CN102429882A - 加巴喷丁前体药物持续释放口服剂型 - Google Patents
加巴喷丁前体药物持续释放口服剂型 Download PDFInfo
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- CN102429882A CN102429882A CN2011104078904A CN201110407890A CN102429882A CN 102429882 A CN102429882 A CN 102429882A CN 2011104078904 A CN2011104078904 A CN 2011104078904A CN 201110407890 A CN201110407890 A CN 201110407890A CN 102429882 A CN102429882 A CN 102429882A
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Abstract
公开了加巴喷丁前体药物1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的持续释放口服剂型。这些剂型可用于治疗或预防加巴喷丁在治疗上对其有效的疾病和障碍。
Description
本申请是中国专利申请号2005800409309(PCT/US2004/010137),申请日2005年11月3日,发明名称为“加巴喷丁前体药物持续释放口服剂型”的分案申请。
本申请请求2004年11月4日提交的美国临时申请US 60/625,737的利益,将该文献完整地引入作为参考。
领域
本说明书涉及1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的持续释放口服剂型和通过给予这类剂型治疗或预防加巴喷丁在治疗上可有效针对的疾病和障碍的方法。
背景
1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸(1),即γ-氨基丁酸(GABA)类似物加巴喷丁(2)的前体药物在通过口服给药或直接给药入哺乳动物结肠时具有如加巴喷丁的高生物利用度(Gallop等国际公开号WO 02/100347;Cundy等J Pharmacol Exp Ther.2004,311:315-323;Cundy等J Pharmacol Exp Ther.2004,311:324-333。高生物利用度使得化合物(1)成为口服剂型中有价值的成分(包括持续释放剂型),该口服剂型用于治疗或预防癫痫;疼痛(尤其是神经性疼痛和肌肉和骨骼痛);抑郁症;焦虑;精神病;昏晕发作;运动功能减退;颅脑障碍;神经变性障碍;恐慌;炎性疾病(即关节炎);失眠;胃肠道障碍;热潮红;不宁腿综合征;尿失禁;和酒精戒断综合征。
将如Gallop等在国际公开号WO 02/100347中制备的化合物(1)在从含水乙腈中冻干后以玻璃状固体分离。通过该方法获得的物质为部分或完全无定形的,并且某些碱金属盐形式为吸湿性的。更近来,已经描述了1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的结晶形式及其合成方法(Estrada等国际公开号WO 2005/037784)。化合物(1)的结晶形式具有可用于药物加工和药物组合物的改善的物化特性。
概述
本文披露了化合物(1)的持续释放口服剂型。在某些实施方案中,在对一个或多个禁食人类患者以约1100mg-约1300mg的剂量给予1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,化合物(1)的持续释放口服剂型提供的加巴喷丁血浆浓度曲线(profile)的特征在于Cmax在约3μg/mL-约6μg/mL,Tmax在约4小时-约7小时,且AUC在约30μg·hr/mL-约70μg·hr/mL;或在对一个或多个摄食人类患者以约1100mg-约1300mg的剂量给予1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,其提供的加巴喷丁血浆浓度的特征在于Cmax在约5μg/mL-约8μg/mL,Tmax在约6小时-约11小时,且AUC在约60μg·hr/mL-约110μg·hr/mL。
例如,剂型可以为片剂,其包含:(a)约10wt%-约80wt%的化合物(1)和(b)约1wt%-约50wt%的调节释放速率的聚合物,其中wt%基于该剂型的总干重。合适的调节释放速率的聚合物包括甘油酯类,诸如单硬脂酸甘油酯、二十二烷酸甘油酯、棕榈酰硬脂酸甘油酯、月桂酰聚乙二醇甘油酯和硬脂酰聚乙二醇甘油酯。其它合适的改善释放速率的聚合物包括甲基丙烯酸酯共聚物、铵基烷基甲基丙烯酸酯共聚物(ammonioalkyl methacrylate copolymer)及其共聚物和组合。
当通过口服对患者给药时(即通过患者吞咽片剂),所述的剂型可以提供随时间变化的在血浆中加巴喷丁的浓度曲线,该曲线具有如附图1和2所示的形状和达到最大血浆浓度(Tmax)所需的时间。
附图简述
附图1为如实施例3中所述对禁食患者口服给予含有化合物(1)的持续释放片剂(2×600mg)(治疗A)后加巴喷丁在血浆中的平均浓度±SD的示意图。
附图2为如实施例3中所述对摄食患者口服给予含有化合物(1)的持续释放片剂(2×600mg)(治疗B)后加巴喷丁在血浆中的平均浓度±SD的示意图。
附图3为如实施例4中所述对摄食患者口服给予含有化合物(1)的持续释放片剂(1×300mg;1×600mg;和2×600mg)(治疗B)后加巴喷丁在血浆中的平均浓度的示意图。
附图4为如实施例5中所述对禁食成年雄性Cynomologous猴口服给予含有化合物(1)的持续释放片剂(1×600mg)后加巴喷丁在血浆中的平均浓度±SD的示意图。
附图5为如实施例7中所述对禁食成年雄性Cynomologous猴口服给予含有化合物(1)的持续释放片剂(1×600mg)后加巴喷丁在血浆中的平均浓度±SD的示意图。
附图6表示如实施例1中所述制备的本发明剂型的体外溶出曲线(profile)。
附图7A和7B表示如实施例2中所述制备的本发明其它剂型的体外溶出曲线。
附图8表示如实施例6中所述制备的本发明另一种剂型的体外溶出曲线。
详细描述
定义
“AUC”为表示对患者给予所述化合物后作为时间函数的该化合物或其代谢物在患者生物流体中的浓度的曲线下的面积。在某些实施方案中,该化合物可以为前体药物并且所述的代谢物可以为药物。生物流体的实例包括血液和血浆。可以通过下列步骤测定AUC:在不同时间间隔使用诸如液相色谱法-串连质谱法(LC/MS/MS)这类方法测定诸如血浆或血液这类生物流体中化合物或其代谢物的浓度,并且计算血浆浓度与时间曲线下的面积。用于根据药物浓度与时间曲线计算AUC的合适的方法为本领域众所周知的。作为与本文披露的内容相关的,可以通过测定口服给予包含化合物(1),即1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的剂型后患者血浆和/或血液中加巴喷丁的浓度来测定加巴喷丁的AUC。
“生物利用度”意旨在对患者给予药物或前体药物后达到患者全身循环并且可以通过评价例如化合物的血浆和/或血药浓度与时间的曲线测定的药物的速率和量。用于表征血浆和/或血药浓度与时间曲线的参数包括曲线下的面积(AUC)、达到峰值浓度所需的时间(Tmax)和最大药物浓度(Cmax)。
“生物等价”意旨在对患者给予等剂量的药物或前体药物后药物吸收的速率和程度的等价性。作为本文所用的,如果两种曲线的平均反应比的90%置信区间在0.8和1.25极限内,那么两种血浆或血药浓度曲线为生物等价的。平均反应包括曲线的特征参数中的至少一种,诸如Cmax、Tmax和AUC。
“C max ”为对患者给予药物或前体药物剂量后患者血浆或血液中药物的最大浓度。
“T max ”为对患者给予药物或前体药物剂量后达到患者血浆或血液中药物的最大浓度的时间(Cmax)。
“禁食患者”意旨在对患者给予剂量时和给药后至少4小时其胃中基本上不含食物的患者。膳食后患者胃中变为基本上不含食物的时间取决于许多因素,包括:例如膳食的容量,诸如卡路里数;膳食的内含物,诸如脂肪含量;患者的健康;和患者胃肠道的情况。健康人体受试者的胃一般在摄食后约4-约8小时后基本上不含食物。在某些实施方案中,禁食患者在给药前约10小时到给药后约4小时不食用任何食物(但可以摄入任意量的水或澄清液体),在给药前约2小时和约1小时饮约250mL水和在给药后约2小时饮约250mL水,在给药后约4小时吃午餐,和在给药后约10小时吃晚餐。
“摄食患者”意旨胃中含食物的患者。在某些实施方案中,摄食患者从给药前约30分钟开始食用测试膳食并且在给药前约5分钟食用完测试膳食;在给药后4小时吃午餐并且在给药后约10小时吃晚餐。测试膳食包含高脂肪(约50%的测试膳食中的总卡路里数)和高卡路里(约1000总卡路里)早餐,诸如,例如2个黄油煎鸡蛋,2条咸肉,2片含黄油的小麦土司面包,4盎司碎的棕色土豆和8盎司全脂奶。测试膳食含有约150蛋白质卡路里、250碳水化合物卡路里和约500-600脂肪卡路里。
“患者”意旨哺乳动物,例如人。
“药学上可接受的”意旨由联邦或州政府管理局批准或可由其批准或美国药典或其它一般用于动物且更具体地说是用于人类的公认的药典中所列的。
“药学上可接受的盐”意旨为药学上可接受的并且具有母体化合物药理学活性的本说明书中的化合物的盐。这类盐包括:(1)与无机酸,诸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成的盐;或与有机酸形成的酸加成的盐,所述的有机酸诸如乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙-二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1-甲酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、粘康酸等;或(2)在存在于母体化合物上的酸性质子被金属离子,例如碱金属离子、碱土金属离子或铝离子取代时形成的盐;或与有机碱,诸如乙醇胺、二乙醇胺、三乙醇胺、N-甲基葡糖胺等的配位物。
“预防(Preventing)”或“预防(prevention)”意旨使获得疾病或障碍的风险降低(即导致疾病的至少一种临床症状不在可能接触或易感该病,但尚未发生或展示出该障碍状的患者中发生)。
“前体药物”意旨要求在体内转化而释放活性药物的药物分子的衍生物。化合物(1)胃在患者体内代谢成母体药物加巴喷丁的前体药物,且由此化合物(1)为加巴喷丁的前体药物。化合物(1),即1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸包括化合物(1)游离酸形式的药学上可接受的盐或药学上可接受的溶剂合物以及任意上述化合物的结晶形式。
“溶剂合物”意旨化合物与一种或多种溶剂分子以化学计算或非化学计算量的分子复合物。这类溶剂合物分子为那些常用于药学领域的物质,已知它们对患者无害,例如水、乙醇等。可以通过非共价键的分子内力,诸如静电力、范德华力或氢键使化合物或化合物的部分与溶剂的分子复合物保持稳定。术语“水合物”意旨一种或多种溶剂分子为水的复合物。
“持续释放”意旨与通过口服给予化合物(1)的即刻释放制剂所达到的治疗或预防浓度相比,化合物(1)在延长的时间期限内在全身血液循环中以有效获得化合物(1)或其活性代谢物的治疗或预防浓度的速率从剂型中释放。在某些实施方案中,化合物(1)在至少6小时期限内发生释放;在某些实施方案中,至少约12小时,在某些实施方案中,至少约18小时,且在某些实施方案中,至少约24小时。
“治疗有效量”意旨在对患者给药用于治疗或预防疾病时,化合物(1)的用量足以对该病进行这类治疗或预防。“治疗有效量”根据疾病及其严重程度以及具有所治疗或预防疾病的患者的年龄、体重等的不同而改变。
疾病或障碍的“治疗(Treating)”或“治疗(treatment)”在某些实施方案中意旨改善疾病或障碍(即阻止或持续释放疾病或其至少一种临床症状发展)。在其它实施方案中,“治疗(treating)”或“治疗(treatment)”意旨改善可以由患者辨别或无法辨别的至少一种身体(physical)参数。在某些实施方案中,“治疗(treating)”或“治疗(treatment)”意旨抑制从身体上(例如稳定可辨别的症状),生理上(例如稳定身体参数)或它们两者抑制疾病或障碍。在某些实施方案中,“治疗(treating)”或“治疗(treatment)”意旨延缓疾病或障碍发作。
“Wt%”意旨占组合物或剂型总干重的组分或成分的重量,例如重量百分比。例如,包含40wt%的化合物(1)的剂型且重1000mg含有400mg的化合物(1)。当意旨化合物(1)的盐和/或溶剂合物时,wt%意旨形成化合物(1)的药学上可接受的盐和/或药学上可接受的溶剂合物的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的质量当量。
现在对剂型和方法的某些实施方案进行详细描述。公开的实施方案并非起限定作用。相反,权利要求旨在覆盖所公开的实施方案的所有备选、变型和等同方案。
持续释放口服剂型
尽管本说明书的某些实施方案提供了片剂形式的持续释放口服剂型,但是持续释放口服剂型领域的技术人员可以理解,也可以使用其它持续释放口服剂型,诸如用于重配的粉剂、颗粒、小药囊、液体混悬液和/或胶囊。在某些实施方案中,剂型可以为片剂,它可以具有适合于药物口服给药的任意形状,诸如球形、立方形椭圆形或椭圆体。片剂可以包含单位剂量的化合物(1),或就迷你片(mini-tablets)而言,其包含低于单位剂量的剂量,可以将迷你片填充入胶囊以便提供单位剂量。在某些实施方案中,片剂可以为多层片,其中不同的层含有不同颗粒群和/或影响化合物(1)从片剂各层中释放特性的不同赋形剂。片剂的实例包括崩解片、速溶片、泡腾片、速熔片、咀嚼片、可压碎片和迷你片。一般而言,可以将片剂剂型压制成至少约15千克力(kp)(等于147.1牛顿)的硬度。可以按照本领域公知的方式制备剂型,并且,如果合适,那么这些剂型可以进一步包括药学上可接受的赋形剂。
在某些实施方案中,持续释放口服剂型包含(a)约10wt%-约80wt%的化合物(1)和(b)约1wt%-约30wt%的调节释放速率的聚合物。
在某些实施方案中,持续释放口服剂型包含(a)约10wt%-约80wt%的化合物(1)和(b)约1wt%-约50wt%的调节释放速率的聚合物。
在某些实施方案中,持续释放口服剂型包含(a)约30wt%-约75wt%的化合物(1)和(b)约1wt%-约50wt%的调节释放速率的聚合物。
在某些实施方案中,持续释放口服剂型包含(a)约40wt%-约65wt%的化合物(1)和(b)约1wt%-约50wt%的调节释放速率的聚合物。
在某些实施方案中,持续释放口服剂型包含(a)约50wt%-约60wt%的化合物(1)和(b)约20wt%-约50wt%的调节释放速率的聚合物。
本说明书中的剂型为基质系统,其中化合物(1)均匀地分散在调节释放速率的聚合物和任选的赋形剂中。基质系统为本领域中众所周知的,例如,在“Handbook of Pharmaceutical Controlled ReleaseTechnology,”ed.D.L.Wise,Marcel Dekker,Inc.(2000)和“Treatise on Controlled Drug Delivery,Fundamentals,Optimization,和Applications,”ed.A.Kydonieus,Marcel Dekker,Inc.(1992)中所述。调节释放速率的聚合物可以延缓药物从剂型中释放。合适的调节释放速率的聚合物包括但不限于:pH敏感性聚合物;pH不敏感性聚合物;在接触水或含水介质时具有高溶胀度的亲水性聚合物;接触水或含水介质时形成凝胶的聚合物;接触水或含水介质时表现出溶胀和胶凝特性的聚合物;脂肪族化合物,诸如蜡;和生物可降解聚合物。
在某些实施方案中,调节释放速率的聚合物可以为:pH敏感性聚合物,诸如丙烯酸和甲基丙烯酸聚合物和共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸乙氧基乙酯、甲基丙烯酸氰基乙酯、聚(丙烯酸)、聚(甲基丙烯酸)、甲基丙烯酸烷基酰胺共聚物、聚(甲基丙烯酸甲酯)、聚甲基丙烯酸酯、聚(甲基丙烯酸甲酯)共聚物、聚丙烯酰胺、甲基丙烯酸氨基烷基酯共聚物、聚(甲基丙烯酸酐)、甲基丙烯酸缩水甘油酯共聚物、甲基丙烯酸铵基烷基酯共聚物和上述任意物质的组合。在某些实施方案中,pH-依赖性聚合物可以为由甲基丙烯酸二乙基氨基乙酯和其它中性甲基丙烯酸酯类合成的共聚物,也称作甲基丙烯酸共聚物或作为EudragitTM(Rohm Pharma)商购的聚合物甲基丙烯酸酯类。
在某些实施方案中,pH不敏感性聚合物为甲基丙烯酸铵基烷基酯共聚物,诸如EudragitTM RS和EudragitTM RL,其为包含具有低含量季铵基团的丙烯酸和甲基丙烯酸酯类的共聚物的丙烯酸树脂。
表现出高溶胀度的调节释放速率的亲水性聚合物的实例包括交联羧甲基纤维素钠、交联羟丙基纤维素、高分子量羟丙基甲基纤维素、羧甲基酰胺、甲基丙烯酸钾二乙烯基苯共聚物、聚甲基丙烯酸甲酯、聚乙烯吡咯烷酮、高分子量聚乙烯醇类、甲基纤维素、乙烯基乙酸酯共聚物等。
接触水胶凝的调节释放速率的聚合物的实例包括甲基纤维素、羧甲基纤维素、低分子量羟丙基甲基纤维素、低分子量聚乙烯醇类、聚乙二醇类、非交联聚乙烯吡咯烷酮、黄原胶等。
表现出高溶胀和胶凝特性的调节释放速率的聚合物的实例包括中等粘度的羟丙基甲基纤维素和中等粘度的聚乙烯醇类。
在某些实施方案中,调节释放速率的聚合物为甘油酯,诸如单硬脂酸甘油酯、二十二烷酸甘油酯、棕榈酰硬脂酸甘油酯、月桂酰聚乙二醇甘油酯、硬脂酰聚乙二醇甘油酯或上述任意物质的组合。在某些实施方案中,调节释放速率的聚合物为二十二烷酸甘油酯。其它脂肪族和/或蜡的调节释放速率的聚合物包括月桂醇、肉豆蔻醇、十八烷醇、鲸蜡醇、十八醇十六醇混合物、棕榈酰醇、ouricury wax、氢化植物油、小烛树蜡、西班牙草蜡、硬脂酸、石蜡、蜂蜡、glycowax、蓖麻蜡和巴西棕榈蜡。
生物蚀解的聚合物的实例包括胶原蛋白、明胶、聚乙烯醇类、聚原酸酯类、polyacetyls、聚原碳酸酯类、聚酰胺类、聚氨基酸类、聚酯类、聚乳酸类、聚乙醇酸类、聚碳水化合物、聚原酸酯类、聚原碳酸酯类、polyacetyls、聚酐类、polydehydropyrans、polydioxinones等。
可以掺入本说明书的剂型中的其它合适的调节释放的聚合物包括:水胶体,诸如天然或合成树胶;基于碳水化合物的物质,诸如阿拉伯胶、西黄蓍胶、豆角胶、瓜尔胶、琼脂、果胶、carageenin、可溶性和不溶性藻酸盐、羧聚乙烯、酪蛋白、玉米蛋白、聚氧化乙烯、马来酐/甲基乙烯基醚共聚物和蛋白质物质。诸如明胶。
调节释放速率的聚合物可以单独使用或与一种或多种其它调节释放速率的聚合物联用和/或可以为一种以上调节释放速率的聚合物的共聚物。
可以使用本领域众所周知的标准技术,诸如湿制粒法、流化床制粒、干法制粒和直接压片法制备化合物(1)和一种或多种调节释放的聚合物的制剂(参见“Remington’s Pharmaceutical Sciences,”Lippincott Williams & Wilkins,889-928,(2005)。例如,可以通过干法掺合调节释放的聚合物、填充剂、化合物(1)和赋形剂,随后使用醇对该混合物制粒,直到获得合适的颗粒来制备基质制剂。可以通过本领域公知的方法进行制粒。可以在流化床干燥器中干燥湿颗粒,过筛并且研磨成适当大小。可以将润滑剂与干燥颗粒混合成最终制剂。在某些实施方案中,可以通过本领域众所周知的方法将这类制剂压制成片剂剂型。
在某些实施方案中,化合物(1)在剂型中的量在约50mg-约800mg,在某些实施方案中,约100mg-约800mg,并且在某些实施方案中,在约300mg-约700mg。就包含化合物(1)的药学上可接受的盐和/或溶剂合物的剂型而言,化合物(1)在剂型中的量意指化合物(1)的质量当量。剂型中包含的化合物(1)的量或负荷量可以取决于所治疗的具体疾病和从吸收后的前体药物负荷量产生的加巴喷丁的量。
除本文所述的化合物(1)和调节释放速率的聚合物外,剂型还可以包含一种或多种药学上可接受的赋形剂,诸如表面活性剂、润滑剂、稀释剂、抗粘着剂、助流剂、缓冲剂、染料、湿润剂、乳化剂、pH缓冲剂、稳定剂、增稠剂、崩解剂和着色剂。这类赋形剂包括淀粉、糖类、明胶、麦牙、稻米。面粉、白垩粉、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、甘油、丙二醇、水、乙醇等。
可以加入稀释剂以便增加物质团快使得形成用于压缩的实际大小的剂型。有用的稀释剂的实例包括磷酸氢钙、磷酸氢钙二水合物、硫酸钙、磷酸二钙、磷酸三钙、乳糖、纤维素,包括微晶纤维素、高岭土、甘露糖醇、氯化钠、干淀粉、预胶凝化淀粉、可压缩糖、甘露糖醇和任意上述物质的组合。在某些实施方案中,稀释剂选自磷酸氢钙和微晶纤维素。在某些实施方案中,其中稀释剂为磷酸氢钙,剂型可以包含约30wt%-约50wt%用量的稀释剂,并且在某些实施方案中,稀释剂用量约35wt%-约45wt%。并且在某些实施方案中,其中稀释剂为微晶纤维素,剂型可以包含约5wt%-约20wt%用量的稀释剂,并且在某些实施方案中,稀释剂用量约10wt%-约16wt%。
在本说明书的剂型中可以包括助流剂以便减少加工、成膜和/或干燥过程中的粘附作用。有用的助流剂的实例包括滑石粉、硬脂酸镁、单硬脂酸甘油酯、胶态二氧化硅、沉淀二氧化硅和上述任意物质的组合。在某些实施方案中,助流剂为胶态二氧化硅。剂型可以包含低于约2wt%的助流剂,并且在某些实施方案中,助流剂低于约1wt%。
在本说明书的剂型中可以包括润滑剂和抗粘着剂以便有助于加工。有用的润滑剂和/或抗粘着剂的实例包括硬脂酸钙、二十二烷酸甘油酯、单硬脂酸甘油酯、硬脂酸镁、矿物油、聚乙二醇、硬脂酰醇富马酸钠、十二烷基硫酸钠、硬脂酸、滑石粉、氢化蓖麻油、硬脂酸锌和上述任意物质的组合。在某些实施方案中,润滑剂为单硬脂酸甘油酯。在某些实施方案中,润滑剂为硬脂酸镁。剂型可以包含约1wt%-约13wt%用量的润滑剂和/或抗粘着剂,并且在某些实施方案中,该用量约4wt%-约102t%。
用于本说明书的剂型的表面活性剂的实例包括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(两亲性/两亲)表面活性剂、非离子型表面活性剂、聚乙二醇酯类或醚类和上述任意物质的组合。合适的药学上可接受的阴离子型表面活性剂的实例包括一价烷基羧酸盐;酰基乳酰乳酸盐(acyllactylates);烷基醚羧酸盐;N-酰基肌氨酸盐;多价烷基碳酸盐;N-酰基谷氨酸盐酯类;脂肪酸-多肽缩合物;硫酸酯类;烷基硫酸酯,诸如月桂基硫酸钠和十二烷基硫酸钠;乙氧基化烷基硫酸酯;酯连接的磺酸盐,诸如多库酯钠和二辛基琥珀酸钠;α烯烃磺酸盐;或磷酸化乙氧基化醇类。合适的药学上可接受的阳离子型表面活性剂的实例包括一烷基季铵盐、二烷基季铵化合物、酰氨基胺类和胺化酰亚胺。合适的药学上可接受的两性表面活性剂的实例包括N-取代的烷基酰胺类、N-烷基甜菜碱、磺基甜菜碱和N-烷基-6-氨基丙酸酯类。合适的药学上可接受的聚乙二醇酯类或醚类的实例包括聚乙氧基化蓖麻油、聚乙氧基化氢化蓖麻油和氢化蓖麻油。在某些实施方案中,表面活性剂选自月桂基硫酸钠和十二烷基硫酸钠。在某些实施方案中,剂型可以包含低于约3wt%的表面活性剂,并且在某些实施方案中,表面活性剂低于约2wt%。
本说明书的剂型,诸如片剂剂型可以进一步包含一种或多种包衣。一种或多种额外的包衣的目的在于物理防护、美观、易于吞咽、鉴别和/或有利于颗粒的进一步加工。尽管某些包衣可以用于改变或影响化合物(1)在胃肠道中从剂型中释放,但是其它包衣不具有这类作用。包衣不能够透过水分或可以透过水分。可透过水分的外部片剂包衣可以用于维持剂型中的低含水量,该剂型在有干燥剂存在下包装并且由此可以促进例如剂型的贮存稳定性。可以通过本领域技术人员公知的方法将这些额外的包衣涂布在本说明书的剂型上。用于进行物理防护的包衣的材料包括可透性或可溶性材料,诸如羟丙基甲基纤维素、羟丙基纤维素、羟丙基乙基纤维和黄原胶。用于有利于进一步加工的材料的实例包括滑石粉、胶态二氧化硅、聚乙烯醇、二氧化钛、微粉化二氧化硅、热解法二氧化硅、单硬脂酸甘油酯、三硅酸镁和硬脂酸镁。包衣可以包含单一材料或一种以上材料的组合,包括本文披露的任意那些材料。
本说明书的剂型可以基本上不含化合物(1)和/或加巴喷丁的分子内环化形成的内酰胺副产物。剂型优选对延长的贮存稳定(更优选大于1年),而基本上无内酰胺形成(优选低于0.5%内酰胺重量,更优选低于0.2%内酰胺重量,最优选低于0.1%内酰胺重量)。
在某些实施方案中,剂型中的化合物(1)为Estrada等在2005年7月14日公布的美国专利申请公开号US 2005/0154057中披露的晶体形式。
当通过口服对患者给药(即通过患者吞咽片剂)时,本说明书的剂型可以提供随时间变化的加巴喷丁在血浆或血液中的浓度的曲线。就具有实施例1中所述组成和负荷量的剂型而言,在对患者给予化合物(1)后,加巴喷丁血浆浓度曲线对禁食和摄食人类患者而言分别具有附图1和2中所示的形状、等级和AUC。这些曲线不同于单独给予加巴喷丁后获得的曲线。一个重要的区别在于达到最大血药浓度(Cmax)所需的时间(Tmax)。在禁食患者中,本说明书的持续释放口服剂型的Tmax大于约4小时。在摄食患者中,持续释放口服剂型的Tmax大于约6小时。相反,单独对禁食和摄食患者给予加巴喷丁后的Tmax约为2-4小时。本说明书的持续释放口服剂型的另一个重要的优点在于加巴喷丁代谢物的生物利用度。在1200mg化合物(1)的负荷剂量下,本说明书的剂型可以在禁食患者中提供比给予等摩尔剂量的加巴喷丁至少高20%的加巴喷丁生物利用度,并且在某些实施方案中,在禁食患者中提供比给予等摩尔剂量的加巴喷丁至少高25%的加巴喷丁生物利用度。在1200mg化合物(1)的负荷剂量下,本说明书的剂型可以在摄食患者中提供比给予等摩尔剂量的加巴喷丁至少高50%的加巴喷丁生物利用度,并且在某些实施方案中,在摄食患者中提供比给予等摩尔剂量的加巴喷丁至少高100%的加巴喷丁生物利用度。
在某些实施方案中,当以约1100mg-约1300mg剂量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的持续释放口服剂型对一个或多个禁食人类患者给药时,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸可以提供的加巴喷丁血浆浓度曲线的特征在于Cmax在约3μg/mL-约6μg/mL,Tmax在约4小时-约7小时,并且AUC在约30μg·hr/mL-约70μg·hr/mL。
在某些实施方案中,当以约1100mg-约1300mg剂量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的持续释放口服剂型对一个或多个摄食人类患者给药时,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸可以提供的加巴喷丁血浆浓度曲线的特征在于Cmax在约5μg/mL-约8μg/mL,Tmax在约6小时-约11小时,并且AUC在约60μg·hr/mL-约110μg·hr/mL。
在某些实施方案中,当以约1100mg-约1300mg剂量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的持续释放口服剂型对禁食人类患者群体给药时,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸可以提供的加巴喷丁血浆浓度曲线的特征在于平均Cmax在约3μg/mL-约6μg/mL,平均Tmax在约4小时-约7小时,并且平均AUC在约30μg·hr/mL-约70μg·hr/mL;并且当以约1100mg-约1300mg剂量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的持续释放口服剂型对摄食人类患者群体给药时,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸可以提供的加巴喷丁血浆浓度曲线的特征在于平均Cmax在约5μg/mL-约8μg/mL,平均Tmax在约6小时-约11小时,并且平均AUC在约60μg·hr/mL-约110μg·hr/mL。
在某些实施方案中,对一个或多个禁食人类患者口服给予两种持续释放口服剂型,每种剂型包含600mg 1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,可以提供的加巴喷丁血浆浓度曲线的特征在于Cmax在约3μg/mL-约6μg/mL,Tmax在约4小时-约7小时,并且AUC在约30μg·hr/mL-约70μg·hr/mL。
在某些实施方案中,对一个或多个摄食人类患者口服给予两种持续释放口服剂型,每种剂型包含600mg 1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,可以提供的加巴喷丁血浆浓度曲线的特征在于Cmax在约5μg/mL-约8μg/mL,Tmax在约6小时-约11小时,并且AUC在约60μg·hr/mL-约110μg·hr/mL。
在某些实施方案中,对禁食人类患者群体口服给予两种持续释放口服剂型,每种剂型包含600mg 1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,可以提供的加巴喷丁血浆浓度曲线的特征在于Cmax在约3μg/mL-约6μg/mL,Tmax在约4小时-约7小时,并且AUC在约30μg·hr/mL-约70μg·hr/mL;并且对摄食人类患者群体口服给予两种持续释放口服剂型,每种剂型包含600mg 1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,可以提供的加巴喷丁血浆浓度曲线的特征在于平均Cmax在约5μg/mL-约8μg/mL,平均Tmax在约6小时-约11小时,并且平均AUC在约60μg·hr/mL-约110μg·hr/mL。
本说明书的剂型包括就吸收速率和程度而言与本文披露的剂型生物等价的剂型,例如,如美国食品与药品监督管理局规定和在“Guidance for Industry-Bioavailability and BioequivalenceStudies for Orally Administered Drug Products”(2003)中所讨论的。
在某些实施方案中,当以约1100mg-约1300mg剂量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸对一个或多个禁食人类患者给药时,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的持续释放口服剂型提供与附图1中所示曲线生物等价的加巴喷丁血浆浓度曲线;或当对一个或多个摄食人类患者给药时,其可以提供与附图2中所示曲线生物等价的加巴喷丁血浆浓度曲线。
在某些实施方案中,在当约1100mg-约1300mg剂量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸对一个或多个禁食人类患者给药时,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的持续释放口服剂型提供与附图1中所示曲线生物等价的加巴喷丁血浆浓度曲线;并且当对一个或多个摄食人类患者给药时,其提供与附图2中所示曲线生物等价的加巴喷丁血浆浓度曲线。
在某些实施方案中,对一个或多个禁食人类患者口服给予两种持续释放口服剂型,每种剂型包含600mg 1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,可以提供与附图1中所示曲线生物等价的加巴喷丁血浆浓度曲线;或对一个或多个摄食人类患者口服给予相同剂型可以提供与附图2中所示曲线生物等价的加巴喷丁血浆浓度曲线。
在某些实施方案中,对一个或多个禁食人类患者口服给予两种持续释放口服剂型,每种剂型包含600mg 1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,可以提供与附图1中所示曲线生物等价的加巴喷丁血浆浓度曲线;并且对一个或多个摄食人类患者口服给予相同剂型可以提供与附图2中所示曲线生物等价的加巴喷丁血浆浓度曲线。
在口服给药后,本说明书的剂型可以在患者血液和/或血浆中提供至少约6小时的加巴喷丁治疗性或预防性浓度,在某些实施方案中,至少约12小时,在某些实施方案中,至少约18小时,并且在某些实施方案中至少约24小时。加巴喷丁在患者血液和/或血浆中的治疗或预防有效浓度可以取决于许多因素,包括,例如所治疗的疾病、疾病的严重程度、患者体重、患者健康状况等。
在某些实施方案中,可以将本说明书的剂型每天给药两次,并且在某些实施方案中,每天给药一次。
治疗应用
可以对患有已知或下文发现为治疗有效的母体药物加巴喷丁所针对的任意疾病或障碍的患者给予本说明书的持续释放口服剂型。开据加巴喷丁处方且由此本文披露的剂型也有效的障碍包括:癫痫;抑郁症;焦虑;精神病;认知;精神分裂症;昏晕发作;运动功能减退;颅脑障碍;神经变性障碍;恐慌;疼痛(尤其是神经性疼痛(例如疱疹后神经痛)、肌肉和骨骼痛);不宁腿综合征;热潮红;尿失禁;炎性疾病(即关节炎);失眠;胃肠道障碍;和酒精/可卡因成瘾;酒精戒断综合征;外阴痛;早泄;和作为谷氨酰胺能情况。还可以针对上述疾病或障碍对患者给予这些剂型作为预防性措施,因此,可以将所述剂型作为预防性措施对具有下列疾病遗传因素的患者给药:癫痫;抑郁症;焦虑;精神病;昏晕发作;运动功能减退;颅脑障碍;神经变性障碍;恐慌;疼痛(尤其是神经性疼痛和肌肉和骨骼痛);炎性疾病(即关节炎);失眠;胃肠道障碍;酒精戒断综合征;早泄;和外阴痛。因此,所述的剂型可以用于预防一种疾病或障碍,并且可以同时用于治疗另一种疾病或障碍(例如预防精神病,同时治疗胃肠道障碍;预防神经性疼痛,同时治疗酒精戒断综合征)。这些剂型可以与其它药物,诸如抗病毒药在病毒感染初期联用以便预防或减少随后发生神经病性障碍。另外,这些剂型可以与自身已知可导致神经病性障碍作为副作用的其它药物联用,由此预防或减少所述副作用发生。
可以通过本领域中所述的方法确定所述剂型在治疗或预防上述疾病和病症中的适合性(例如,参见Satzinger等美国专利US4,024,175;Satzinger等美国专利US4,087,544;Woodruff,美国专利US5,084,169;Silverman等美国专利US 5,563,175;Singh,美国专利US6,001,876;Horwell等美国专利US6,020,370;Silverman等美国专利US 6,028,214;Horwell等美国专利US6,103,932;Silverman等美国专利US6,117,906;Silverman,国际公开号WO 92/09560;Silverman等国际公开号WO 93/23383;Horwell等国际公开号WO97/29101,Horwell等国际公开号WO 97/33858;Horwell等国际公开号WO 97/33859;Bryans等国际公开号WO 98/17627;Guglietta等国际公开号WO 99/08671;Bryans等国际公开号WO 99/21824;Bryans等国际公开号WO 99/31057;Magnus-Miller等国际公开号WO99/37296;Bryans等国际公开号WO 99/31075;Bryans等国际公开号WO 99/61424;Pande,国际公开号WO 00/23067;Bryans,国际公开号WO 00/31020;Bryans等国际公开号WO 00/50027;Bryans等国际公开号WO 02/00209;2005年8月5日提交的美国申请顺序号US60/711,477;和2005年8月5日提交的美国申请顺序号US60/710,963)。
给药
有效治疗本文披露的特定疾病、障碍或病症的化合物(1)的用量至少部分取决于所述障碍或病症的性质,并且可以如上所述通过标准临床技术测定。此外,体外或体内试验可以任选用于辅助鉴定最佳剂量范围。当然,给予的前体药物的量取决于所治疗的疾病、受试者体重、疾病严重程度、给药方式和开据处方的临床医师的判断等因素。
在某些实施方案中,持续释放口服剂型适合于对患者每天给药1-3次。在其它实施方案中,持续释放口服剂型适合于对患者每天给药1-2次。可以提供单独给药或与其它药物联用,并且可以持续进行,只要是有效治疗或预防疾病或障碍所需的。
加巴喷丁的合适的剂量范围一般在约100mg/天-3600mg/天并且可以调整化合物(1)或其药学上可接受的盐或药学上可接受的溶剂合物的剂量以便提供等摩尔量的加巴喷丁。剂量范围易于通过本领域技术人员公知的方法测定。
下列实施例进一步解释了持续释放口服剂型、用于制备持续释放口服剂型的方法和物质以及对患者给予所述剂型时获得的效果。
实施例
实施例1
制备具有表1中所示成分的含有化合物(1)的持续释放口服剂型片剂:
表1
按照下列步骤制备片剂。称重化合物(1)、磷酸氢钙、二十二烷酸甘油酯、滑石粉和胶态二氧化硅,通过#20目筛过筛并且在V-掺合机中混合15分钟。称重月桂基硫酸钠的预压片部分并且使其通过#30目筛。称重硬脂酸镁的预压片部分并且使其通过#40目筛。将过筛的月桂基硫酸钠和硬脂酸镁加入到V-掺合机中并且掺合5分钟。放出掺合物并且在压片机上压制成约400mg重量的预压片。然后使预压片通过Comil 194Ultra研磨机(Quadro Engineering,Inc.,Millburn,NJ)而获得用于进一步压制的研磨物质。称重月桂基硫酸钠的压片部分并且使其通过#30目筛。称重硬脂酸镁的压片部分并且使其通过#40目筛。将月桂基硫酸钠和硬脂酸镁的研磨物质和压片部分加入到V-掺合机中并且掺合3分钟。放出掺合的物质并且压制成具有1310mg总重和600mg化合物(1)负荷量(45.8wt%)的片剂。这些片剂具有的最终平均硬度为16.1-22.2kp(158-218牛顿)。
实施例2
使用另一种方法,按照下列步骤制备具有表1中所示成分的持续释放口服剂型片剂。称重化合物(1)、磷酸氢钙、二十二烷酸甘油酯、滑石粉和胶态二氧化硅,通过#20目筛过筛并且在V-掺合机中混合15分钟。称重月桂基硫酸钠的压紧部分并且使其通过#30目筛。称重硬脂酸镁的压紧部分并且使其通过#40目筛。将过筛的月桂基硫酸钠和硬脂酸镁加入到V-掺合机中并且掺合5分钟。放出掺合物并且在Chilsonator(FitzPatrick,Elmhurst,IL的滚筒式压紧机)机器上压制成压紧物。然后使获得的压紧物通过锤磨机(FitzPatrick,Elmhurst,IL)而获得用于进一步压制的研磨物质。称重月桂基硫酸钠的压片部分并且使其通过#30目筛。称重硬脂酸镁的压片部分并且使其通过#40目筛。将月桂基硫酸钠和硬脂酸镁的研磨物质和压片部分加入到V-掺合机中并且掺合3分钟。放出掺合的物质并且压制成具有1310mg总重和600mg化合物(1)负荷量(45.8wt%)的片剂。另外将所述的掺合物压制成具有300mg化合物(1)负荷量的655mg片剂。这些片剂具有的最终平均硬度分别为15.7-18.9kp和11.1-13.7kp。
实施例3
在健康成年患者中对化合物(1)的持续释放口服剂型的安全性、耐受性和药代动力学进行随机化、交叉摄食/禁食单剂量研究。使用实施例1的持续释放口服剂型。设计本研究是为了评价该制剂与商品加巴喷丁胶囊剂相比在人体中的性能。12位健康成年人志愿者(7位男性和5位女性)参与本研究。平均体重为75.6kg。所有患者均接受两种不同的随机顺序的治疗,在治疗之间存在一周的清除期。两种治疗为:A)禁食过夜后单口服剂量的实施例1片剂(2×600mg化合物(1));和B)高脂肪早餐后单口服剂量的实施例1片剂(2×600mg化合物(1))。
在给药前并且在给药后0.5,1,1.5,2,3,4,6,8,12,18,24和36小时从所有患者中采集血液和血浆样品。在给药前从所有患者中采集尿样,并且在给药后0-4,4-8,8-12,12-18,18-24和24-36小时间隔获得完全尿排出量。使用甲醇即刻骤冷血样并且冷冻贮存在≤70℃下。制备样品的等分部分以便使用敏感性和特异性LC/MS/MS方法分析加巴喷丁和化合物(1)。
对禁食和摄食健康成年患者口服给予实施例1制备的持续释放口服剂型后加巴喷丁血浆浓度±1SD分别如附图1和2中所示。
在口服给予所述片剂(禁食)后加巴喷丁在血浆中的平均值±SDCmax为4.21±1.15μg/mL。在高脂肪早餐后给予所述片剂后,加巴喷丁在血浆中的Cmax进一步增加至6.24±1.55μg/mL。口服给予所述片剂(禁食)后加巴喷丁在血浆中的平均值±SD AUC为54.5±12.2μg·hr/mL。在高脂肪早餐后给予所述片剂后,加巴喷丁在血浆中的AUC进一步增加至83.0±21.8μg·hr/mL。在有食物存在下,口服给予所述片剂后接触加巴喷丁比禁食患者额外增加了52%。
在口服给予所述片剂后达到加巴喷丁的峰值血浆浓度所需的时间(Tmax)得到明显延缓。在禁食患者中,口服给予所述片剂产生的加巴喷丁Tmax为5.08±1.62hr。与之相比,典型的即刻释放加巴喷丁的Tmax约为2-4hrs。在有食物存在下口服给予所述片剂后加巴喷丁的Tmax进一步延缓至8.40±2.07hr。加巴喷丁在血浆中的表观末端消除半衰期对所有治疗而言均类似:所述片剂在禁食患者中为6.47±0.77hr,并且上片剂在摄食患者中为5.38±0.80hr。
在口服给予所述片剂后,对禁食患者而言,在尿中回收的加巴喷丁剂量百分比为46.5±15.8%,并且对摄食患者而言为73.7±7.2%。
在口服给予所述片剂后接触完整前体药物较少。在禁食患者中口服给予所述片剂后,完整化合物(1)在血浆中的浓度达到最大值0.040μg/mL,约为相应峰值加巴喷丁浓度的1.0%。类似地,化合物(1)在这些患者血浆中的AUC为加巴喷丁在血浆中的相应AUC的0.3%。在所述片剂在摄食患者中口服给药后,完整化合物(1)在血浆中的浓度达到最大值0.018μg/mL,约为相应峰值加巴喷丁浓度的0.3%。类似地,化合物(1)在这些患者血浆中的AUC<加巴喷丁在血浆中的AUC的0.1%。
实施例4
对摄食人类患者口服给予实施例2制备的持续释放口服剂型后加巴喷丁的平均血浆浓度如附图3中所示。在给予下列剂型后按照实施例3中披露的方法测定加巴喷丁在12位人类患者中的平均血浆浓度:(a)包含300mg化合物(1)的一种片剂;(b)包含600mg化合物(1)的一种片剂;和(c)在两种片剂中的1200mg化合物(1),每种片剂包含600mg化合物(1)。
实施例5
对Cynomologous猴口服给予实施例1制备的持续释放口服剂型后加巴喷丁的血药浓度±1SD如附图4中所示。按照下列操作步骤测定加巴喷丁在Cynomologous猴中的血药浓度。
给药方案
通过口服给药对4只成年雄性Cynomologous(Macacafascicularis)猴(重约3kg)的组给予包含化合物(1)的片剂(1×600mg化合物(1)/片)。对每只猴给予一片。在研究前使动物禁食过夜,直到给药后4小时。在口服给药后24小时内间隔通过股静脉获得血样(1.0mL)。使用甲醇即刻骤冷血液并且冷冻在-20℃下,直到分析为止。对猴给予测试化合物,在两次给药期之间存在最少72-小时的清除期。
吸收药物的样品制备
将300μL甲醇加入到1.5mL埃彭道夫管(Eppendorf tube)中以便制备样品和标准品。
样品制备:在不同时间点采血并且即刻将100μL血液加入到含有300μL甲醇的埃彭道夫管中并且通过涡旋混合。
标准品制备:将90μL血液加入到在埃彭道夫管中的300μL甲醇中。将10μL加巴喷丁标准溶液(0.04,0.2,1,5,25和100μg/mL)加入到每支管中以便制成最终的校准标准品(0.004,0.02,0.1,0.5,2.5和10μg/mL)。
将20μL对-氯苯丙氨酸加入到所有样品和标准品中。
涡旋样品并且以14,000rpm离心20分钟。
将上清液用于LC/MS/MS分析。
LC/MS/MS分析
使用安装了Shimadzu SCL-10AVP和LEAP自动采样器的API 2000LC/MS/MS仪器测定猴血液中加巴喷丁的浓度。柱为在室温下操作的Zorbax C8XDB 4.6×150mm柱。流动相为:(A)在水中的0.1%甲酸;和(B)在乙腈中的0.1%甲酸。梯度条件为:2%B,3.5分钟,在3.5分钟内增加至95%B并且维持2分钟,然后在5.6分钟内降至2%B并且维持2.3分钟。将30μL样品注入柱。使用Turbo-IonSpray源并且在172/137的MRM跃迁的正离子模式中检测加巴喷丁。使用Analyst 1.2定量软件对峰进行积分。
实施例6
制备具有表2中所示成分的含有化合物(1)的持续释放口服剂型片剂:
表2
按照下列步骤制备片剂。称重化合物(1)、微晶纤维素(MCCPH113)、二十二烷酸甘油酯、滑石粉、胶态二氧化硅和十二烷基硫酸钠(SDS)(第一掺合部分)和硬脂酸镁(第一掺合部分),通过#20目筛过筛并且在V-掺合机中混合7分钟(MaxiBlend Lab Blender MB-1(Globepharma))。将掺合的成分倾入滚筒式压紧机的进料斗(BO50PHCompactor,接收滚筒/密闭末端,3.9英寸-滚筒直径,1.5英寸-滚筒宽,11.6kN滚筒压力,12rpm转速和7rpm水平螺旋进料速度)。然后使压紧的物质通过Quadro Underdriven Comil Model U5研磨机(Quadro Engineering,Inc.,Millburn,NJ,0.079-英寸磨孔(graterhole)大小,1607叶轮型,2500叶轮rpm))而获得用于进一步压制的研磨的物质。将研磨的物质转入掺合机(MaxiBlend Lab Blender MB-1型(Globepharma),25rpm外部速度)并且混合5分钟。如果必要,加入额外的SDS(第二掺合部分)和/或硬脂酸镁(第二掺合部分)以获得指定量。放出掺合的物质并且压制成具有1100mg总重和600mg(54.55wt%)化合物(1)负荷量的片剂。片剂具有的最终平均硬度为14-17kp(137-214牛顿)。
实施例7
对Cynomologous猴口服给予实施例6制备的持续释放口服剂型(1×600mg)后加巴喷丁的血药浓度±1SD如附图5中所示。按照实施例5中披露的方法测定加巴喷丁在Cynomologous猴中的血药浓度。
实施例8
将下列步骤用于测定实施例1,2和6制备的剂型的体外溶出曲线。在37℃下将剂型放入含有900mL 10mM磷酸二氢钾缓冲液(KH2PO4,pH7.4)和1%(wt/体积)月桂基硫酸钠的溶出容器内。以50rpm(USP,II型,桨式)搅拌溶出介质。在0.5,1,2,4,6,8,12和24小时取样品并且通过反相HPLC,使用C18柱和磷酸盐缓冲液/乙腈/水等度流动相及在210nm处的光电二极管检测化合物(1)在溶液中的含量。
正如附图6中所示,实施例1制备的剂型在约2小时后释放约20%的化合物(1),在约5小时后释放约50%,并且在约8小时后释放约80%。正如附图7A中所示,实施例2制备的包含300mg化合物(1)的剂型在约2小时后释放约20%的化合物(1),在约6小时后释放约50%,并且在约10小时后释放约80%。正如附图7B中所示,实施例2制备的包含600mg化合物(1)的剂型在约2小时后释放约20%的化合物(1),在约5小时后释放约50%,并且在约8小时后释放约80%。正如附图8中所示,实施例6制备的剂型在约5小时后释放约30%的化合物(1),在约10小时后释放约60%,并且在约15小时后释放约80%。
最终,应注意存在实施本发明的备选方式。因此,本发明的实施方案被视为例示性的并且本发明并不限于本文给出的详细描述,而可以根据本文请求的权利要求范围和等同范围内进行变型。
将本文引述的所有的公开文献和专利完整地引入作为参考。
Claims (31)
1.一种持续释放口服片剂,包含:
(a)10wt%-80wt%的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸;和
(b)1wt%-30wt%的脂肪族化合物;
其中,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸与脂肪族化合物的比例是约10∶1,和
其中wt%基于该片剂的总干重,
当对一个或多个禁食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,该片剂提供的加巴喷丁血浆浓度曲线的特征在于Cmax在3μg/mL-6μg/mL,Tmax在4小时-7小时,且AUC在30μg·hr/mL-70μg·hr/mL;或
当对一个或多个摄食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,该片剂提供的加巴喷丁血浆浓度曲线的特征在于Cmax在5μg/mL-8μg/mL,Tmax在6小时-11小时,且AUC在60μg·hr/mL-110μg·hr/mL。
2.一种持续释放口服片剂,包含:
(a)10wt%-80wt%的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸;和
(b)1wt%-30wt%的脂肪族化合物;
其中,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸与脂肪族化合物的比例是约10∶1,和
其中wt%基于该片剂的总干重,
当对一个或多个禁食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,该片剂提供的加巴喷丁血浆浓度曲线与附图1中所示的曲线生物等价;或
当对一个或多个摄食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,该片剂提供的加巴喷丁血浆浓度曲线与附图2中所示的曲线生物等价。
3.权利要求1或2的片剂,其压制成至少15千克力的硬度。
4.权利要求1-3任一项所述的片剂,其中所述的脂肪族化合物为甘油酯。
5.权利要求4所述的片剂,其中所述的甘油酯选自单硬脂酸甘油酯、二十二烷酸甘油酯、棕榈酰硬脂酸甘油酯、月桂酰聚乙二醇甘油酯、硬脂酰聚乙二醇甘油酯和上述任意物质的组合。
6.权利要求5所述的片剂,其中所述的甘油酯为二十二烷酸甘油酯。
7.权利要求1-3任一项所述的片剂,其中所述的脂肪族化合物选自月桂醇、肉豆蔻醇、十八烷醇、鲸蜡醇、十八醇十六醇混合物、棕榈酰醇、ouricury wax、氢化植物油、小烛树蜡、西班牙草蜡、硬脂酸、石蜡、蜂蜡、glycowax、蓖麻蜡和巴西棕榈蜡。
8.权利要求1或2所述的片剂,包含300mg-700mg用量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸。
9.权利要求1或2所述的片剂,其中1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸为晶体形式。
10.权利要求1或2所述的片剂,包含一种或多种药学上可接受的赋形剂,其选自稀释剂、润滑剂、抗粘着剂、助流剂、表面活性剂、崩解剂和上述任意物质的组合。
11.权利要求10所述的片剂,其中所述的稀释剂选自磷酸氢钙和微晶纤维素。
12.权利要求11的片剂,其中所述的稀释剂是磷酸氢钙,并且所述的片剂包括30wt%-50wt%的稀释剂。
13.权利要求1或2所述的片剂,其中该片剂包含600mg 1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸的片剂,并且所述剂量包含两片。
14.权利要求1或2所述的片剂,包含包衣。
15.权利要求1所述的片剂,
当对一个或多个禁食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,该片剂提供的加巴喷丁血浆浓度曲线的特征在于Cmax在3μg/mL-6μg/mL,Tmax在4小时-7小时,且AUC在30μg·hr/mL-70μg·hr/mL;且
当对一个或多个摄食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,该片剂提供的加巴喷丁血浆浓度曲线的特征在于Cmax在5μg/mL-8μg/mL,Tmax在6小时-11小时,且AUC在60μg·hr/mL-110μg·hr/mL。
16.权利要求1所述的片剂,
当对一个或多个所述的禁食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,该片剂提供的加巴喷丁血浆浓度曲线的特征在于平均Cmax在3μg/mL-6μg/mL,平均Tmax在4小时-7小时,且平均AUC在30μg·hr/mL-70μg·hr/mL;且
当对一个或多个所述的摄食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,该片剂提供的加巴喷丁血浆浓度曲线的特征在于平均Cmax在5μg/mL-8μg/mL,平均Tmax在6小时-11小时,且平均AUC在60μg·hr/mL-110μg·hr/mL。
17.权利要求2所述的片剂,
当对一个或多个禁食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,该片剂提供的加巴喷丁血浆浓度曲线与附图1中所示的曲线生物等价;且
当对一个或多个摄食人类患者给予1100mg-1300mg剂量范围的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸时,该片剂提供的加巴喷丁血浆浓度曲线与附图2中所示的曲线生物等价。
18.权利要求1或2的片剂,其中
一个或多个禁食人类患者从给药前10小时直到给药后4小时不食用任何食物,在给药前2小时和1小时饮用250mL水,和在给药后2小时饮用250mL水,在给药后4小时吃午餐,和在给药后10小时吃晚餐;并且
一个或多个摄食人类患者在给予所述剂量前30分钟开始食用测试膳食并且在给予该剂量前5分钟完成食用测试膳食;在给药后4小时吃午餐;和在给药后10小时吃晚餐,其中所述的测试膳食包含1000总卡路里,其中500卡路里包含脂肪卡路里。
19.一种持续释放口服片剂,包含:
(a)10wt%-80wt%的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸;和
(b)1wt%-30wt%的脂肪族化合物;
其中,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸与脂肪族化合物的比例是约10∶1,
其中wt%基于该片剂的总干重,
当将其置于以50rpm搅拌的pH 7.4和37℃的10mM磷酸二氢钾缓冲液和1%(wt/体积)十二烷基硫酸钠(USP,II型)中时,该片剂在2小时后释放20%的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,在5小时后释放50%,并且在8小时后释放80%。
20.权利要求19所述的片剂,包含500mg-700mg用量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸。
21.权利要求19所述的片剂,包含磷酸氢钙。
22.一种持续释放口服的片剂,包含:
(a)10wt%-80wt%的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸;和
(b)1wt%-30wt%的脂肪族化合物;
其中,1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸与脂肪族化合物的比例是约10∶1,和
其中wt%基于该片剂的总干重,当将其置于以50rpm搅拌的pH 7.4和37℃的10mM磷酸二氢钾缓冲液和1%(wt/体积)十二烷基硫酸钠(USP,I I型)中时,该片剂在5小时后释放30%的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸,在10小时后释放60%,并且在15小时后释放80%。
23.权利要求22所述的片剂,包含500mg-700mg用量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸。
24.权利要求22所述的片剂,包含微晶纤维素。
25.一种持续释放口服的片剂,包含:
45.8wt%的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸;
39.56wt%的磷酸氢钙二水合物;
4.58wt%的二十二烷酸甘油酯
6.11wt%的滑石粉;
0.41wt%的胶态二氧化硅;
1.84wt%的月桂基硫酸钠;和
1.69wt%的硬脂酸镁,
所述片剂任选地包衣。
26.权利要求25所述的片剂,包含300mg-700mg用量的1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸。
27.权利要求1-26任一项的所述的片剂,在制备用于治疗人类或动物体的药物中的应用。
28.权利要求1-26任一项的所述的片剂,在制备用于治疗不宁腿综合征的药物中的应用。
29.权利要求1-26任一项的所述的片剂,在制备用于治疗疱疹后神经痛的药物中的应用。
30.1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸在制备用于治疗不宁腿综合征的根据权利要求1-26任一项的持续释放口服片剂中的应用。
31.1-{[(α-异丁酰氧基乙氧基)羰基]氨甲基}-1-环己烷乙酸在制备用于治疗疱疹后神经痛的根据权利要求1-26任一项的持续释放口服片剂中的应用。
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