CN101489560B - 具有s形释放曲线的奥卡西平控释制剂 - Google Patents
具有s形释放曲线的奥卡西平控释制剂 Download PDFInfo
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- CN101489560B CN101489560B CN200780021787.8A CN200780021787A CN101489560B CN 101489560 B CN101489560 B CN 101489560B CN 200780021787 A CN200780021787 A CN 200780021787A CN 101489560 B CN101489560 B CN 101489560B
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Abstract
本发明公开了用于每天施用一次的奥卡西平及其衍生物的控释制剂。本发明的组合物包括溶解和/或释放增强剂,以提供定制的释药曲线,优选S形释放曲线。还公开了包括本发明组合物的治疗方法。
Description
相关申请的交叉参考
本申请要求2006年4月26日提交的美国临时申请号60/794,837的优先权,该文献的内容全部纳入本文作为参考。
技术领域
本发明涉及用于每天施用一次的奥卡西平及其衍生物的控释制剂。
背景技术
奥卡西平属于苯二氮杂类药物,在世界范围内被注册为抗癫痫药。奥卡西平被批准作为用于治疗成人和儿童的部分发作和全身强直性-阵挛性癫痫发作的辅助药物或单一疗法。目前奥卡西平即释(IR)剂型以商品名曲 出售,每天施用两次来控制癫痫发作。这种即释组合物以一定的方式向患者提供药物,导致血浆药物浓度迅速上升,然后迅速下降。这种药物浓度的锐变可能导致副作用,并且必须每天多次施用药物,以便保持药物在体内的治疗水平。对于长期服用的药物像奥卡西平和衍生物的控释剂型的需要是不言而喻的。使用例如每天服用一次的控释(CR)剂型极大地改善了患者依从性。而且,使用控释剂型存在明显的临床优点,例如更好的治疗效果以及减少的副作用。
本发明考虑的奥卡西平及其衍生物微溶于水。由于它们的溶解性差,它们从缓释剂型中的释放相当不完全。尽管奥卡西平的体外释放度取决于溶出方法,包括所用的溶出介质,但通过计算机建模发现,奥卡西平从常规缓释剂型中的体内释放度相当低。这导致药物的生物利用度下降,使剂型不能在体内提供治疗有效的浓度。这对于成功研制奥卡西平及其衍生物的缓释剂型提出了严峻的挑战。
药物从剂型中的释放速率对于药物的治疗有用性及其副作用具有显著影响。因此,必须定制释药曲线以满足患者的治疗需要。定制释放曲线的一个例子是S形释放模式,其特征在于初始缓慢释放,然后快速释放,然后再缓慢释放,直到所有药物从剂型中释放出来为止。
本领域描述了奥卡西平和衍生物的缓释剂型。例如,Katzhendler等(US专利6,296,873)描述了卡马西平及其衍生物的缓释递药系统。Katzhendler等教导,通过使用亲水和疏水聚合物获得了卡马西平和衍生物的零级释放曲线。使用高分子量羟丙基甲基纤维素(HPMC)以及一些任选的疏水赋形剂获得了零级(恒定)释放。Shah等教导了类似的方式(US专利申请20020169145)。Franke等(US专利申请20040142033)公开了奥卡西平的缓释剂型,其特征在于在15分钟内释放55%-85%药物,并且在30分钟内释放高至95%药物。根据作者所述,这些释放曲线提供了充分的缓释来获得每天施用一次奥卡西平。然而,来自这些增强制剂的药物的溶解度和生物利用度适合每天施用一次。现有领域没有教导如何制备以S形释放曲线为特征的奥卡西平和衍生物的制剂。
发明内容
本发明的目的是提供用于每天施用一次的奥卡西平控释制剂。本发明的组合物每天施用一次,但仍然满足患者的治疗需要。本发明的另一个目的是改善奥卡西平及其衍生物的生物利用度。本发明的还一个目的是满足患者的治疗需要,而不会引起可能导致毒性的血药浓度“尖峰”。本发明的还一个目的是将药物的血液浓度维持在治疗窗内。本发明的还一个目的是使Cmax与Cmin之间的波动最小化,这种波动对于许多即释和持续释放制剂是典型的。
通过包含增溶剂和促释剂两者、并且以释放曲线满足每天施用一次的需要为特征的剂型,本发明可以实现这些目的中的许多甚至绝大部分目的。通过将具有不同释放曲线的多种单元组合到一个剂量单元内,也可以实现所述目的。可以按照特定比率混合的微型丸剂/颗粒剂/片剂提供了满足上述治疗目的的剂型。
本发明还涉及多层片。可以制备多层片,使每层的释药速率均不同于另一层的释放速率。在多层片中,每层可以包衣或不包衣。
每天施用一次药物所致的所有优点均适合本发明的组合物。本发明的一些具体优点可以为:在治疗过程中减少Cmax与Cmin之间的波动并因此得到更好的治疗效果、减少副作用、改善患者依从性和改善药物的生物利用度。
附图说明
图1显示了不含溶解/释放增强剂的三种示例(CR-F、CR-M和CR-S)奥卡西平制剂的溶出曲线。所述曲线显示了具有迟滞的非零级释放。CR-F、CR-M、和CR-S剂型的T80s(体外释放80%剂量的时间),分别为2Hr、5Hr和11Hr。以60RPM使用USP装置II。溶出介质为1%SLS水溶液。
图2显示了实施例1的三种示例控释制剂相对于即释参比产品(曲600mg)的奥卡西平人体药代动力学(PK)曲线。每种剂型的强度为600mg奥卡西平/片。
图3显示了实施例1的三种示例控释制剂相对于即释参比产品(曲600mg)的奥卡西平代谢物(MHD)的PK曲线。每种制剂的强度为600mg奥卡西平/片。
图4显示了用选择的赋形剂溶解奥卡西平的结果。
图5显示了包含增溶剂(CRe)、不含增溶剂(CR)和实施例1研制的“快速制剂”(CR-F)的奥卡西平CR剂型的溶出曲线。CRe、CR和CR-F溶解80%药物所用的时间(T80)分别为5-6Hr、8Hr和1.5Hr。
图6显示了包含溶解/释放增强剂的快速(CRe-F)、中速(CRe-M)和慢速(CRe-S)奥卡西平制剂的溶出曲线。CRe-F、CRe-M和CRe-S的T80s分别为1.5Hr、5Hr和8Hr。以60RPM使用USP装置II。溶出介质为1%SLS水溶液。
图7显示了包含奥卡西平的增强制剂(CRe)与未增强制剂(CR和CR-F)相比的奥卡西平犬药代动力学曲线。
图8显示了包含奥卡西平的增强制剂(CRe)与未增强制剂(CR和CR-F)相比的MHD犬药代动力学曲线。
图9显示了对于每天两次300mgIR,图8所示PK曲线的计算机预测(insilicopredicted)PK曲线。
图10显示了各种体外释放曲线的计算机预测PK曲线。
图11显示了图10所述体系的计算机预测体内释放曲线。
图12显示了实施例4的三种奥卡西平CR制剂(CRe-F、CRe-M、CRe-S)和作为IR对照的曲(按照BID给药)的MHD人体血浆浓度-时间曲线。
图13显示了实施例4的三种奥卡西平CR制剂(CRe-F、CRe-M、CRe-S)和作为IR对照的曲(按照BID给药)的奥卡西平人体血浆浓度-时间曲线。
图14显示了实施例4所述的三种示例制剂(CRe-F、CRe-M、CRe-S)的计算机预测稳态血浆曲线。
发明详述
本发明的目的是提供适合每天施用一次的控释奥卡西平剂型。本发明的另一个目的是将增溶赋形剂和/或促释剂的组合掺加到所述制剂中以提高奥卡西平及其衍生物的生物利用度。这些组合物被称为增强制剂。
配制奥卡西平,从而提供以初始缓慢释放、然后快速释放、然后再缓慢释放为特征的释放曲线。本领域技术人员已知这种释放曲线为S形曲线。在人体药代动力学(PK)研究中测试具有S形释放曲线的奥卡西平制剂。基于人体数据,通过掺加增溶剂和/或促释赋形剂,制剂得到了改善(这种制剂被称为增强的制剂)。在犬模型中测试了所述增强制剂,并且令人惊讶地发现,与不含溶解/释放增强赋形剂的制剂相比,提供了明显增强的奥卡西平生物利用度。
在包含微溶性药物如奥卡西平的制剂中掺加增溶剂对于药物的体内溶解度和因此生物利用度具有深远的影响。增强奥卡西平的溶解度导致提高其生物利用度和因此更好的药物治疗效果。本发明考虑将溶解与释放促进剂组合。优选的促释剂是pH依赖性聚合物,也称为肠溶聚合物。这些材料是本领域技术人员熟知的,具有pH依赖性溶解度,从而它们在高于约4.0的pH值下溶解,而在低于4.0的pH值下保持不溶。增溶剂通过提高微溶性药物的水溶性而起作用。当包含肠溶聚合物和增溶剂两者的制剂暴露于pH高于4.0的水性介质时,肠溶聚合物迅速溶解,留下多孔性结构,使水性介质与微溶性药物之间的接触表面增加。这种增加的表面积增强了增溶剂的功效,因此药物的总体溶解度和释放速率被增强到一定的程度,以至于影响了药物对于患者全身吸收的可用性。
作为增溶剂起作用的赋形剂可以是离子型和非离子型表面活性剂、络合剂、亲水聚合物、pH修改剂如酸化剂和碱化剂、以及通过分子截留来提高微溶性药物的溶解度的分子。可以同时利用几种增溶剂。在低于约4.0的pH值下保持完整并在高于4.0、优选高于5.0、最优选高于约6.0的pH值下溶解的所有肠溶聚合物都被认为可以用作本发明的促释剂。
合适的pH敏感型肠溶聚合物包括:邻苯二甲酸醋酸纤维素、琥珀酸醋酸纤维素、邻苯二甲酸甲基纤维素、邻苯二甲酸羟乙基纤维素、聚乙酸乙烯邻苯二甲酸酯、聚丁酸乙烯乙酸酯、乙酸乙烯酯-马来酸酐共聚物、苯乙烯-马来酸单酯共聚物、丙烯酸甲酯-甲基丙烯酸共聚物、甲基丙烯酸酯-甲基丙烯酸-丙烯酸辛酯共聚物等。它们可以单独或组合使用,或者与除上面所列以外的其它聚合物一起使用。优选的肠溶聚合物是药学上可接受的甲基丙烯酸共聚物。这些共聚物是基于甲基丙烯酸和甲基丙烯酸甲酯的阴离子型聚合物,并且优选具有约135000的平均分子量。在这些共聚物中,游离羧基与甲基酯化羧基的比率可以为例如1:1至1:3,例如约1:1或1:2。这些聚合物以商品名EudragitTM出售,例如EudragitL系列,如EudragitL12.5TM、EudragitL12.5PTM、EudragitL100TM、EudragitL100-55TM、EudragitL-30DTM、EudragitL-30D-55TM、EudragitSTM系列,如EudragitS12.5TM、EudragitS12.5PTM、EudragitS100TM。所述促释剂不限于pH依赖性聚合物。能迅速溶解并从剂型中快速滤出以留下多孔结构的其它亲水分子也可以用于相同的目的。
促释剂的掺加量可以占剂量单元重量的10%至90%,优选20%至80%,最优选30%至70%。所述试剂可以在制粒之前或之后掺入剂型中。促释剂可以作为干料添加到剂型中,或者它可以分散或溶解到适当的溶剂中,并在制粒过程中分散。
本发明的优选增溶剂包括:表面活性试剂如多库酯钠、十二烷基硫酸钠、硬脂基富马酸钠、和Spans(PEO修饰的失水山梨醇单酯和脂肪酸失水山梨醇酯)、聚(环氧乙烷)-聚环氧丙烷-聚(环氧乙烷)嵌段共聚物(即PluronicsTM);络合剂如低分子量聚乙烯基吡咯烷酮和低分子量羟丙基甲基纤维素;通过分子截留来帮助溶解的分子如环糊精,和pH修改剂,包括酸化剂如柠檬酸、富马酸、酒石酸、和盐酸;和碱化剂如甲葡胺和氢氧化钠。
增溶剂通常占剂型重量的1%至80%,优选1%至60%,更优选1%至50%,并且可以各种方式掺合。它们可以在制粒之前以干燥或湿润形式掺入剂型。它们也可以在剩余材料制粒或以其它方式处理后添加到剂型中。在制粒过程中,增溶剂可以作为包含或不含粘合剂的溶液喷洒。
本发明还预期了包括奥卡西平的控释制剂,所述制剂在GI道内以可变的速度释放药物。本发明的另一个目的是设计递药体系,从而在早期以极低的速率递送药物,然后以相对上升的速率递药。本发明的另一个目的是提供释药曲线,所述曲线的特征在于即释,然后是调释(modified-release)如延长释放(XR)或延迟释放(DR)。这些类型的释放曲线确保将Cmax(药物在血液/血浆中的最大浓度)维持在治疗窗内,同时延长有效药物水平在体内的维持时间。本发明的目标是研制奥卡西平的控释药物组合物,所述组合物提供浓度为约2μg/ml至约10μg/ml的MHD稳态血液水平,MHD是奥卡西平的活性代谢物。在优选实施方案中,MHD的稳态血液Cmax水平在约6μg/ml至约10μg/ml的范围内,MHD的Cmin水平在约2μg/ml至约5μg/ml的范围内。在治疗过程中减少Cmax与Cmin之间的波动导致更好的治疗效果、减少的副作用、改善的患者依从性和改善的药物生物利用度。
通过使用在水性介质如生物学流体中水化并膨胀的“骨架”聚合物来实现本发明预期的期望释药模式。随着这些聚合物膨胀,它们形成均匀的骨架结构,所述骨架结构在释药过程中保持其形状并作为药物的载体、增溶剂和/或促释剂。骨架聚合物的初始水化相导致缓慢释放药物(迟滞相)。一旦聚合物完全水化并膨胀,骨架的多孔性由于pH依赖性促释剂的滤出而上升,药物以更快的速率被释放。然后释药速率变得恒定,并且是扩散通过水化聚合物凝胶的药物的函数。
因此,所述释放度-时间曲线的特征在于至少两个斜率:一个斜率是释药速率低下的迟滞相,在第二个斜率处释药较快。释放度-时间曲线的上升部分的斜率可以定制成匹配药物从体内消除的速率。通过将可膨胀的聚合物单独使用或与粘合剂如胶凝形成聚合物和/或网络形成聚合物联用,可以获得期望的释放曲线。
可用于本发明的水膨胀型骨架形成聚合物选自:纤维素聚合物,如羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、甲基纤维素(MC)、粉末化的纤维素如微晶纤维素、乙酸纤维素、羧甲基纤维素钠、羧甲基纤维素的钙盐和乙基纤维素;藻酸盐、树胶如瓜尔胶和黄原胶;交联聚丙烯酸衍生物如可从NoveonInc.(Cinncinatti,Ohio)以各种分子量级别获得的卡波姆(即CarbopolTM);鹿角菜胶;聚乙烯基吡咯烷酮及其衍生物如交联聚维酮;聚环氧乙烷;和聚乙烯醇。优选的可膨胀聚合物是纤维素化合物,最优选HPMC。
所述可膨胀聚合物可以按1%至50%、优选5%至40%、最优选5%至20%的重量比掺入剂型中。可膨胀的聚合物和粘合剂可以在制粒之前或之后掺入剂型中。所述聚合物也可以分散到有机溶剂或醇水溶液中并在制粒过程中喷洒。
本发明的还一方面是制备组合了多个调释“单元”的奥卡西平剂型,每个“单元”均根据上面公开剂型中的任何一种或多种制备,以提供定制的释放曲线。
所述调释单元包括微型丸剂/颗粒剂/片剂等,分别具有独特的释放曲线,可以按照特定的比率混合以提供符合上述治疗目的的剂型。或者,多个调释单元可以成形为多层片。可以制备多层片,使每层释放活性化合物的速率都不同于另一层释放活性化合物的速率。在多层片中,每层可以任选用控释聚合物包衣。组合剂型的释放曲线可以包括即释(IR)、延迟释放(DR)和延长释放(XR)剂型的任何/所有可能的组合。丸剂/颗粒剂/片剂或单个片剂的每层可以任选被包衣。
可以使用各种疏水赋形剂来改变剂量单元在暴露于水或水性介质时的水化速率。这些赋形剂阻碍剂量单元的润湿,因此改变活性试剂的释放。适合本发明的疏水赋形剂的代表包括但不限于:单硬脂酸甘油酯、单硬脂酸甘油酯与单棕榈酸甘油酯的混合物(Myvaplex,EastmanFineChemicalCompany)、单油酸甘油酯、甘油一酯、甘油二酯和甘油三酯的混合物(ATMUL84S)、单月桂酸甘油酯、山嵛酸甘油酯、石蜡、白蜡、长链羧酸、长链羧酸酯和长链羧酸醇。
可用于本发明的饱和直链酸的例子为:正十二烷酸、正十四烷酸、正十六烷酸、己酸、辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山嵛酸、褐霉酸和蜂花酸。还可以使用不饱和单烯直链单羧酸。其例子为油酸、鳕油酸和芥酸。还可以使用不饱和(多烯)直链单羧酸如亚油酸、亚麻酸、花生四烯酸和behenolicacid。有用的支链酸包括例如二乙酰基酒石酸。
长链羧酸酯的例子包括但不限于:单硬脂酸甘油酯;单棕榈酸甘油酯;单硬脂酸甘油酯与单棕榈酸甘油酯的混合物(Myvaplex600,EastmanFineChemicalCompany);单亚油酸甘油酯;单油酸甘油酯;单棕榈酸甘油酯、单硬脂酸甘油酯、单油酸甘油酯和单亚油酸甘油酯的混合物(Myverol18-92,EastmanFineChemicalCompany);单亚油酸甘油酯;单鳕油酸甘油酯;单棕榈酸甘油酯、单硬脂酸甘油酯、单油酸甘油酯、单亚油酸甘油酯、单亚油酸甘油酯和单鳕油酸甘油酯的混合物(Myverol18-99,EastmanFineChemicalCompany);乙酰化的甘油酯如蒸馏的乙酰化单甘油酯(Myvacet5-07、7-07和9-45,EastmanFineChemicalCompany);丙二醇单酯、蒸馏的单甘油酯、硬脂酰乳酸钠和二氧化硅的混合物(MyvatexTL,EastmanFineChemicalCompany);丙二醇单酯、蒸馏的单甘油酯、硬脂酰乳酸钠和二氧化硅的混合物(MyvatexTL,EastmanFineChemicalCompany);d-α生育酚聚乙二醇1000琥珀酸酯(维生素ETPGS,EastmanChemicalCompany);甘油一酯和甘油二酯的混合物如Atmul(HumkoChemicalDivisionofWitcoChemical);硬脂酰乳酸钙;乙氧基化的甘油一酯和甘油二酯;乳酸化的甘油一酯和甘油二酯;甘油和丙二醇的乳酸盐羧酸酯;长链羧酸的乳酸酯;长链羧酸的聚甘油酯、长链羧酸的丙二醇单酯和二酯;硬脂酰乳酸钠;单硬脂酸失水山梨醇酯;单油酸失水山梨醇酯;长链羧酸的其它失水山梨醇酯;琥珀酰化的单甘油酯;硬脂基柠檬酸单甘油酯;硬脂基庚酸酯;蜡的鲸蜡基酯;鲸蜡酰辛酸酯;C10-C30胆固醇/lavosterol酯;和蔗糖长链羧酸酯。此外,蜡可以单独使用或优选与上面所列的材料联用。其例子为白蜡、石蜡和巴西棕榈蜡。
通常将药物、聚合物和其它赋形剂合并并使用制粒流体湿法制粒。然而,形成颗粒的其它方法如压块和滚筒挤压也可以用于制造骨架颗粒。也可以通过直接压缩来制备骨架片。在湿法制粒中,典型的制粒液体为:水、水与醇的混合物、无水醇。湿法制粒可以在任何制粒设备如混合器、高剪切制粒机和流化床制粒机中进行。颗粒可以在适当的干燥设备如流化床干燥器、烘箱、微波干燥器等中干燥。颗粒也可以被风干。可以使用适当的研磨设备来研磨干燥的颗粒,以获得特定的粒度分布。颗粒可以填充到胶囊中,或者与其它赋形剂共混并在压片机上压片。颗粒也可以包装到药袋中供喷撒应用。用于辅助制片的其它赋形剂是本领域技术人员熟知的,包括硬脂酸镁、滑石、胶态二氧化硅等。颗粒和片剂可以任选被包衣,以进一步改变释放速率。此外,剂型还可以任选包含染料。
任选但优选地,所述片剂组合物可以包含一种或多种润滑剂,可以添加它们以保证适当的制片。润滑剂的非限制性例子包括:硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸、聚乙二醇、亮氨酸、山嵛酸甘油酯、硬脂基富马酸钠、氢化植物油和其它蜡,包括但不限于蜂蜡、巴西棕榈蜡、鲸蜡醇、硬脂酸甘油酯、棕榈酸甘油酯和硬脂醇。当存在时,润滑剂的含量通常占组合物的约0.1wt.%至约20wt.%,优选约1wt.%至约10wt.%,更优选约0.3wt.%至约3.0wt.%。
奥卡西平剂量可以配制成片剂、颗粒剂和丸剂。制造这些剂型所涉及的步骤对于本领域技术人员是熟知的。简而言之,可以由包含活性成分的可直接压缩共混物或预成形颗粒来压制片剂。片剂可以是包衣或未包衣的。包衣可以任选带来对释放的调节。可以通过高剪切制粒或流化床处理来制备颗粒剂。颗粒剂可以是包衣或未包衣的。可以通过在惰性载体如糖球上将药物铺层来制备丸剂。也可以通过挤出/滚圆工艺来制备丸剂。丸剂可以是包衣或未包衣的。包衣的丸剂和颗粒剂可以填充到胶囊中。
本发明的制剂也可以制成丸状形式,将其填充到胶囊中或分配到药袋中供喷撒应用。每个药丸均包括:药物、可膨胀的聚合物和辅助加工的其它赋形剂。可以按照本领域技术人员已知的许多方法之一来制备丸剂。这些方法包括例如:挤出/滚圆和滚筒压缩(压块)。在挤出/滚圆技术中,将药物与可膨胀的聚合物如纤维素聚合物和其它赋形剂混合。然后在高剪切制粒机中将混合物制粒。然后使湿团块经过挤出机并使用球化机球化。然后在烘箱或流化床处理机中将丸剂干燥。将干燥的丸剂进一步加工或者不经进一步加工而包囊。
除非另有定义,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同的意义。本文提及的所有出版物、专利申请、专利和其它参考文献被全文纳入本文作为参考。在有抵触的情况下,将以本说明书、包括定义为主。此外,所述材料、方法和例子仅仅是例示性的,并非用于限制。
现在将通过下列例示性实施例具体描述本发明;然而,本发明的范围将不会、也不应限于下面的示例实施方案。
具体实施方式
实施例1.具有S形释放曲线的奥卡西平制剂
表1提供了具有S形释放曲线的奥卡西平控释制剂的配方组合物。使用无水乙醇作为制粒液体,通过高剪切制粒来制备颗粒。将除硬脂酸镁以外的所有成分投入VG-65/10M高剪切制粒机中。通过将叶片运行3分钟来掺混干粉末,然后以大约40-60gm/min的喷洒速度,将无水乙醇喷洒到正在混合的共混物上。在喷洒约一分钟后,开启VG-65/10M的切碎机并在整个喷洒过程中运行。一旦完成制粒,将颗粒从VG高剪切制粒机中排出,铺展到适当的盘子上并置于40℃烘箱中干燥24Hr。或者,可以使用流化床处理器来干燥颗粒。通过18目筛来筛分干颗粒。以99.5%颗粒和0.5%硬脂酸镁的比例,将筛分的颗粒与硬脂酸镁共混。然后在旋转式压片机上将共混物压片。
*在加工过程中被除去
图1显示了三种示例奥卡西平CR制剂(CR-F、CR-M、和CR-S)的溶出曲线。所述曲线表现出非零级释放。
实施例2.实施例1的奥卡西平CR制剂的人体药代动力学评价
在人体内评价实施例1的三种制剂,以获得药代动力学信息。将即释片(曲600mg)用作对照参比。在健康人志愿者体内,在随机、单剂量、交叉研究中检查所述制剂。分析血样中的母体分子奥卡西平及其代谢物(单羟基衍生物,MHD)两者。
表2提供了MHD的平均PK参数。图2和3显示了PK曲线。
实施例3.增溶剂筛选
如下评价存在赋形剂时的奥卡西平溶解度:
将赋形剂溶于磷酸盐缓冲液中,以使溶液具有表3所示的浓度。然后将1g奥卡西平与19克赋形剂溶液混合。将混合物在室温下摇摆过夜,然后使用过0.22μm滤器过滤。通过HPLC分析滤液。表3和图4给出溶解度结果。
实施例4.增强剂型的制剂
表4和5提供了包含溶解和释放增强剂的制剂组成。使用水作为制粒液体,通过高剪切制粒来制造颗粒。将除硬脂酸镁以外的所有成分投入VG-65/10M高剪切制粒机中。通过将叶片运行3分钟来掺混干粉末,此时以大约40-60gm/min的喷洒速度,将水喷洒到正在混合的共混物上。在喷洒约一分钟后,开启VG-65/10M的切碎机并在整个喷洒过程中运行。一旦完成制粒,将颗粒从VG高剪切制粒机中排出,铺展到适当的盘子上并置于40℃烘箱中干燥24Hr。或者,可以使用流化床处理器来干燥颗粒。通过18目筛来筛分干颗粒。以99.5%颗粒和0.5%硬脂酸镁的比例,将筛分的颗粒与硬脂酸镁共混。然后在旋转式压片机上将所得共混物压片。这些制剂的溶出曲线示于图5和6。
实施例5.来自实施例4、表4和实施例1的制剂的犬PK研究
(SLI530CR-F)
按照表6给出的顺序,给六只雄性比格犬口服所述制剂。以24Hr间隔抽取血液并通过HPLC分析血样。使用非房室数据分析以产生Tmax、Cmax、AUC最后和AUCinf。使用AUC最后和AUCinf,在Excel中计算CRf制剂相对生物利用度作为对照。图7和8给出奥卡西平和10-羟基carbazepine的PK曲线。
实施例6.奥卡西平XR的各种释放曲线的计算机建模
对各种假想体系进行计算机建模。图9-11显示了结果。
实施例7.实施例4的增强溶解度的奥卡西平CR制剂的人体药代
动力学评价
在人体内评价实施例4的三种增强溶解度的原型,以获得药代动力学信息。使用按照BID给予的即释片(曲300mg)作为参比。在健康人志愿者体内,在随机、单剂量、交叉研究中检查所述制剂。分析血样中的母体分子奥卡西平及其代谢物(单羟基衍生物,MHD)两者。
表8提供了MHD的平均PK参数。图12和13显示了PK曲线。
Claims (21)
1.用于每天施用一次奥卡西平的、由均匀的骨架结构组成的药物制剂,其中所述均匀的骨架结构包括:
(a)奥卡西平;
(b)骨架形成聚合物,其选自:纤维素聚合物和聚乙烯基吡咯烷酮;
(c)至少一种提高奥卡西平溶解度的物质,其选自表面活性剂;和
(d)至少一种促释剂,其包含选自下述的pH依赖性溶解度聚合物:EudragitL100-55和丙烯酸甲酯-甲基丙烯酸共聚物。
2.权利要求1的药物制剂,其中所述表面活性剂选自:多库酯钠、十二烷基硫酸钠、硬脂基富马酸钠、聚环氧乙烷修饰的失水山梨醇单酯、脂肪酸失水山梨醇酯和聚环氧乙烷-聚环氧丙烷-(聚(环氧乙烷))嵌段共聚物。
3.权利要求1的药物制剂,其中纤维素聚合物选自羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、甲基纤维素、粉末化的纤维素、乙酸纤维素、羧甲基纤维素钠、羧甲基纤维素的钙盐和乙基纤维素。
4.权利要求1的药物制剂,其中pH依赖性聚合物在低于4的pH值下保持完整,并在大于4的pH值下溶解。
5.权利要求4的药物制剂,其中pH依赖性聚合物在大于5的pH值下溶解。
6.权利要求4的药物制剂,其中pH依赖性聚合物在大于6的pH值下溶解。
7.权利要求1的药物制剂,其中所述促释剂的量占制剂重量的10%至90%。,所述增溶剂的量占制剂重量的1%至80%。
8.权利要求7的药物制剂,其中所述促释剂的量占制剂重量的30%至70%,所述增溶剂的量占制剂重量的1%至50%。
9.权利要求1的药物制剂,其中所述奥卡西平的量使奥卡西平单羟基衍生物的稳态血液水平处于2μg/ml至10μg/ml的范围内。
10.权利要求9的药物制剂,其中奥卡西平代谢物的Cmax水平在6μg/ml至10μg/ml的范围内,奥卡西平代谢物的Cmin水平在2μg/ml至5μg/ml的范围内。
11.权利要求1的药物制剂,其在胃肠道内提供可变的奥卡西平释放速率。
12.权利要求11的药物制剂,其将具有调释模式的多个单元组合到一个剂量单元内。
13.权利要求12的药物制剂,其中所述单元为微型丸剂、微型颗粒剂、微型片剂和分层物的形式。
14.权利要求1的药物制剂,为丸剂、片剂、颗粒剂或胶囊的形式。
15.权利要求1的药物制剂,其中奥卡西平的量是600mg。
16.权利要求14的药物制剂,为片剂形式。
17.权利要求16的药物制剂,其中每片包含600mg奥卡西平。
18.权利要求1的药物制剂,其中骨架形成聚合物的量占制剂重量的1%至50%
19.权利要求16的药物制剂,还包含润滑剂,选自:硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸、聚乙二醇、亮氨酸、山嵛酸甘油酯、硬脂基富马酸钠、氢化植物油和蜡。
20.权利要求19的药物制剂,其中所述蜡选自蜂蜡、巴西棕榈蜡、鲸蜡醇、硬脂酸甘油酯、棕榈酸甘油酯和硬脂醇。
21.权利要求19的药物制剂,其中所述润滑剂的含量占制剂重量的0.1%至20%。
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