲线。
发明详述
本发明涉及固体剂量药学制剂,其包含:
(1) N-[(3R,
6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾,或其水合物或乙醇化物,或其无定形形式;
(2) 精氨酸;和
(3) 药学上可接受的表面活性剂。
在特定的实施方案中,所述制剂包含N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的乙醇化物。
在其他实施方案中,所述制剂包含I型或II型的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的乙醇化物,或I型和II型的混合物。
如本发明的组合物中所使用的,I型可通过如本文描述的其特征x-射线衍射峰中的一个或多个来检测,诸如8.27、4.01和3.32埃的d-间距。
如本发明的组合物中所使用的,I型可通过如本文描述的其特征固态碳-13 NMR光谱峰中的一个或多个来检测,诸如109.1 ppm、55.8 ppm和54.6 ppm。
如本发明的组合物中所使用的,I型可通过如本文描述的其特征拉曼光谱中的一个或多个来检测,例如在646.3、707.4、761.5、832.9、1063.3、1365.5、1402.0、1445.7或1455.3的峰 (cm-1)。
如本发明的组合物中所使用的,II型可通过如本文描述的其特征x-射线衍射峰中的一个或多个来检测,诸如11.62、7.80和4.92埃的d-间距。
在其他的实施方案中,所述制剂包含N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的水合物。
如本发明的组合物中所使用的,所述水合物可通过如本文描述的其特征x-射线衍射峰中的一个或多个来检测,诸如16.96、8.50和4.26埃的d-间距。
如本发明的组合物中所使用的,所述水合物可通过如本文描述的其特征固态碳-13 NMR光谱峰中的一个或多个来检测,诸如126.1 ppm、54.4 ppm和36.6 ppm。
如本发明的组合物中所使用的,所述水合物可通过如本文描述的其特征拉曼光谱中的一个或多个来检测,例如通过646.8、707.0、753.7、832.7、1064.7、1364.3、1403.0或1441.0的峰 (cm-1)。
在另一个实施方案中,所述制剂包含无定形形式的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾。
所述制剂可包含从约0.005 mg 至约1000 mg 的活性成分N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺,其由N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾替卡格泮作为水合物、乙醇化物或无定形形式的当量重量测量结果所决定。适合的制剂可包含基于当量重量的从约10 mg至800 mg、或从25 mg至750 mg、或从50 mg至700 mg、或从100 mg至500 mg的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺。适合的具体的制剂包含约140 mg、约150 mg、约280 mg或约300 mg的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺。
所述制剂可包含按重量计约25%至约75%的作为活性成分的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺,例如按重量计约35%至约55%。典型地,所述组合物可包含按重量计约50%。重量百分比由N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾作为水合物、乙醇化物 (I型或II型,或其混合物) 或无定形形式的当量重量测量结果所决定。
已经发现在体内于患者的胃中或者在模拟的胃液中,替卡格泮不能从标准的药学制剂有效地释放。认为标准制剂的表面胶凝,由此妨碍了水渗透入该制剂并抑制了替卡格泮活性成分的释放。在标准的制剂中,该钾盐转化为中性形式,在片剂的周围形成了相对不溶的壳。所述壳有效地防止了药物的溶出。
如以上所解释的,本发明涉及包含精氨酸的替卡格泮的固体剂量制剂,其具有与替卡格泮的液体制剂相当的生物利用度。认为精氨酸在该固体剂量制剂中起药学上可接受的碱化/溶出促进剂的作用。该碱化/溶出促进剂促进活性成分的释放而不会显著地影响制剂的其他有利性质。该碱化/溶出促进剂的存在有利于片剂在胃中在酸性条件下溶蚀和溶出时药物从所述制剂释放。
因此,本发明的制剂包括 "碱化/溶出促进剂" ,即,单氨基二羧酸精氨酸((NH2CH-COOH(CH2)3-NH-CNH(NH2))。认为精氨酸的碱化/溶出促进性质是由于其相对高的溶解度,以及其高的pKa 和等电点。精氨酸具有2.03、9.00和12.1的pKa,以及10.76的pI(等电点) 。
氨基酸碱化/溶出促进剂起到预防或抑制在胃中或在模拟胃液中的溶出期间片剂表面上不溶性壳形成(中性形式)的作用。本发明的适合制剂可包含碱化/溶出促进量的碱化/溶出促进剂(即精氨酸)。适合的量是至少5.0%的碱化/溶出促进剂,或至少10.0%的碱化/溶出促进剂。碱化/溶出促进剂的适合的量可至多90.0%碱化/溶出促进剂 (精氨酸)。在其他的实施方案中,适合的量至多50.0%,或至多35.0%,或至多30.0%。适合的药学制剂可包含约40.0%的碱化/溶出促进剂,约30.0%的碱化/溶出促进剂,约25.0%的碱化/溶出促进剂,约20.0%的碱化/溶出促进剂,约15.0%的碱化/溶出促进剂或者约10.0%的碱化/溶出促进剂。
在本发明的一个实施方案中,所述固体剂量制剂是片剂。
本发明的制剂还可包含药学上可接受的表面活性剂。如本文所用,术语“药学上可接受的表面活性剂”或“表面活性剂”可互换使用,并且指通过在液体-气体界面吸附而减少水的表面张力的试剂。表面活性剂通常是两亲性的有机化合物,即包含疏水性基团和亲水性基团的分子。表面活性剂按制剂重量计的存在量通常可以达约1%至50%。
适合在本发明使用的表面活性剂可分类为药学上可接受的阴离子型表面活性剂、阳离子型表面活性剂、两性的(兼性的/双嗜性的)表面活性剂,以及非离子型表面活性剂。
优选的表面活性剂是非离子型表面活性剂。术语“非离子型表面活性剂”根据药学制剂领域技术人员的理解是指在水中不解离成离子的表面活性剂类别。用于本发明制剂的优选的非离子型表面活性剂是聚氧丙烯嵌段共聚物,也称为"泊洛沙姆",其包含中央的聚氧丙烯疏水链和两条聚氧乙烯亲水链。适合的泊洛沙姆包括泊洛沙姆407。
该制剂可包括至多50%的泊洛沙姆,在某些实施方案中,至多10%,在其他实施方案中至多7.5%。适合的药学制剂可包括约10.0%泊洛沙姆,约7.5%泊洛沙姆,约5.0%,,或约2.0%泊洛沙姆。
适合的药学上可接受的阴离子表面活性剂包括,例如单价烷基羧酸盐、酰基乳酸盐、烷基醚羧酸盐、N-酰基肌氨酸盐、多价烷基碳酸盐、N-酰基谷氨酸盐、脂肪酸-多肽缩合物、硫酸酯、烷基硫酸盐(包括月桂基硫酸钠(SLS)、乙氧基化烷基硫酸盐、酯连接的磺酸盐(包括多库酯钠或二辛基琥珀酸钠(DSS)、α烯烃磺酸盐和磷酸化乙氧基化醇(phosphated ethoxylated
alcohol)。
适合的药学上可接受的阳离子表面活性剂包括,例如单烷基季铵盐、二烷基季铵盐化合物、酰氨基胺和胺化酰亚胺。
适合的药学上可接受的两性的(兼性的/双嗜性的)表面活性剂包括,例如N-取代的烷基酰胺、N-烷基甜菜碱、磺基甜菜碱、和N-烷基β-氨基丙酸盐。
其他适合与本发明结合使用的表面活性剂包括聚乙二醇作为酯或醚。实例包括聚乙氧基化蓖麻油、聚乙氧基化氢化蓖麻油、或源于蓖麻油的聚乙氧基化脂肪酸或源于氢化蓖麻油的聚乙氧基化脂肪酸。可使用已知的以商品名Cremophor、Myrj、Polyoxyl 40 硬脂酸酯、Emerest 2675、Lipal 395和PEG 3350商购的表面活性剂。
还有其他实施方案中,该制剂包括药学上可接受的崩解剂。崩解剂是添加到药学片剂中有助于片剂在施用后分散或崩解的物质。适合的崩解剂是淀粉(包括玉米淀粉和马铃薯淀粉)、粘土、纤维素、aligns、树胶和交联聚合物。适合的崩解剂包括有“超级崩解剂”之称的崩解剂种类,其用量通常可低于其他的崩解剂。示例性的超级崩解剂的种类包括交联羧甲纤维素,交联聚乙烯吡咯烷酮(也称为交聚维酮)和glycosate淀粉钠。
崩解剂(包括超级崩解剂)的存在量按重量计可以至多为制剂的约20%。
还有其他的实施方案中,该制剂包含另外的药学上可接受的赋形剂,包括,例如填充剂、助流剂、润滑剂、着色剂、包衣剂和蜡。
向制剂中加入填充剂是为了提供体积以便于处理和加工。适合在本发明中使用的药学上可接受的填充剂包括甘露醇、AVICEL、非乳糖填充剂以及其他与胺基无相互作用的填充剂。
助流剂改善粉末的流动特性。适合在本发明中使用的助流剂包括胶体二氧化硅和滑石。助流剂通常在制剂中的存在量按重量计至多约1%。在本发明的一些实施方案中,润滑剂的存在量按重量计至多0.5%。
润滑剂也减少颗粒间摩擦,有助于片剂从模具中顶出。在本发明中使用的示例性润滑剂包括滑石、硬脂酸镁(颗粒内和/或颗粒外),硬脂酸钙、硬脂酸、山萮酸甘油酯(glyceryl behanate)、氢化植物油和聚乙二醇。润滑剂通常在制剂中的存在量按重量计至多2%。在本发明的一些实施方案中,润滑剂的存在量按重量计至多1%,或按重量计至多0.5%。着色剂改善药物制剂的美观性,并且帮助在制造期间分辨和识别制剂。在本发明中有用的着色剂包括任何被the Food and Drug
Administration批准用于药学制剂的色料。
还可使用薄膜包衣剂包衣制剂。适合的薄膜包衣剂包括OPADRY和OPADRY II(具有不同着色剂的混合物),由Colorcon公司制造。这些是羟丙基纤维素,HPMC 2910/羟丙甲纤维素6 cp基料和聚乙烯醇基料包衣制剂。
本发明还涉及治疗头痛的方法,包括给患者施用本发明的固体剂量制剂。
本发明还涉及本发明制剂治疗与CGRP有关的疾病或疾患,例如头痛,包括丛集性头痛和偏头痛的用途。
本发明的另一个实施方案涉及治疗、控制、改善或降低患者与CGRP受体有关的疾病或疾患(例如头痛)的风险的方法,包括给患者施用本发明的制剂。
在一个实施方案中,本发明的固体剂量制剂提供的血中Cmax为至少2.75μM。在其他实施方案中,本发明的固体剂量制剂提供的血中Cmax为至少3.0μM。在特定的实施方案中,对于包括约280 mg替卡格泮活性成分的制剂,和包括约300 mg 替卡格泮活性成分的制剂,实现以上所列的理想Cmax值。
在一个实施方案中,本发明的固体剂量制剂在施用后不超过1.0小时的时间点达到Tmax。在另一个实施方案中,本发明的固体剂量制剂在施用后不超过1.25小时的时间点达到Tmax。在又一其他的实施方案中,本发明的固体剂量制剂在施用后不超过约1.5小时的时间点达到Tmax。
在一个实施方案中,本发明的固体剂量制剂显示的血中AUC0-Tmax不超过2.5 μM hr。在其他的实施方案中,本发明的固体剂量制剂显示的血中AUC0 ~ Tmax不超过2.0μM hr。
在一个实施方案中,本发明的固体剂量制剂显示的血中AUC0-2hr不超过5.5μM hr。在其他的实施方案中,本发明的固体剂量制剂显示的血中AUC0-2hr不超过4.5μM hr。
在一个实施方案中,本发明的固体剂量制剂显示的血中AUC0-4hr不超过10.0μM hr。在其他的实施方案中,本发明的固体剂量制剂显示的血中AUC0-4hr不超过9.0μM hr。
在一个实施方案中,本发明的固体剂量制剂显示的血中AUC0- ∞不超过15.5μM hr。在其他的实施方案中,本发明的固体剂量制剂显示的血中AUC0- ∞不超过15.0μM hr。
示例性的制剂示于以下表1中:
表1
核芯片剂重量根据本领域技术人员已知的盐换算因数计算(例如,1.1494 g替卡格泮钾盐相当于1 g中性替卡格泮)。
定义
如本文所用,术语“替卡格泮”和“化合物1”使用时互换,均指化合物N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺:
USAN委员会采用的术语“替卡格泮钾”指N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺和乙醇的钾盐。然而,如本文所用,术语“替卡格泮钾”指N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺的钾盐的全部形式或溶剂化物(化合物1A):
如本文所用,术语“替卡格泮钾乙醇化物”指N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的乙醇化物(化合物1C):
。
如本文所用,术语“替卡格泮钾水合物”指N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的水合物(化合物1B):
。
如本文所用,术语“治疗”(treatment),“治疗”(treating)等等指获得期望的药理学和/或生理学效果。就疾病、疾患或病症、或其症状的完全或部分预防而言,效果可以是预防性的;和/或就疾病、疾患或症状,和/或归因于其的副作用的部分或完全治愈而言,效果可以是治疗性的。如本文所用,“治疗”涵盖了哺乳动物,尤其是人类中疾病、疾患或病症的任何治疗,并且包括:(a)在可能易于患但尚未被诊断出患有疾病、疾患或病症的受治疗者中,预防疾病、疾患或病症的发生;(b)抑制疾病、疾患或病症,即阻滞其发展;和(c) 缓解疾病、疾患或病症,即引起复原。
本文使用的术语“个体”、“受治疗者”和“患者”可互换,指哺乳动物,包括但不限于鼠类、猿猴、人类、哺乳类农畜、哺乳类运动动物(sport animal)和哺乳类宠物。优选地,患者是人类(男性或女性)。
“治疗有效量”或“有效量”指给哺乳动物或其他受治疗者施用以治疗疾病时,替卡格泮或其盐或溶剂化物的量(例如,替卡格泮的量,或其盐或溶剂化物的量)足以实现对疾病的此类治疗。“治疗有效量”将根据化合物、疾病及其严重程度和所治疗的受治疗者的年龄、体重等而变化。
当在诸如“药学上可接受的赋形剂”、“药学上可接受的稀释剂”、“药学上可接受的载体”和“药学上可接受的助剂”的短语中单独使用时,术语“药学上可接受的”指在药学制剂制备中适用的赋形剂、稀释剂、载体、助剂或类似材料通常是安全、无毒的并且没有生物学或其他方面的不适,并且包括兽医用途以及人类药学用途可接受的赋形剂、稀释剂、载体和助剂。“药学上可接受的”材料指在合理的医学判断范围内适合与人类和动物的组织接触而没有过度的毒性、刺激、变态反应或其他问题并发症(与合理的益处/风险比相称)。在一些实施方案中,术语“药学上可接受的”指被联邦或州政府管理机构批准或列于美国药典或其他所公认的国际药典中而用于动物,尤其是用于人的。
如说明书和权利要求书所用,“药学上可接受的赋形剂”或药学上可接受的“稀释剂”、“载体”或“助剂”包括一种或多于一种此类赋形剂、稀释剂、载体或助剂。“赋形剂”、“稀释剂”、“载体”或“助剂”指在固体剂量药学制剂的配方中使用的物质,并且其本身通常具有极少或不具有治疗价值。可在本发明中使用各种赋形剂、稀释剂、载体或助剂,包括描述于Remington: The Science and
Practice of Pharmacy, 第21版,第317-318页(2006)的那些。这些包括,但不限于表面活性剂、崩解剂、填充剂、抗氧剂、抗菌剂(预防如与表现出治疗效果的那些作用相反的制剂本身的衰败)、防腐剂、螯合剂、缓冲剂、助流剂、润滑剂、调节毒性的试剂、着色剂、调味剂和稀释剂、乳化剂和悬浮剂,以及其他具有药学应用的物质。
如本文所用,术语“固体单元剂量形式”指物理分立的固体单元,适合作为用于人类和动物受治疗者的单元剂量,每个单元含有经计算其量足以产生期望效果的预定量的本发明的化合物和药学上可接受的稀释剂、载体或媒介物。示例性的“固体单元剂量形式”是片剂、胶囊、丸剂、锭剂、扁囊剂和小丸。本发明的固体剂量制剂被设计用于口服施用的途径。
如本文所用,“药学制剂”意指包括适合给受治疗者,例如哺乳动物,尤其是人口服施用的组合物。通常,“药学制剂”无菌,并且通常不含有能够在受治疗者中引起不希望响应的杂质(例如,药学组合物中的化合物是制药级的)。
替卡格泮的形式
乙醇化物
如上所述,替卡格泮钾乙醇化物,以及合成方法公开于国际申请WO2007/120592中。制造I型替卡格泮钾乙醇化物的方法公开于国际申请WO2007/120592实施例3-6中。当没有向替卡格泮钾溶液中加入I型种子(晶体)时在制造过程中已经观察到II型乙醇化物形成。
I型钾盐乙醇化物显示对应于8.27、4.01、和3.32埃的d-间距的衍射峰。I型钾盐乙醇化物进一步以16.52、7.55和7.02埃的d-间距表征。I型钾盐乙醇化物甚至进一步以5.52、5.08和4.63埃的 d-间距表征。
II型钾盐乙醇化物显示的特征衍射峰对应于11.62、7.80和4.92埃的d-间距。II型钾盐乙醇化物进一步以4.55、4.31和4.11埃的d-间距表征。II型钾盐乙醇化物更进一步以3.85、3.55和2.88埃的d-间距表征。
I型以固态碳-13 NMR光谱的109.1 ppm、55.8 ppm和54.6 ppm峰表征。
I型替卡格泮钾盐乙醇化物的拉曼光谱以峰(cm-1)646.3、707.4、761.5、832.9、1063.3、1365.5、1402.0、1445.7、1455.3表征。
水合物
替卡格泮钾水合物和合成方法公开于国际申请WO 2007/120592中。
钾盐水合物显示的特征衍射峰对应于16.96、8.50和4.26埃的d-间距。钾盐水合物进一步以7.41、6.88和3.79埃的d-间距表征。钾盐水合物更进一步以5.00、3.41和3.06埃的d-间距表征。
钾盐水合物以固态碳-13NMR光谱的126.1 ppm、54.4 ppm和36.6 ppm峰表征。
钾盐水合物的拉曼光谱以峰(cm-1) 646.8、707.0、753.7、832.7、1064.7、1364.3、1403.0、1441.0表征。
无定形形式
如本文所用,术语“无定形形式”指化学和物理稳定的无定形的、非晶体形式的替卡格泮钾。无定形形式在贮存中不会转化成晶体形式,但如果不保护使之免受湿气的影响,则易吸湿并吸水。
可在不添加任何聚合物的情况下,通过将替卡格泮钾盐的有机溶液喷雾干燥来获得无定形形式。在喷雾干燥工艺中,液体原料雾化成微米尺寸的液滴喷雾,当液滴在干燥室中与热处理气体接触,溶剂快速蒸发。在受控的温度和气体流量条件下进行干燥颗粒的形成。有机溶剂的快速蒸发导致无定形药物的形成。适合的有机溶剂包括甲醇和丙酮。
可选地,可通过加热替卡格泮钾盐乙醇化物,并且在乙醇化物上方通过湿氮气来制备该无定形形式。
该无定形形式可通过撞击喷射(impinging jet)工艺来获得,其中将浓缩的替卡格泮的乙酸异丙酯溶液与反溶剂(例如庚烷)快速混合,由此形成作为沉淀物的该无定形形式。向原料流中加入少量的水改善该无定形形式的颗粒的形态。
根据如何制备该无定形形式,其形态、粒度分布和表面积不同。通过喷雾干燥制备的该无定形形式一般更小,并且是相对粘聚的材料。喷雾干燥的无定形形式在40℃/75%相对湿度下化学稳定6周。
由喷雾干燥产生的该无定形形式所具有的平均粒度小于15μm,经常小于10μm;密度(g/cm3)为0.20或更小,经常为0.15或更小;Carr's系数(压缩百分比)为35-45%;Hausner比为约1.64;并且表面积(m2/g)为3.0或更小;经常为2.5或更小,经常为2.0或更小。
Carr's系数在药学技术中经常用作粉末流动性的指示。参见Mark Gibson, “Pharmaceutical
Preformulation and Formulation: A Practical Guide from Candidate Drug Selection
to Commercial Dosage Form,”Boca Raton: CRC Press. (2001)。
Hausner比为粉末流动性的量度。
由溶液沉淀制备的无定形形式具有更宽的粒度分布、高的表面积。预期由溶液沉淀制备的无定形形式将会是多孔的材料。
由沉淀产生的无定形形式所具有的平均粒度小于150μm,经常小于125μm,经常小于110μm;Carr's系数(压缩百分比)为25-30%;Hausner比为约1.38或更多;并且表面积 (m2/g) 为50-100 m2/g,更经常为70-90 m2/g。
该无定形的钾盐在逆热流曲线中显示热容量的变化,中点温度为189.00℃, 对应于无定形的钾盐的玻璃转化温度。
该无定形形式的钾盐以固态碳-13 NMR光谱的126.0 ppm、53.7 ppm和29.1 ppm峰表征。
该无定形的钾盐的拉曼光谱以峰(cm-1) 646.8、706.8、752.3、832.4、1063.6、1365.2、1437.6表征。
制剂的制造
本发明的制剂可通过干法制粒来制备。对于N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺的所有药物物质形式(钾盐水合物,钾盐乙醇化物(I型或II型,或其混合物)、钾盐无定形),片剂制造工艺基本相同。以下所示制造工艺流程图描述了适合于制造本发明固体剂量制剂的工艺:
可选地,可使用湿法制粒工艺。用于生产药学片剂的湿法制粒法对于本领域技术人员来说是熟知的。一般地,湿法制粒工艺涉及如下步骤:称重、混合、制粒、筛分湿物质、干燥、干筛、润滑并将物质压缩成片剂。混合步骤在掺混机,例如双壳掺混机、双锥鼓掺混机或带形掺混机中进行,或在行星式混合机或高速/高剪切混合机中进行。
制剂还可通过流化床制粒工艺制备。
干法制粒、湿法制粒和流化床制粒工艺描述于Remington's“The Science and Practice
of Pharmacy”,第21版(2006),第896-901页。
本发明制剂的剂量和用途。
本发明制剂作为CGRP拮抗剂的能力使得它们可以用作涉及人类和动物,特别是涉及人类中CGRP的疾患的有效药理学试剂。
本发明的制剂具有治疗、预防、改善、控制或减小以下一种或多种病症或疾病风险的功效:头痛;偏头痛;丛集性头痛;慢性紧张性头痛;疼痛;慢性疼痛;神经源性炎症和炎性疼痛;神经病性疼痛;眼痛;牙痛;糖尿病;非胰岛素依赖性糖尿病;血管疾患;炎症;关节炎;支气管高反应性,哮喘;休克;脓毒症;阿片样物质戒断综合征;吗啡耐受;男性和女性热潮红;变应性皮炎;银屑病;脑炎;脑外伤;癫痫;神经变性疾病;皮肤病;神经性皮肤发红,皮肤玫瑰疹和红斑;耳鸣;炎性肠病,肠应激综合征,膀胱炎;及其它可能通过拮抗CGRP受体治疗或预防的病症。特别重要的是急性或预防性治疗包括偏头痛和丛集性头痛在内的头痛。
所施用的替卡格泮钾盐(或其水合物或其乙醇化物或其无定形形式)的剂量取决于受者的年龄、健康和体重,同时治疗的类型(如果有的话)、治疗的频率以及期望效果的性质。本发明制剂可含有的根据本发明的替卡格泮钾盐(或其水合物或其乙醇化物或其无定形形式)的数量是有效治疗所治疗的受治疗者的病症、疾患或疾病的量。本领域普通技术人员将会意识到给需要的患者施用药学有效量的替卡格泮钾盐(或其水合物或其乙醇化物(I型或II型,或其混合物),或其无定形形式)的方法可凭经验确定,或根据医学领域当前所认可的标准确定。将理解到,例如,当给人类患者施用时本发明制剂的药物的全部日剂量将在主治医师合理的医学判断范围内决定。
对本发明剂量的描述是根据可获得的作为活性成分的替卡格泮中性形式N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺的量。如技术人员所理解,活性成分的量根据换算因数计算,以制剂中使用的替卡格泮的形式(钾盐乙醇化物、钾盐水合物、钾盐无定形)和其他要素,例如,制造批次的测定和纯度(水、乙醇、溶剂或其他杂质的量)为基础计算。乙醇化物示例性的换算因数为1.1494 g乙醇化物相当于1.0 g活性成分(或中性形式)。水合物示例性的换算因数是1.157 g水合物相当于1.0 g活性成分(或中性形式)。无定形形式示例性的换算因数是1.067 g无定形形式相当于1.0 g活性成分(或中性形式)。
因此,100 mg单位剂量制剂将包括115.2 mg乙醇化物(如果替卡格泮为钾盐的乙醇化物形式),115.7 mg水合物(如果替卡格泮为钾盐的水合物形式),或106.7 mg无定形(如果替卡格泮为钾盐的无定形形式)。
在需要拮抗CGRP 受体活性从而治疗、预防、控制、改善或者降低病症风险时,适当的剂量水平通常将是约0.01至500毫克替卡格泮活性成分/kg患者体重/天,其可以单剂量或者多个剂量施用。适宜的剂量水平可以为约0.01至250mg/kg/天、约0.05至100mg/kg/天或者约0.1至50mg/kg/天。替卡格泮活性成分(钾盐水合物、乙醇化物的形式或无定形形式)可以按照每天施用1至4次的方案施用,或者可以每天施用一次或者两次。可以对此剂量方案进行调节,从而提供最佳的治疗学响应。
可与载体材料组合以生产单剂量形式的替卡格泮活性成分的量将根据所治疗的宿主和特定的施用方式而变化。例如,用于给人类口服施用的制剂可以适当地含有约0.005 mg至约2.5 g 替卡格泮,与适宜并且适当量的载体材料混合。单元剂量形式通常将含有约0.005 mg至约1000 mg 替卡格泮,一般含0.005 mg、0.01 mg、0.05 mg、0.25 mg、1 mg、5 mg、25 mg、50mg、100 mg、150 mg、200 mg、250 mg、300 mg、350 mg、400 mg、500 mg、600 mg、800 mg或1000 mg,每天施用1次、2次或3次。优选的单元剂量形式是100至200 mg、或250 mg至350 mg。
任何特定患者的替卡格泮活性成分的具体治疗有效剂量水平将取决于根据多种因素:所达到的细胞响应的类型和程度;使用的具体药物的活性;所使用的具体药物;患者的年龄、体重、一般健康、性别和饮食;施用时间,施用途径,药物排泄速率;治疗持续时间;药物联用或与特定药物协同;以及医学领域已知的相似因素。例如,以比需要实现期望治疗效果的剂量更低的剂量水平作为替卡格泮起始剂量,逐渐增加剂量直到实现期望效果,这完全在技术人员的技能范围内。
本发明制剂的组合疗法
本发明制剂可以组合使用抗炎剂或镇痛剂或抗偏头痛剂比如麦角胺或5-HT1激动剂,特别是5-HT1B/1D激动剂,例如舒马曲坦、那拉曲坦、佐米曲坦、依利曲坦、阿莫曲坦、夫罗曲普坦、多尼普曲坦和利扎曲坦;环氧合酶抑制剂,比如选择性环氧合酶-2抑制剂,例如罗非考昔、艾托考昔、西利考昔、伐地考昔或者帕瑞考昔;非甾族抗炎剂或者细胞因子-抑制抗炎剂,例如与诸如以下的化合物:阿司匹林、布洛芬、酮洛芬、非诺洛芬、萘普生、吲哚美辛、舒林酸、美洛昔康、吡罗昔康、替诺昔康、氯诺昔康、酮洛酸、依托度酸、甲灭酸、甲氯灭酸、氟灭酸、托芬那酸、双氯芬酸、奥沙普嗪、阿扎丙宗、尼美舒利、奈丁美酮、替尼达普、依那西普、托美丁、苯丁唑酮、羟保泰松、二氟尼柳、双水杨酯、奥沙拉秦或者柳氮磺吡啶等等;或者甾族镇痛剂。类似地,本发明化合物可以与止痛剂一起施用,比如对乙酰氨基酚、非那西汀、可待因、芬太尼、舒芬太尼、美沙酮、乙酰美沙醇、丁丙诺啡或者吗啡。
另外,本发明制剂可以组合下列物质使用:白介素抑制剂,比如白介素-1抑制剂;NK-1受体拮抗剂,例如阿瑞吡坦;NMDA拮抗剂;NR2B拮抗剂;血管舒缓激肽-1受体拮抗剂;腺苷A1受体激动剂;钠通道阻断剂,例如拉莫三嗪;阿片制剂激动剂,比如左旋乙酰美沙酮或者醋美沙朵;脂氧合酶抑制剂,比如5-脂氧合酶抑制剂;α受体拮抗剂,例如吲哚拉明;α受体激动剂;辣椒素受体拮抗剂;mGluR5激动剂、拮抗剂或者增效剂;GABA A受体调节剂,例如阿坎酸钙;烟碱样拮抗剂或者激动剂,包括尼古丁;毒蕈碱样激动剂或者拮抗剂;选择性5-羟色胺再摄取抑制剂,例如氟西汀、帕罗西汀、珊特拉林、度洛西汀、艾司西酞普兰或者西酞普兰;三环抗抑郁药,例如阿米替林、多塞平、普罗替林、地昔帕明、曲米帕明或者丙咪嗪;白细胞三烯拮抗剂,例如孟鲁司特或者扎鲁司特;一氧化氮抑制剂或者一氧化氮合成抑制剂。
此外,本发明制剂可以组合以下物质使用:麦角生物碱,例如麦角胺、麦角新碱、麦角新碱、甲基麦角新碱、甲麦角林、甲磺酰麦角碱、二氢麦角胺、二氢麦角考宁、二氢麦角日亭、二氢麦角隐亭、二氢-I-麦角隐亭、二氢-θ-麦角隐亭、麦角毒碱、麦角考宁、麦角日亭、麦角隐亭、I-麦角隐亭、θ-麦角隐亭、麦角辛、麦角甾烷、溴隐亭或二甲麦角新碱。
另外,本发明制剂可以组合以下物质使用:β-肾上腺素拮抗剂,比如噻吗洛尔、普萘洛尔、阿替洛尔或者纳多洛尔等等;MAO抑制剂,例如苯乙肼;钙通道阻断剂,例如氟桂嗪、尼莫地平、洛美利嗪、维拉帕米、硝苯地平、普鲁氯哌嗪或者加巴喷丁;安定药,比如奥氮平和喹硫平;抗惊厥药,比如托吡酯、唑尼沙胺、托那博沙、卡拉博沙或者双丙戊酸钠;血管紧张素II拮抗剂,例如洛沙坦和坎地沙坦西酯;血管紧张素转化酶抑制剂,比如赖诺普利;或者A型肉毒杆菌毒素。
本发明制剂可以组合下列物质使用:增效剂,比如咖啡因、H2-拮抗剂、二甲基硅油、氢氧化铝或者氢氧化镁;解充血药,比如苯肾上腺素、苯丙醇胺、伪麻黄碱、羟甲唑啉、肾上腺素、萘唑啉、赛洛唑啉、丙己君或者左-脱氧-麻黄素;止咳药,比如可待因、氢可酮、卡拉美芬、维静宁或者右美沙芬;利尿剂;促动力剂,比如甲氧氯普胺或者多潘立酮;以及镇静性或者非镇静性抗组胺。
在特别优选的实施方案中,本发明制剂用于与下列物质组合使用:抗偏头痛剂,比如:麦角胺;5-HT1激动剂,特别是5-HT1B/1D激动剂(特别是叔马曲坦、那拉曲坦、佐米曲坦、依利曲坦、阿莫曲坦、夫罗曲普坦、达尼曲坦和利扎曲坦);和环加氧酶抑制剂,比如选择性环加氧酶-2抑制剂,特别是罗非考昔、艾托考昔、西利考昔、美洛昔康、伐地考昔或者帕瑞考昔( paracoxib)。
以上组合不仅包括具有一种其他活性化合物的本发明制剂,而且包括具有两种或更多其他活性化合物的本发明制剂。同样地,本发明制剂可以结合其它用于预防、治疗、控制、改善或者降低本发明化合物可以用于处理的疾病或者病症风险的药物使用。所述其它药物可以以对此通常使用的途径和量与本发明化合物同时或者顺序施用。
在此类组合中,本发明制剂和其它活性成分可以单独施用或者联合施用。此外,一种成分可以在施用其它试剂之前、同时或者之后施用,并且它们可以经相同或者不同的施用途径施用。
除非另外定义,本文所使用的全部技术和科学术语具有与本发明所属领域的普通技术人员的通常理解相同的含义。虽然可以使用任何与本文描述的那些类似的方法和材料或其等价物实践或测试本发明,但是现在描述优选的方法和材料。将本文所提及的所有出版物引入以做参考,以揭示和描述与引用的出版物有关的方法和/或材料。
“任选的”或“任选地”指随后描述的事件、状况、特征或要素可以但不是必需存在,这样的描述包括了事件或状况存在的情况和不存在的情况。
必须指出的是如本文和所附权利要求书所用,除非上下文另外明确指明,单数形式“a”、“an”和“该(the)”包括复数对象。进一步需要指出的是权利要求书可被撰写成排除任何任选要素。因此,这种声明旨在充当与权利要求要素的引述有关的如“只”、“仅”之类的排他性术语的使用或“否定性”限制的使用的先行基础。
在进一步描述本发明之前,应该理解本发明并不限于所描述的特定实施方式,其本身自然可以变化。还应该理解本文所使用的术语仅仅是为了描述特定的实施方案,而不是意欲限制,因为本发明的范围仅受所附的权利要求书所限。
实施例
实施例1 - 无定形形式的替卡格泮钾
将替卡格泮钾盐乙醇化物的样品以12重量%溶于甲醇中。将溶液在SD-Micro(由丹麦Niro A/S 制造)中在以下条件下进行喷雾干燥:
处理气体速率:30 kg/hr
雾化速率:2 kg/hr
进料速率:15 mL/min
进口温度:136℃
出口温度:65℃。
使用X'pert X射线衍射仪(Philips公司制造)通过X射线粉末衍射谱测量所得粉末。衍射角是4至40°。单独的无定形形成由宽光晕(broad halo)的轮廓指示。
所得粉末的照片示于图1A (100μm比例尺(scale bar))和1B(20μm比例尺)。
所得粉末特征为具有7 µm的平均粒度。95%粉末具有小于18µm的粒度,10%具有小于2µm的粒度。测量的粉末密度为:“松”密度0.11g/cm3,“叩击(tapped)”密度0.18g/cm3。
测量的Carr's密度为39%, 和Hausner比为1.64。表面积为1.5 m2/g。
在25℃/75%相对湿度下测定的水含量为18%。
实施例2 - 无定形形式的替卡格泮钾的沉淀法
在乙酸乙酯或其他良好溶剂(例如,THF)中以40-300 mg/ml的范围制备浓缩的替卡格泮钾盐流。可向浓缩的M溶液中加入水以使水含量在0-2 wt%。水有助于形成易于过滤的三维颗粒。然后使用“撞击喷射”技术通过使用撞击喷射接触装置将浓缩流与庚烷或其他反溶剂(例如,环己烷)以1份体积浓缩批料:2份或更多份体积的庚烷比例接触使无定形替卡格泮钾盐沉淀。在该装置中,用注射泵持续将浓缩流进料入小体积,同时以注射泵将反溶剂加入该体积。在料流接触后产物沉淀,在收集烧瓶中收集所得产物浆料。在这种方法中,该装置呈现“T”型,具有用于批料和庚烷的进口和用于产物浆料的出口。将浆料过滤并用庚烷洗涤。然后在真空炉中于40-50℃干燥。
由实施例2的工艺生产的粉末照片示于图2A(300μm比例尺)和2B(50μm比例尺)。
所得粉末特征为具有99µm的平均粒度,95%粉末具有小于296 µm的粒度,10%具有小于11µm的粒度。测量的粉末密度为:“松”密度0.24 g/cm3,“叩击”密度0.33 g/cm3。
测量的Carr's密度为27%, 和Hausner比为1.38。表面积为80.6 m2/g。
在25℃/75%相对湿度下测定的水含量为约18%。
实施例3 - 替卡格泮钾形式的X射线粉末衍射研究
X-射线粉末衍射研究广泛应用在表征分子结构,结晶度和多晶型。I型和II型钾盐乙醇化物以及钾盐水合物的X-射线粉末衍射图谱是在配有PW3040/60控制台的Philips Analytical X'Pert PRO X-射线衍射系统上产生的。PW3373/00陶瓷铜LEF X-射线管K-α射线作为放射源。图3显示I型钾盐乙醇化物X射线粉末衍射图谱。I型钾盐乙醇化物显示的特征衍射峰对应的d-间距为8.27、4.01和3.32 埃。I型钾盐乙醇化物进一步由16.52、7.55和7.02埃的d-间距表征。I型钾盐乙醇化物更进一步由5.52、5.08和4.63埃的d-间距表征。
图4显示II型钾盐乙醇化物X射线粉末衍射图谱。II型钾盐乙醇化物显示的特征衍射峰对应的d-间距为11.62、7.80和4.92埃。II型钾盐乙醇化物进一步由4.55、4.31和4.11埃的d-间距表征。II型钾盐乙醇化物更进一步由3.85、3.55和2.88埃的d-间距表征。
图5显示钾盐水合物X射线粉末衍射图谱。钾盐水合物显示的特征衍射峰对应的d-间距为16.96、8.50和4.26埃。钾盐水合物进一步由7.41、6.88和3.79埃的的d-间距表征。钾盐水合物更进一步由5.00、3.41和3.06埃的d-间距表征。
实施例4 - 无定形形式的替卡格泮钾的调制DSC研究
使用TA Instruments DSC Q1000获得调制DSC数据。MDSC使用加热曲线中的正弦或调制改变代替常规DSC中使用的单线性加热速率。这使得热流可以分离成可逆和不可逆组分。由于样品热容量的改变,无定形物质的玻璃化转变在可逆热流曲线中随基线方面的变化检测。
将2至6毫克的替卡格泮无定形钾盐样品称重到开口锅中。该开口锅用盖子覆盖,但是不卷边,以使任何被吸附的湿气被除去。将该锅置于量热计槽中的样品位置。空锅放置在参照位置。将量热计槽封闭并将氮气流通过该槽。设定加热程序从而以2℃/分钟的加热速率加热样品,调制周期为60秒并且调制振幅为±0.5℃。当运行完成时,数据使用系统软件中的DSC分析程序分析。
图6是无定形钾盐的调制DSC曲线。在逆热流曲线中观察到的热容变化,中点温度为189.00℃,对应于无定形钾盐的玻璃转化温度。
实施例5 - 替卡格泮钾形式的固态C13 NMR光谱
除了以上描述的X粉末衍射图谱外,通过固态碳-13核磁共振(NMR)谱来进一步表征替卡格泮钾乙醇化物。在Bruker DSX 400WB NMR 系统上使用Bruker 4 mm H/X CPMAS探头获得固态碳-13 NMR光谱。碳-13 NMR光谱利用质子/碳-13交叉极化魔角自旋与可变振幅交叉极化,全边带抑制,在100kHz TPPM去耦合。样品在10.0 kHz自旋,收集总共512次扫描,循环延迟90秒。在进行FT前将10 Hz 的谱线增宽应用于谱图。使用甘氨酸的羰基碳(176.03 p.p.m.)作为次级参考物报道了依照TMS标度的化学位移。
I型以固态碳-13 NMR光谱的109.1 ppm、55.8 ppm和54.6 ppm峰进行表征。
表2A - 图7的化学位移和相对强度(I型替卡格泮钾乙醇化物)
峰 (ppm) | 相对强度 |
109.1 | 100 |
55.8 | 93 |
54.6 | 90 |
126.4 | 83 |
36.3 | 83 |
45.0 | 83 |
47.9 | 82 |
31.9 | 77 |
134.0 | 68 |
124.7 | 58 |
26.8 | 53 |
15.7 | 52 |
替卡格泮钾盐水合物以固态碳-13 NMR光谱的126.1 ppm、54.4 ppm和36.6 ppm峰进行表征。
表2B - 图8的化学位移和相对强度(替卡格泮钾水合物)
峰 (ppm) | 相对强度 |
126.1 | 100 |
54.4 | 88 |
36.6 | 86 |
44.7 | 72 |
165.5 | 66 |
49.3 | 64 |
27.5 | 57 |
157.2 | 52 |
133.8 | 47 |
135.9 | 47 |
47.7 | 45 |
29.5 | 44 |
111.4 | 42 |
30.8 | 41 |
158.4 | 39 |
175.4 | 39 |
120.7 | 39 |
32.4 | 37 |
115.5 | 36 |
26.2 | 36 |
41.3 | 35 |
154.3 | 33 |
无定形形式的替卡格泮钾盐以固态碳-13 NMR光谱的126.0 ppm、53.7ppm和29.1 ppm峰进行表征。
表2C - 图9的化学位移和相对强度(无定形替卡格泮钾)
峰 (ppm) | 相对强度 |
126.0 | 100 |
53.7 | 99 |
29.1 | 97 |
49.0 | 85 |
43.5 | 81 |
111.6 | 63 |
157.2 | 61 |
165.5 | 50 |
174.9 | 46 |
132.9 | 40 |
138.2 | 39 |
149.3 | 38 |
实施例6 - 替卡格泮钾形式的拉曼光谱
条件:
测试设备: HoloLab Series 5000,Kaiser Optical Systems公司,具有 插入探头(insertion probe)。
样品条件:固体粉末没有进行预处理。
取样方式:收集每份图谱,5秒暴露和5次累积。
表3 - 替卡格泮钾形式的主要的拉曼光谱峰
晶型 | 拉曼峰 (cm-1) |
I型乙醇化物 | 646.3, 707.4, 761.5, 832.9, 1063.3, 1365.5, 1402.0, 1445.7, 1455.3 |
水合物 | 646.8, 707.0, 753.7, 832.7, 1064.7, 1364.3, 1403.0, 1441.0 |
无定形 | 646.8, 706.8, 752.3, 832.4, 1063.6, 1365.2, 1437.6 |
在图10(I型替卡格泮钾乙醇化物)、11(水合物)和12(无定形形式)中描述了该光谱。
实施例7 - I型和II型替卡格泮钾乙醇化物相对稳定性
在5℃和40℃进行浆料实验,向乙醇中加入等量的I型和II型。由浆料实验中回收的固体的XPRD显示转化成I型,提示I型在5℃至40℃范围内更稳定。
实施例8 - 片剂的示例性制造
本发明的制剂可通过干法制粒来制备。对于所有建议的制剂和药物物质形式,片剂制造工艺过程相同。如以下所示制造工艺流程图所示,根据本发明的适合工艺由以下步骤组成:
1. 将替卡格泮钾、精氨酸、甘露醇、泊洛沙姆407、二氧化硅和交聚维酮共同过筛。
2. 将过筛的材料在适当的掺混机中掺混约10分钟,然后用1/2批量的硬脂酸镁润滑。
3. 使用辊压机将粉末混合物干法制粒。
4. 将所得压实颗粒研磨。
5. 用剩余的硬脂酸镁润滑经研磨的颗粒。
6. 将润滑的材料压成片剂。
7. 使用白色薄膜包衣悬浮液(包括纯水和OPADRY®白色、褐色或其他颜色)将片剂包衣。
实施例9 - 示例性的替卡格泮钾盐制剂
示例性的替卡格泮钾盐片剂制剂示于以下表4A(I型乙醇化物)、4B (水合物)和4C (无定形形式)。
表4A - I型替卡格泮钾乙醇化物的片剂制剂
表4B - 钾盐水合物片剂制剂
表4C - 无定形形式钾盐的片剂配方
实施例10:替卡格泮制剂的比较研究
进行开放标记、随机、6周期交叉研究以确定6种替卡格泮制剂单剂量口服施用于36名健康男性和女性受治疗者的相对生物利用度。6种制剂包括5种固体制剂(表5),和一种口服软弹液体填充胶囊 (C1)。三种固体剂量制剂含有I型替卡格泮钾,另一种含替卡格泮钾水合物,第5种制剂含无定形形式的替卡格泮钾。
各制剂描述于以下表5中。
表5 - 按百分重量计的替卡格泮钾盐固体剂量制剂
成分 | F | G | H | I | J |
替卡格泮钾盐的乙醇化物(I型) | 42.50% | 50.00% | 50.00% | ||
替卡格泮钾盐的水合物 | 50.00% | ||||
替卡格泮钾盐的无定形形式 | 50.00% | ||||
泊洛沙姆407 | 7.50% | 5.00% | 5.00% | 5.00% | 5.00% |
精氨酸 | 30.00% | 25.00% | 15.00% | 25.00% | 25.00% |
其他赋形剂 | 20.00% | 20.00% | 30.00% | 20.00% | 20.00% |
在制剂中包括的“其他赋形剂”是硬脂酸镁、交聚维酮、二氧化硅、甘露醇和包衣材料。
在本研究中还包括液体填充的口服软弹胶囊制剂,C1,其包括以下成分:
替卡格泮钾盐乙醇化物
28.56%
PEG
400
23.36%
丙二醇
7.14%
Cremophor
EL
18.09%
聚山梨醇酯 80
18.09%
丁羟基甲苯
0.04%
水
4.72%
在过夜禁食8小时后,每个受治疗者接受单次口服300-mg剂量的6种制剂中的1种,用240 mL水施用。在药物施用前和施用后1小时限制饮水,受治疗者接受每个剂量的次序根据计算机生成的分配安排表是随机的。每个治疗周期相隔最小5天的洗净期。
在施用单剂量替卡格泮制剂后的平均血浆浓度-时间曲线的形状与制剂C1(口服液体填充胶囊,图13)没有显著不同。每种制剂的曲线提示快速吸收(中值Tmax≤1.5小时),制剂具有相似的Tmax和在替卡格泮血浆浓度后峰中至少一种双指数下降,制剂具有相似的表观末端半衰期 (图13)。
以下表6A-6G提供了本研究各种药物动力学数据的统计分析结果。以下定义是相关的:
GM = 几何平均值
GMR vs. C1 =
几何平均值比vs. C1
HM = 调和平均值
%CV = %变异系数
90% CI = 90%置信区间
AUC =“AUC”或“曲线下面积”是药物血浆浓度的经时变化的量度,并且是药物暴露的量度。AUC的测量对于制剂领域的技术人员来说是熟知的。
Cmax = Cmax是观察到的最高血浆药物浓度的量度。
Tmax = Tmax是第一次达到Cmax的时间。
半衰期=体内药物浓度或量减少一半所需的时间。
这些术语的进一步解释可在Goodman and Gilman’The Pharmacological Basis
of Therapeutics, 第18-19页,第1790-1791页 (第11版,2006)中找到。
表6A-G单剂量施用6种替卡格泮制剂后药物动力学结果的总结
表6A - AUC0- ∞的量度(μM hr)
表6B - Cmax (μM)
表6C - AUC0-4 hr(μM hr)
表6D - AUC0-2 hr(μM hr)
表6E - AUC0-Tmax
(μM hr)
表6F - Tmax (hr)
表6G - 半衰期(hr)
在测试制剂和参考的液体填充的胶囊之间,Tmax没有统计学上显著的差异。
实施例11 - 替卡格泮钾乙醇化物和替卡格泮钾水合物的制剂的比较
在II期研究中施用替卡格泮制剂C1 (上文所述),液体填充的胶囊 (300和600 mg)会产生优于安慰剂的2小时疼痛消失和疼痛缓解计数。在III期研究中施用替卡格泮制剂C1 (150 mg和300 mg)会产生优于安慰剂的2小时疼痛消失和疼痛缓解计数。
在本研究中将替卡格泮乙醇化物盐的固体制剂,即制剂G1与C1进行比较。本研究以随机、交叉的方式直接比较280 mg 替卡格泮乙醇化物盐(制剂G1片剂,略微改变的制剂G片剂)与280 mg 替卡格泮水合物(制剂I片剂)的药物动力学曲线。
表7 - 制剂G1和I的重量百分数描述
成分 | G1 | I |
替卡格泮钾盐的乙醇化物(I型) | 50.00% | |
替卡格泮钾盐的水合物 | 50.00% | |
泊洛沙姆407 | 5.00% | 5.00% |
精氨酸 | 25.00% | 25.00% |
其他赋形剂 | 20.00% | 20.00% |
进行开放标记、随机、2周期交叉研究以评估2种替卡格泮制剂(制剂G1和I)单剂量口服施用于36名健康男性和女性受治疗者的生物等效性。
每个受治疗者在2个周期内同时接受每种剂量的替卡格泮。在过夜禁食8小时后,每个受治疗者接受单次口服280-mg剂量的固体剂量制剂G1或单次口服280-mg剂量的固体剂量制剂I。这些剂量用240 mL水施用。在药物施用前和施用后1小时限制饮水,受治疗者接受每个剂量的顺序根据计算机生成的分配安排表是随机的。在两个周期中在服药前和施用药物后48小时内的特定时间点收集受治疗者血液用于药物动力学测量。在两个治疗周期内在给药后受治疗者在临床研究单位(CRU)停留24小时以便药物动力学测量。受治疗者可被要求给药后于研究单位逗留至多48小时,由研究者决定。治疗周期期间有最小5天的洗净期(~15个半衰期)。通过仔细询问不利事件、ECGs、监测生命体征和实验室安全性评价来评价安全性和耐受性。
结果
2种替卡格泮制剂的平均血浆浓度-时间曲线的形状没有显著不同。每种制剂的曲线都提示快速吸收,在替卡格泮血浆浓度后峰上具有至少一种双指数下降。
表8提供了药物动力学数据的统计分析的结果。将280-mg固体剂量制剂G1与280-mg 替卡格泮水合物固体剂量制剂比较,几何平均值比(制剂G1/制剂I)和相应的AUC0- ∞与Cmax 的90%置信区间分别是0.94(0.88、0.99)和0.95(0.83、1.08)。
以下定义是相关的
GM = 几何平均值
MSE = 平均平方误差
%CV = %变异系数
90% CI = 90%
置信区间
AUC =“AUC”或“曲线下面积”是药物血浆浓度的经时变化的量度,并且是药物暴露的量度。AUC的测量对于制剂领域的技术人员来说是熟知的。
Cmax = Cmax是观察到的最高血浆药物浓度的量度。
Tmax = Tmax是第一次达到Cmax的时间。
半衰期 = 体内药物浓度或量减少一半所需的时间。
表8 - 单剂量施用280 mg 替卡格泮固体剂量后药物动力学结果的总结
将I型乙醇化物(G1)制剂和水合物制剂(I)给予健康受治疗者
虽然参考某些具体实施方案对本发明进行了描述和说明,但是本领域技术人员应当理解,可以在不背离本发明的精神和范围的情况下对所述方法和方案进行各种修改、改变、变型、替换、删除或者添加。例如,由于本发明上述化合物治疗任何症状时接受治疗的哺乳动物响应发生了变化,因此可以应用不同于如上所述具体剂量的有效剂量。同样,所观察到的具体药理学响应可以根据和取决于所选择的具体活性化合物或者是否存在药物载体以及所应用的制剂类型和给药模式变化而变化,且这种产生的结果的预期变化或者差异被认为是与本发明的目的和实践相一致。因此,本发明意图通过随后的权利要求的范围进行限定,应当将这些权利要求解释为合理宽的范围。
Claims (29)
1. 一种固体剂量药学制剂,其包含
(1) N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾,或其水合物或乙醇化物,或其无定形形式;
(2) 精氨酸;和
(3) 药学上可接受的表面活性剂。
2. 如权利要求1所述的固体剂量药学制剂,其中精氨酸以所述制剂重量的至少约10%的量存在。
3. 如权利要求1或2所述的固体剂量药学制剂,其包含约100 mg至约500 mg的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾。
4. 如权利要求1至3任一项所述的固体剂量药学制剂,其包含按重量计约35%至约55%的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾。
5. 如权利要求1至4任一项所述的固体剂量药学制剂,其中所述药学上可接受的表面活性剂是非离子型表面活性剂。
6. 如权利要求5所述的固体剂量药学制剂,其中所述非离子型表面活性剂是聚氧丙烯嵌段共聚物。
7. 如权利要求1至6任一项所述的固体剂量药学制剂,其中所述表面活性剂以所述制剂重量的至多约10%的量存在。
8. 如权利要求1至7任一项所述的固体剂量药学制剂,其包含I型N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾乙醇化物。
9. 如权利要求1至7任一项所述的固体剂量药学制剂,其包含II型N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾乙醇化物。
10. 如权利要求1至7任一项所述的固体剂量药学制剂,其包含N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾水合物。
11. 如权利要求1至7任一项所述的固体剂量药学制剂,其包含无定形N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾。
12. 如权利要求8所述的固体剂量药学制剂,其中所述I型N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾乙醇化物显示109.1 ppm、55.8 ppm和54.6 ppm中的一个或多个固态碳-13 NMR光谱峰。
13. 如权利要求8所述的固体剂量药学制剂,其中I型N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾乙醇化物的拉曼光谱显示646.3、707,4、761,5、832.9、1063.3、1365.5、1402.0、1445.7和1455.3中的一个或多个峰(cm-1)。
14. 如权利要求10所述的固体剂量药学制剂,其中所述N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾水合物显示126.1 ppm、54.4 ppm和36.6 ppm中的一个或多个固态碳-13 NMR光谱峰。
15. 如权利要求10所述的固体剂量药学制剂,其中N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾水合物的拉曼光谱显示646.8、707.0、753.7、832.7、1064.7、1364.3、1403.0和1441.0中的一个或多个峰(cm-1)。
16. 如权利要求11所述的固体剂量药学制剂,其中所述N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾无定形形式显示126.0 ppm、53.7 ppm和29.1 ppm中的一个或多个固态碳-13 NMR光谱峰。
17. 如权利要求11所述的固体剂量药学制剂,其中N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾无定形形式的拉曼光谱显示646.8、706.8、752.3、832.4、1063.6、1365.2和1437.6中的一个或多个峰(cm-1)。
18. 如权利要求1至17任一项所述的固体剂量药学制剂,其包含约280 mg或约300 mg的活性成分N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺。
19. 如权利要求1至18任一项所述的固体剂量药学制剂,其为片剂。
20. 如权利要求1至19任一项所述的固体剂量药学制剂,其在血液中提供至少2.75 μM的Cmax。
21. 如权利要求1至19任一项所述的固体剂量药学制剂,其在施用后不超过1.0小时的时间点达到Tmax。
22. 如权利要求1至19任一项所述的固体剂量药学制剂,其在血液中达到不超过2.5 μM的AUC0-Tmax。
23. 如权利要求1至19任一项所述的固体剂量药学制剂,其在血液中达到不超过5.5 μM的AUC0-2 hr。
24. 如权利要求1至19任一项所述的固体剂量药学制剂,其在血液中达到不超过10.0 μM的AUC0-4 hr。
25. 如权利要求1至19任一项所述的固体剂量药学制剂,其在血液中达到不超过15.5 μM的AUC0-∞。
26.N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的无定形形式,所述无定形形式通过将有机溶液中的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的乙醇化物或水合物进行喷雾干燥的步骤而产生。
27. 如权利要求26所述的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的无定形形式,所述无定形形式具有小于15 μm的平均粒度。
28.N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的无定形形式,所述无定形形式通过将N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾乙醇化物或水合物溶解在甲醇中并将该无定形形式沉淀的步骤而产生。
29. 如权利要求28所述的N-[(3R, 6S)-6-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺钾的无定形形式,所述无定形形式具有小于150 μm的平均粒度。
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PCT/US2009/049009 WO2010002763A1 (en) | 2008-06-30 | 2009-06-29 | Solid dosage formulations of telcagepant potassium |
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EP (1) | EP2303238A1 (zh) |
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AR (1) | AR072395A1 (zh) |
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CA (1) | CA2728547A1 (zh) |
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AU2009267145A1 (en) | 2010-01-07 |
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US20100009967A1 (en) | 2010-01-14 |
WO2010002763A1 (en) | 2010-01-07 |
JP2011526909A (ja) | 2011-10-20 |
MX2010014524A (es) | 2011-02-24 |
CR20110038A (es) | 2011-03-16 |
EP2303238A1 (en) | 2011-04-06 |
TW201004954A (en) | 2010-02-01 |
RU2011103170A (ru) | 2012-08-10 |
IL209833A0 (en) | 2011-02-28 |
DOP2010000409A (es) | 2011-02-15 |
CA2728547A1 (en) | 2010-01-07 |
AR072395A1 (es) | 2010-08-25 |
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