CN1329590A - 治疗产品及其应用 - Google Patents
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Abstract
本发明是基于下述发现完成的:通过采用一些非外消旋比例的各曲马多对映异构体,可获得关于止痛效力和降低与施用外消旋体有关的副作用(例如恶心、呕吐、头昏、便秘、镇静等)的最佳治疗指数。
Description
发明领域
本发明涉及新的、非外消旋形式的曲马多,及其在止痛中的应用。
发明背景
曲马多(顺式-2-二甲基氨基甲基-1-(3-甲氧基苯基)-1-环己醇)是用作高效止痛剂的手性药物。虽然目前曲马多在市场上仅作为外消旋体销售,但是人们对与其单独的对映异构体,即1S,2S-(-)-曲马多和1R,2R-(+)-曲马多有关的生理性质表现出了浓厚的兴趣,后一对映异构体的结构如下面的(1)所示。
特别是,人们已经在由妇科病患者参与的随机双盲实验中用静脉内患者控制的止痛研究了该外消旋体以及各对映异构体的止痛效力和安全性;参见S.Grond等人,Pain(1995)62(3):313-320。虽然看上去(+)-曲马多在产生痛觉缺失方面更有效力,但是其也产生更严重的恶心和呕吐。因为外消旋体的效力比(-)-曲马多强,并且副作用不比(+)-曲马多严重,因此作者推断外消旋体具有更好的临床实用性。
在另一项研究中,据表明在曲马多单独的对映异构体之间有互补和协同的抗感受伤害相互作用;参见R.B.Raffa等人,JPharmacol.Exp.Ther.(1993)267(1):331-340。曲马多的对映异构体在阿片受体、抑制血清素再摄取和去甲肾上腺素再摄取方面有不同的效力。因此看上去曲马多的这两种对映异构体都对止痛作用有贡献。
发明简述
本发明是基于下述发现完成的:通过采用一些非外消旋比例的各曲马多对映异构体,可获得关于止痛效力和降低与施用外消旋体有关的副作用(例如恶心、呕吐、头昏、便秘、镇静等)的最佳治疗指数。
依据本发明第一个方面,本发明提供了作为用于同时、分开或顺序使用来治疗或预防疼痛的联合制剂(药盒)的包含各曲马多对映异构体的非外消旋混合物的产品。
依据本发明第二个方面,本发明提供了各曲马多对映异构体的非外消旋混合物在制备用于治疗或预防疼痛、特别是用于治疗在施用外消旋曲马多时往往会表现出副作用的患者的药物中的应用。然而,所述药物也可用于治疗如下所讨论的其它类型患者。
依据本发明第三个方面,本发明提供了包含各曲马多对映异构体的非外消旋混合物与可药用载体的产品。
发明详述
在本申请上下文中,当提及曲马多的非外消旋混合物时,其包括对映异构纯的(-)-曲马多,或者就(-)-曲马多而言对映异构过量的接近对映异构纯的混合物。
用于本发明的非外消旋混合物一般包含至少60%(重量)的(-)-曲马多。虽然对映异构纯的(-)-曲马多可用于实现止痛,但是优选将(+)-曲马多与至少一些(+)-曲马多配制在一起,因为存在两种对映异构体时,可实现在止痛效力与安全性之间的最佳平衡。这两种对映异构体的特别优选的重量比介于10-40∶90-60(+)-曲马多:(-)-曲马多(+:-),更优选的重量比介于20-40∶80-60(+:-),最优选的重量比介于30-40∶70-60(+:-)。
这些优选的非外消旋混合物可特别用于治疗在施用外消旋曲马多时往往会表现出副作用的患者。上文中给出了这些副作用的数个实例。在施用外消旋曲马多时一般会观察到的其它副作用包括视力模糊、瞌睡、嗜眠、幻觉、呼吸阻抑、和兴奋。然而,本发明可特别用于治疗有恶心和呕吐倾向的患者。这是因为,正如下面的实施例中所解释的那样,据信(-)-曲马多能调制(+)-曲马多的催吐特性,因此降低了外消旋曲马多的总体催吐能力。如下所述,使用不同对映异构体的不同释放分布,可利用该效应以获得最大效益。
据信本发明还特别适于治疗表现出异常CYP2D6肝脏酶活性的患者。编码鹰爪豆碱氧合酶的CYP2D6基因是高度多形体,并且正在鉴定数量不断增加的突变。野生型基因是CYP2D6*1A。没有该野生型基因的任何人都可归类为表现出异常酶活性的个体。任何特定突变的确切性质决定了患者表现出异常酶活性的程度。因此,通过采用简单的实验室遗传分析技术,能够确定特定患者代谢(+)-曲马多的大致速率,以及因此将达到多快和多有效的止痛效果。
依据本发明可以设想,通过表型或基因型手段诊断为能产生广泛的外消旋曲马多代谢变化的患者将特别受益于施用非外消旋曲马多,因为他们尤其易于表现出副作用如恶心和呕吐。此外,一旦任一患者的CYP2D6基因型是已知的,即可针对他或她拟定给药方案以适用于该患者。
根据疼痛的病因和/或欲治疗的患者,也可使用其它非外消旋比例的这两种曲马多对映异构体治疗或预防疼痛。例如,对于特别容易表现出与外消旋曲马多有关的副作用的患者,可使用包含非常高比例(-)-曲马多的混合物,例如重量比介于0-10∶100-90(+:-)。另一选择是采用更加均衡的这两种对映异构体,让效力更强的(+)-对映异构体过量,例如重量比介于60-80∶40-20(+:-)、典型地为60-70∶40-30(+:-)。这样的比例可用于治疗不是特别容易表现出与外消旋曲马多有关的副作用的患者,或者止痛效力应首要考虑的患者。然而,在(+)-曲马多之前施用(-)-曲马多,或者以比施用(+)-曲马多快的速率施用(-)-曲马多也能有利地降低副作用。
在本申请上下文中,所有提及的重量比都应当理解为包括±5wt.%的允许误差。
据信,本发明还可特别用于治疗与偏头痛有关的疼痛和/或其它影响。本发明进一步的方面是,各曲马多对映异构体的非外消旋混合物在制备用于预防或治疗偏头痛的药物中的应用。
给任何特定患者施用的非外消旋曲马多的量取决于患者和施用非外消旋曲马多来治疗的病症、以及所用的非外消旋曲马多是预防应用还是治疗应用。本领域技术人员可容易地确定出合适的给药量。
不同的曲马多对映异构体可同时、分开或顺序给药。可将它们配制成即释或控释剂型,或者这二者的组合,或者将它们配制以便以不同速率或在不同时间释放。优选的给药方式是(-)-曲马多在(+)-曲马多之前释放,或者以(-)-曲马多比(+)-曲马多快的速率释放,以使(-)-曲马多对(+)-曲马多的催吐特性的作用达到最佳。但是可以设想这样的情况,即可能需要相反的情形,和期望在施用(-)-曲马多之前或者以比施用(-)-曲马多快的速率施用(+)-曲马多。
特别优选的给药方式是,通过采用如W0-A-9840053(该文献的内容引入本发明以作参考)所述的即释和控释技术的组合,将(-)-曲马多配制在即释剂型中和将(+)-曲马多配制在控释剂型中。可以想象,这种剂型可能特别有利于实现迅速止痛,同时没有与施用外消旋曲马多有关的伴随的副作用。
对于本发明非外消旋混合物,可采用多种不同剂型,以通过多种途径例如口服、直肠、透皮、经鼻、经眼、经肺和注射(皮下注射或静脉内注射)给药。合适的剂型包括例如片剂、栓剂、胶囊,例如含有多个颗粒的胶囊、贴剂、聚合物植入物、气雾剂、注射用脂质体或微粒、以及其它任何常规剂型。
WO-A-9840053中描述了特别优选的剂型。在该文献描述的剂型当中,包含(-)-曲马多即释层和(+)-曲马多控释层的双层片剂是特别优选的。
在下述实施例中报告本发明所基于的结果。
实施例
目标是,确定出能够提供关于止痛效力和降低与外消旋曲马多有关的恶心和呕吐的最佳治疗指数的最适对映异构体比例范围。
进行两项实验以确定曲马多及其对映异构体分别在大鼠和白鼬中的止痛效力和致呕吐作用。通过比较在这些实验中获得的数据,能够确定对于这些种类的动物最佳对映异构体比例的范围。药动学/药效学模型使得此数据可外推到人。
评价止痛效力
使用Randall Selitto测试(Arch.Int.Pharmacodyn.(1957)111:409-419)在大鼠中测定了曲马多及其纯对映异构体的止痛效力。该测试是设计用来测定曲马多及其对映异构体对酵母诱导的痛觉的作用,并且用痛觉计量器通过提高施加到爪子上的压力来评定痛觉。为了进行比较,还测定了曲马多对映异构体的活性代谢物—O-去甲基曲马多的作用。
将不同量的各测试物对大鼠口服给药,使用10ml/kg的恒定剂量体积。给药后,立即将0.1ml 20%w/v酿酒酵母在盐水中的悬浮液皮下注射到每只大鼠右前爪的足底表面内,以诱导高度痛觉。以类似方式向左后爪内注射0.1ml盐水,作为对照。
测试物给药后30分钟,测定左爪(未发炎)和右爪(发炎)的耐受压。
所观测到的结果如附图1(发炎的爪子)和附图2(未发炎的爪子)所示,结果是以不同剂量的测试物对应的疼痛耐受提高的百分比表示的。在这两个附图中,T=曲马多,M1=O-去甲基曲马多。
恶心的评价
在白鼬中测定了曲马多及其纯对映异构体的致恶心作用。为了进行比较,还测定了(+)-曲马多的活性代谢物—(+)-O-去甲基曲马多((+)-M1)的作用。观察4小时口服给药白鼬的干呕和呕吐征状。在4小时期间发生干呕或呕吐的任何白鼬被视为响应者,即表现出恶心的动物。
所得结果如附图3所示;象在附图1和2中一样,T和M1代表曲马多和O-去甲基曲马多。正如所预计的那样,(+)-M1是高度催吐的。(-)-曲马多在高达200mg/kg的剂量下没有引起呕吐。相比之下,50mg/kg剂量的(+)-曲马多在75%的白鼬中引起了恶心,而100mg/kg的外消旋曲马多在25%的动物中引起了恶心。虽然外消旋体是这两种对映异构体的50∶50混合物,但是其诱导的恶心比根据其(+)-对映异构体含量所预计的要轻。该差异可由(-)-对映异构体能够调控与(+)-对映异构体有关的呕吐来解释。
血浆样本的生物分析和肝脏微粒体分析已经表明曲马多在大鼠、白鼬和人体中以类似方式代谢。因此可以比较在这些实验中获得的数据,以获得对于这些种类动物的最适的对映异构体比例范围。此外,通过药动学/药效学模型技术,能够把所得数据外推到人,以获得用于本发明的最适的对映异构体比例范围。
Claims (20)
1.作为用于同时、分开或顺序使用来治疗或预防疼痛的联合制剂(药盒)的包含各曲马多对映异构体的非外消旋混合物的产品,所述混合物包含至少一些(-)-曲马多。
2.权利要求1的产品,其中包含至少60%(重量)的(-)-曲马多。
3.权利要求2的产品,其中各对映异构体的重量比为10-40∶90-60(+:-)。
4.权利要求2的产品,其中各对映异构体的重量比为20-40∶80-60(+:-)。
5.权利要求2的产品,其中各对映异构体的重量比为0-20∶100-80(+:-)。
6.前述权利要求任一项的产品,其中(-)-对映异构体在(+)-对映异构体之前释放。
7.权利要求1-5任一项的产品,其中(-)-对映异构体释放得比(+)-对映异构体快。
8.权利要求1-5任一项的产品,其中(-)-对映异构体在即释剂型中且(+)-对映异构体在控释剂型中。
9.如权利要求1-5任一项所定义的非外消旋混合物在制备用于治疗或预防疼痛的药物中的应用。
10.权利要求9的应用,其中所述疼痛是与偏头痛有关的疼痛。
11.权利要求9的应用,其中所述药物是用于治疗在施用外消旋曲马多时往往会表现出副作用的患者。
12.权利要求11的应用,其中所述副作用选自恶心、呕吐、头晕、便秘、镇静、视力模糊、瞌睡、嗜眠、幻觉、呼吸阻抑、和兴奋,尤其是恶心和呕吐。
13.权利要求9的应用,其中所述药物是用于治疗表现出异常CYP2D6肝脏酶活性的患者。
14.如权利要求1-5任一项所定义的非外消旋混合物在制备用于治疗或预防偏头痛的药物中的应用。
15.包含如权利要求1-5任一项所述的非外消旋混合物和可药用载体的产品。
16.权利要求15的产品,其中(-)-对映异构体在(+)-对映异构体之前释放。
17.权利要求15的产品,其中(-)-对映异构体释放得比(+)-对映异构体快。
18.权利要求15的产品,其中(-)-对映异构体在即释剂型中且(+)-对映异构体在控释剂型中。
19.权利要求15-18任一项的产品,所述产品在其分开的部分中包含这两种对映异构体。
20.权利要求19的产品,所述产品是在其一个部分中包含(-)-曲马多、在其另一分开的部分中包含(+)-曲马多的双层片剂。
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GB9826536.6 | 1998-12-02 | ||
GBGB9826536.6A GB9826536D0 (en) | 1998-12-02 | 1998-12-02 | Therapeutic product and its use |
GB9826535.8 | 1998-12-02 | ||
GBGB9826537.4A GB9826537D0 (en) | 1998-12-02 | 1998-12-02 | Therapeutic product and its use |
GB9826537.4 | 1998-12-02 | ||
GBGB9826535.8A GB9826535D0 (en) | 1998-12-02 | 1998-12-02 | Therapeutic product and its use |
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EP (1) | EP1135361A1 (zh) |
JP (1) | JP2002531431A (zh) |
KR (1) | KR20010080364A (zh) |
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BR (1) | BR9915873A (zh) |
CA (1) | CA2350635A1 (zh) |
HU (1) | HUP0104420A2 (zh) |
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NO (1) | NO20012738L (zh) |
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WO2001034125A2 (en) * | 1999-11-09 | 2001-05-17 | Darwin Discovery Limited | Therapeutic use and formulation of (-)-tramadol |
AU9497901A (en) * | 2000-10-03 | 2002-04-15 | Penwest Pharmaceuticals Compan | Delivery system for multi-pharmaceutical active materials at various release rates |
DE10108122A1 (de) | 2001-02-21 | 2002-10-02 | Gruenenthal Gmbh | Arzneimittel auf Basis von Tramadol |
US6780891B2 (en) | 2001-11-30 | 2004-08-24 | Sepracor Inc. | Tramadol analogs and uses thereof |
PL1931346T3 (pl) | 2005-09-09 | 2013-01-31 | Angelini Labopharm Llc | Kompozycja trazodonu do podawania raz na dobę |
WO2008100933A2 (en) | 2007-02-12 | 2008-08-21 | Dmi Biosciences, Inc. | Reducing side effects of tramadol |
EP3296289A3 (en) * | 2007-05-31 | 2018-06-20 | Sunovion Pharmaceuticals Inc. | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors |
JOP20190251A1 (ar) * | 2017-05-31 | 2019-10-21 | Metys Pharmaceuticals AG | تركيبات تآزرية تشتمل على (r)-ديميراسيتام (1) و(s)-ديميراسيتام (2) بنسبة غير راسيمية |
WO2019113084A1 (en) | 2017-12-05 | 2019-06-13 | Sunovion Pharmaceuticals Inc. | Crystal forms and production methods thereof |
JP7268026B2 (ja) | 2017-12-05 | 2023-05-02 | サノビオン ファーマシューティカルズ インク | 非ラセミ混合物およびその使用 |
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DE19807535A1 (de) * | 1998-02-21 | 1999-08-26 | Asta Medica Ag | Pharmazeutische Kombinationen mit Tramadol |
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1999
- 1999-12-02 HU HU0104420A patent/HUP0104420A2/hu unknown
- 1999-12-02 EP EP99973016A patent/EP1135361A1/en not_active Withdrawn
- 1999-12-02 CA CA002350635A patent/CA2350635A1/en not_active Abandoned
- 1999-12-02 PL PL99347542A patent/PL347542A1/xx not_active Application Discontinuation
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HUP0104420A2 (en) | 2002-08-28 |
NO20012738D0 (no) | 2001-06-01 |
JP2002531431A (ja) | 2002-09-24 |
BR9915873A (pt) | 2001-08-21 |
EP1135361A1 (en) | 2001-09-26 |
KR20010080364A (ko) | 2001-08-22 |
AU1400100A (en) | 2000-06-19 |
IL142778A0 (en) | 2002-03-10 |
CA2350635A1 (en) | 2000-06-08 |
NO20012738L (no) | 2001-06-01 |
PL347542A1 (en) | 2002-04-08 |
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