CN105520924B - 3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚和抗癫痫药的联合药物 - Google Patents
3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚和抗癫痫药的联合药物 Download PDFInfo
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- CN105520924B CN105520924B CN201510736012.5A CN201510736012A CN105520924B CN 105520924 B CN105520924 B CN 105520924B CN 201510736012 A CN201510736012 A CN 201510736012A CN 105520924 B CN105520924 B CN 105520924B
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Abstract
本发明涉及含(a)至少一种3‑(3‑二甲基氨基‑1‑乙基‑2‑甲基‑丙基)‑苯酚化合物和(b)至少一种抗癫痫药作为组分的联合药物;含所述联合药物的药物制剂和剂型,和治疗疼痛例如神经性疼痛的方法,其中组分(a)和(b)同时或序贯给予哺乳动物,因此组分(a)可在组分(b)之前或之后给予,和因此组分(a)或(b)通过相同或不同的给药途径给予哺乳动物。
Description
本申请是申请号为200980135117.8(国际申请号为PCT/EP2009/006424)、申请日为2009年9月4日、发明名称为“3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚和抗癫痫药的联合药物”的中国专利申请的分案申请。
技术领域
本发明涉及含(a)至少一种3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚化合物和(b)至少一种抗癫痫药作为组分的联合药物(combination);含所述联合药物的药物制剂和剂型;和治疗疼痛例如神经性疼痛(neuropathic pain)的方法,其中组分(a)和(b)同时或序贯给予哺乳动物,因此组分(a)可在组分(b)之前或之后给予,和因此组分(a)或(b)通过相同或不同的给药途径给予哺乳动物。
背景技术
慢性和急性疼痛病症的治疗在医学上及其重要。目前,世界各地均存在另外的不仅限于基于阿片样物质但非常有效的治疗疼痛的需求。在最近应用镇痛药领域出现的和有关痛觉的基础研究工作的大量科学论文中证明了迫切需要患者导向的作用和有目的的疼痛病症的治疗,这表示对患者疼痛的成功和满意的治疗。
即使目前用于治疗疼痛的镇痛药例如阿片样物质、NA-和5HT-再摄取抑制剂、NSAIDS和COX抑制剂可有效镇痛,然而有时会发生副作用。在WO 01/13904中描述了含曲马多物质和抗痉挛药物的物质组合,给药后,此类物质组合显示超-加和作用。由于超-加和作用,总剂量和因此导致的有害副作用的风险可减少。
发明内容
因此,本发明的目的是发现具有改善的性质的另外的联合药物。本发明的目的也是发现以下的另外联合药物:此类联合药物适合治疗疼痛,且优选如果按有效剂量给予,则与其单一组分相比。显示更少的有害副作用
已发现,含(a)至少一种3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚化合物和(b)至少一种抗癫痫药物的联合药物显示镇痛作用。如果这些组分按给予患者后观察到超-加和或协同作用的重量比存在于组合物中,则可降低总给药剂量,从而减少有害副作用的发生。
因此,本发明涉及联合药物,该联合药物含作为组分的:
(a)式(I)3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚
任选为其纯立体异构体,尤其是对映体或非对映体之一的形式,外消旋体,或为其立体异构体,尤其是对映体和/或非对映体按任何混合比例的混合物形式,或其任何相应的酸加成盐,和
(b)至少一种抗癫痫药。
在本发明联合药物的一个实施方案中,式(I)化合物选自
(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚,
(1S,2S)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚,
(1R,2S)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚,
(1S,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚,
及其任何混合物。
在本发明联合药物的另一个实施方案中,式(I)化合物选自
(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚,和
(1S,2S)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚,
及其任何混合物。
在又另一个实施方案中,本发明联合药物含
(a)式(I’)(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚化合物,
或其酸加成盐,和
(b)至少一种抗癫痫药。
式(I)3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚化合物、其立体异构体及其相应盐和它们的制备方法是熟知的,例如可从US 6,248,737 B1发现。该说明书的各部分通过引用结合到本文中,并形成本发明公开内容的一部分。
具体实施方式
本文中使用的组分(a)的定义包括任何可能形式的3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚、其衍生物及其立体异构体,因此尤其包括溶剂合物和多晶型物、盐,尤其是酸加成盐和相应溶剂合物和多晶型物。
本文中使用的术语衍生物尤其包括前药,例如活性物质的醚和酯。用于选择和制备给定物质前药的合适方法见例如″Textbook of Drug Design and Discovery″,第3版,2002年,第14章,第410-458页,编辑:Krogsgaard-Larsen等,Taylor and Francis中所述。所述文献描述的各部分通过引用结合到本文中,并形成本发明公开的一部分。
如果组分(a)以对映体的混合物存在,则这种混合物可含外消旋或非外消旋形式的对映体。非外消旋形式可例如含60±5∶40±5;70±5∶30±5;80±5∶20±5或90±5∶10±5比例的对映体。
组分(a)的3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚化合物及其立体异构体可以酸加成盐的形式存在于本发明药用组合物中,因此可使用能够形成这种加成盐的任何合适的酸。
可按本领域技术人员熟知的方式,例如通过与合适的酸反应,将3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚转化为相应的加成盐。合适的酸包括但不限于盐酸、氢溴酸、硫酸、甲磺酸、甲酸、乙酸、草酸、琥珀酸、酒石酸、扁桃酸、富马酸、乳酸、柠檬酸、谷氨酸和/或天冬氨酸。优选,在溶剂例如***、异丙醚、乙酸烷基酯、丙酮和/或2-丁酮中形成盐。另外,三甲基氯硅烷的水溶液也适用于盐酸盐的制备。
在本领域中,熟知通常又称为抗痉挛药的抗癫痫药,它们包括但不限于巴比妥类和衍生物,例如甲苯比妥、***、扑米酮、巴比沙隆和美沙比妥;乙内酰脲衍生物例如乙苯妥英、苯妥英、氨基(苯妥英)戊酸、米芬妥英和磷苯妥英;唑烷衍生物例如甲乙双酮、三甲双酮和依沙双酮;琥珀酰亚胺衍生物例如乙琥胺、苯琥胺和甲琥胺;苯并二氮杂衍生物例如氯硝西泮;甲酰胺衍生物例如卡马西平、奥卡西平、艾利西平和卢非酰胺;脂肪酸衍生物例如丙戊酸、丙戊酰胺、氨基丁酸、氨己烯酸、普罗加氨和噻加宾;或其他抗癫痫药例如舒噻美、苯乙酰脲、拉莫三嗪、非尔氨酯、托吡酯、加巴喷丁、苯丁酰脲、左乙拉西坦、布瓦西坦、selectracetam、唑尼沙胺、普加巴林、司替戊醇、拉科酰胺和贝克拉胺。
这些前述种类的抗癫痫药和其中多数单独药物的代表例如列于WHO使用的[N03]项下的与有机物结构相关的治疗化学物质(ATC)分类(Anatomical Therapeutic Chemical(ATC)classification),其用于药物活性成分的分类(优选的版本:2008年1月或2009年)。有关ATC索引的进一步细节,可参考U.Fricke,J.Anatomisch-therapeutisch-chemische Klassifikation mit Tagesdosen fur den deutschen Arzneimittelmarkt:Methodik der ATC-Klassifikation und DDD-Festlegung.ATC-Index mit DDD-Angaben,Wissenschaftliches lnstitut der AOK;和Swiss Pharmaceutical Society,IndexNominum:International Drug Directory,CRC Press;第18版(2004年1月31日)。
其它合适的抗癫痫药包括例如美西律、瑞替加滨和沙芬酰胺。
已知一些抗癫痫药可用于治疗神经性疼痛。在本发明的一个实施方案中,这些抗癫痫药中的一种或多种用作组分(b)。
也包括所述抗癫痫药组分的立体异构体、盐、溶剂合物、多晶型物和衍生物和前述任何形式的混合物。
在本发明联合药物的一个实施方案中,组分(b)的抗癫痫药选自普加巴林、加巴喷丁、托吡酯、拉莫三嗪、卡马西平、奥卡西平(oxcarbamazepine)、艾利西平、美西律、拉科酰胺、苯妥英、左乙拉西坦、布瓦西坦、selectracetam、瑞替加滨、丙戊酸和沙芬酰胺。
在本发明联合药物的另一个实施方案中,组分(b)的抗癫痫药选自普加巴林、加巴喷丁、托吡酯、拉莫三嗪、卡马西平、美西律、拉科酰胺、苯妥英、左乙拉西坦、瑞替加滨、丙戊酸和沙芬酰胺。
在本发明联合药物的另一个实施方案中,组分(b)的抗癫痫药为普加巴林。
在本发明联合药物的又另一个实施方案中,组分(b)的抗癫痫药为(S)-普加巴林。
本发明的一个具体实施方案为联合药物,该联合药物含(a)(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚或其酸加成盐例如盐酸加成盐,和(b)一种或多种抗癫痫药,所述抗癫痫药选自普加巴林、加巴喷丁、托吡酯、拉莫三嗪、卡马西平、奥卡西平、艾利西平、美西律、拉科酰胺、苯妥英、左乙拉西坦、布瓦西坦、selectracetam、瑞替加滨、丙戊酸和沙芬酰胺。
本发明的一个具体实施方案为联合药物,该联合药物含(a)(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚或其酸加成盐例如盐酸加成盐,和(b)一种或多种抗癫痫药,所述抗癫痫药选自普加巴林、加巴喷丁、托吡酯、拉莫三嗪、卡马西平、美西律、拉科酰胺、苯妥英、左乙拉西坦、瑞替加滨、丙戊酸和沙芬酰胺。
本发明的另一个具体实施方案为联合药物,该联合药物含(a)(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚或其酸加成盐例如盐酸加成盐,和(b)普加巴林。
本发明的又另一个具体实施方案为联合药物,该联合药物含(a)(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚或其酸加成盐例如盐酸加成盐,和(b)(S)-普加巴林。
一些抗癫痫药含有官能团例如酸性基团,例如能够与式(I)的3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚组分形成盐的羧基,从而将组分(a)和(b)两者结合为一种且相同的盐。
因此,在本发明的另一个实施方案中,本发明联合药物含由这两种组分形成的盐形式的组分(a)和(b)。这种盐形成可为部分的形成,即本发明组合物也以它们的非盐形式含这些组分之一或两者,或盐形成可基本上是完全的。
作为本发明联合药物一部分的组分(a)和(b)两者的给药量可最高达它们的最大日剂量,本领域技术人员已知它们的最大日剂量。化合物普加巴林可优选按1-1200mg日剂量给予患者,化合物加巴喷丁可优选按1-5000mg日剂量给予患者。化合物(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚可优选按25-1000mg日剂量,尤其优选按50-800mg剂量,更尤其优选按100-600mg剂量给予患者。
当作为本发明联合药物一部分给予时,每日给予组分(a)和/或组分(b)的量可小于各自的最大日剂量,例如为各组分各自最大日剂量的75±15%(重量)、75±10%(重量)、75±5%(重量)、50±15%(重量)、50±10%(重量)、50±5%(重量)、25±15%(重量)、25±10%(重量)和25±5%(重量)。
在本发明的另一个实施方案中,本发明联合药物可含基本上等效(equieffective)比例的组分(a)和(b)。
在本发明联合药物的又再一个实施方案中,组分(a)和(b)按使得到的组合物给予患者后将发挥超-加性或协同作用的重量比存在。合适的重量比可通过本领域技术人员熟知的方法测定。
组分(a)和(b)两者也可按偏离等效比的比例存在于本发明联合药物。例如,各组分可按等效量的1/50-50倍等效量、等效量的1/20-20倍等效量、等效量的1/10-10倍等效量、等效量的1/5-5倍等效量、等效量的1/4-4倍等效量、等效量的1/3-3倍等效量或等效量的1/2-2倍等效量存在。
在本发明的另一个实施方案中,可按特定剂量方案给予组分(a)和组分(b)以治疗疼痛,例如神经性疼痛。组分(a)和(b)可同时或相互序贯给予,在各情况中,通过相同或不同的给药途径。
因此,本发明的另一个方面为治疗疼痛的方法,该方法的特征在于组分(a)和(b)同时或序贯给予哺乳动物,其中组分(a)可在组分(b)之前或之后给予,和其中组分(a)或(b)通过相同或不同的给药途径给予哺乳动物。
本文中使用的术语疼痛包括但不限于炎性疼痛、神经性疼痛、急性疼痛、慢性疼痛、内脏痛、偏头痛和癌性疼痛。
合适的给药途径包括但不限于口服、静脉内、动脉内、腹膜内、皮内、透皮、鞘内(intrathekal)、肌内、鼻内、透粘膜、皮下和直肠给药。
本发明联合药物在毒理学上是安全的,因此适合治疗哺乳动物,尤其是人,包括婴儿、儿童和成人。
因此,在再一方面,本发明涉及药用组合物,该组合物含本文中所述本发明联合药物和一种或多种助剂。
在再一方面,本发明涉及药物剂型,该剂型含本文中所述本发明联合药物和一种或多种助剂。
在一个实施方案中,本发明药物剂型还含咖啡因。
在一个实施方案中,本发明药物剂型适合通过以下途径给药:口服、静脉内、动脉内、腹膜内、皮内、透皮、鞘内、肌内、鼻内、透粘膜、皮下或直肠。
本发明制剂和剂型可含助剂,例如载体、填充剂、溶剂、稀释剂、着色剂和/或粘合剂。助剂和助剂用量的选择取决于例如如何给予药物,例如经口服、静脉内、动脉内、腹膜内、皮内、透皮、肌内、鼻内或例如用于皮肤、眼粘膜感染的局部给药。
在本发明上下文中,合适的助剂尤其是本领域技术人员已知的可用于制备盖仑制剂的任何物质。合适的助剂的实例包括但不限于:水、乙醇、2-丙醇、甘油、乙二醇、丙二醇、聚乙二醇、聚丙二醇、葡萄糖、果糖、乳糖、蔗糖、右旋糖、糖蜜、淀粉、改性淀粉、明胶、山梨醇、肌醇、甘露醇、微晶纤维素、甲基纤维素、羧甲基纤维素、醋酸纤维素、虫胶、鲸蜡醇、聚乙烯吡咯烷酮、石蜡、蜡、天然和合成胶、***胶、藻酸盐、右旋糖苷、饱和和不饱和脂肪酸、硬脂酸、硬脂酸镁、硬脂酸锌、甘油硬脂酸酯、十二烷基硫酸钠、食用油、芝麻油、椰子油、花生油、大豆油、卵磷脂、乳酸钠、聚氧乙烯和聚丙烯的脂肪酸酯、脱水山梨醇脂肪酸酯、山梨酸、苯甲酸、柠檬酸、抗坏血酸、鞣酸、氯化钠、氯化钾、氯化镁、氯化钙、氧化镁、氧化锌、二氧化硅、氧化钛、二氧化钛、硫酸镁、硫酸锌、磷酸钙、钾碱、磷酸钙、磷酸二钙、溴化钾、碘化钾、滑石、高岭土、果胶、交联聚维酮、琼脂和膨润土。
片剂、泡腾片、咀嚼片、糖锭剂、胶囊剂、滴剂、液汁或糖浆形式的药物制剂(剂型)例如适合经口给药。口服药物制剂也可以是多颗粒形式,例如颗粒、小丸、球、晶体等,任选压制成片剂,填充在胶囊中;填充在小药囊或悬浮在合适的液体介质中。也可将口服药物制剂用肠溶衣包衣。
适合肠胃外、局部和吸入给药的药物制剂包括但不限于溶液、混悬液、容易重新溶解的干燥制剂和喷雾剂。
栓剂为用于直肠给药的合适的药物制剂。储库形式、溶解形式的制剂例如任选加入试剂以促进皮肤渗透的贴剂,为经皮给药的合适制剂的实例。
组分(a)和(b)之一或两者可按至少部分控释形式存在于本发明药物制剂。另外,所述组分的任何控释/即释组合也可存在于本发明药物制剂。例如,所述组分之一或两者可从本发明制剂中释放,并具有一定延迟,例如如果经口、直肠或经皮给药。此类制剂尤其可用于“每日一次”或“每日两次”制剂,它们分别每日仅需摄取一次或每日两次。本领域技术人员熟知合适的控释材料。
可用在药物制剂现有技术中熟知的材料、手段、装置和方法,制备本发明药物制剂,见例如″Remington′s Pharmaceutical Sciences″,A.R.Gennaro(ed.),第17版,MackPublishing Company,Easton,Pa.(1985),尤其是第8部分,第76-93章中所述。
为得到固体药物制剂例如片剂,例如,可用药物载体例如常规片剂成分例如玉米淀粉、乳糖、蔗糖、山梨醇、滑石粉、硬脂酸镁、磷酸二钙或药学上可接受的胶和药物稀释剂例如水,将药用组合物的组分制粒,以便形成含均匀分布的组分的固体组合物。术语“均匀分布”表示组分均匀分布在整个组合物中,以便使所述组合物可容易的分为相等有效的单位剂量形式,例如片剂、丸剂或胶囊剂等。然后将固体组合物分为单位剂量形式。也可将本发明药用组合物的片剂或丸剂包衣或按不同方式混合,以提供具有控释特性的剂量形式。
如果组分中的一种将在另一种组分之前,例如之前至少30分钟或1小时释放,可制备具有相应释放特性的药物制剂。这种制剂的一个实例为渗透驱动的释放***,该释放***通过包衣实现一种组分的延迟释放,该包衣本身含有因此较早释放的另一种组分。在尤其适用于经口给予的这种释放***中,该释放***的至少部分,优选所有的表面,优选与释放介质接触的那些部分为半透性的,优选包有半透性包衣,以使一个或多个表面对释放介质是可渗透的,但对活性成分基本上、优选完全是不可渗透的,一个或多个表面和/或任选包衣含至少一个用于释放活性成分的孔。另外,与释放介质接触的那个/那些表面精确的提供有包衣,该包衣含有并释放另一种组分。这优选表示片剂形式的***,该***含释放孔、渗透性药用组合物芯、半透膜和膨胀时施加压力的聚合物部分。这种***的合适实例为由ALZA Corporation,USA按商品名尤其是Push-PullTM***、延迟的Push-PullTM***、多层Push-PullTM***、Push-Stick***,在特殊情况下也按L-OROSTM销售的***。
渗透驱动的释放***的实施方案和实例为例如在美国专利4,765,989、4,783,337和4,612,008中公开的那些,这些专利的各自内容全部通过引用结合到本文中,且形成本发明公开的一部分。
合适的药物制剂的又一个实例为凝胶骨架片,例如由Penwest Pharmaceuticals(例如名为TimeRX)开发的产品。在美国专利5,330,761、5,399,362、5,472,711和5,455,046中提供了合适的实例,这些专利的各自内容全部通过引用结合到本文中,并形成本发明公开的一部分。药物活性成分不均匀分布的延迟型骨架制剂尤其合适,因此,例如,一种组分可分布在骨架外部区域(与释放介质最快接触的部分),另一种组分分布在骨架的内部。当与释放介质接触时,外部骨架层开始(且迅速)膨胀,且首先释放第一组分,然后另一种组分显著(更多)的延迟释放。合适的骨架的实例包括含1-80%(重量)的一种或多种亲水或疏水聚合物作为药学上可接受的骨架形成物的骨架。合适的骨架的又一个实例可从US 4,389,393中推测,其相应的内容通过引用结合到本文中,且形成本发明公开的一部分。
本发明药物活性联合药物给予患者的量可不同,取决于本领域技术人员熟知的不同因素,例如患者的体重、给药途径或疾病的严重性。
在再一个方面,本发明涉及本文中所述本发明联合药物治疗疼痛的用途,所述疼痛优选包括但不限于炎性疼痛、神经性疼痛、急性疼痛、慢性疼痛、内脏痛、偏头痛和癌性疼痛。
在另一个方面,本发明涉及本文中所述本发明联合药物在制备用于治疗疼痛的药物中的用途,所述疼痛优选包括但不限于炎性疼痛、神经性疼痛、急性疼痛、慢性疼痛、内脏痛、偏头痛和癌性疼痛。
在另一个方面,本发明涉及在哺乳动物,优选人中治疗疼痛的方法,该方法包括给予所述哺乳动物有效量的本文中所述本发明联合药物。
实施例
药理方法:
根据Chung的体内试验
可按Kim SH,Chung JM所述的Kim&Chung试验,测定导致本发明组合物的超-加性作用/协同作用的组分(a)和(b)的重量比。通过将大鼠的脊柱段神经结扎制备外周单神经病的实验模型。Pain 1992;50:355-63。所述参考文献通过引用结合到本文,并形成本发明公开的一部分。
将绷带施加在雄性Sprague-Dawley大鼠(140-160g体重,Janvier,GenestSt.Isle,France)的左L5/L6脊神经上。动物在同侧爪上发生触觉异常性疼痛。手术后3-4周,在同侧和对侧后爪上,通过电子von Frey爪触觉测试仪测量触觉异常性疼痛阈值基线(缩回阈值)(Somedic,Schweden)。试验和基线测量后,将(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚盐酸盐(下文中称为盐酸他喷他多或他喷他多-HCl)、(S)-普加巴林和本发明他喷他多-HCl和(S)-普加巴林联合药物分别溶于0.9%NaCl溶液,通过静脉内(i.v.)途径注射(施用体积5ml/kg)。将动物随机分组,每组10只,用于各试验剂量和溶媒(0.9%NaCl溶液),在给药前0.5h和静脉内给药后几个时间点(0.5、1和3小时)测试触觉缩回阈值。测试同侧和对侧后爪反应。用电子von Frey长丝进行刺激,由5次独立刺激得到的结果计算在给定时间各动物的缩回阈值的中值。通过与Chung动物的前药阈值(=0%MPE)和假性手术动物的对照阈值(100%MPE)相比较,损伤爪的缩回阈值按%MPE(最大可能的作用)表示。截止值设在100%MPE。在各试验时间点,作为个体间%MPE值,计算各化合物和溶媒的作用。
通过两因素方差分析(ANOVA),并重复测量,分析数据(抗异常性疼痛效力(%MPE)、同侧、爪缩回阈值(g)、同侧-和对侧)。如果有显著治疗作用,进行事后分析和Bonferroni调整。如果P<0.05,则认为结果在统计学上有显著性。通过回归分析,来确定各药物达到峰值作用时的抗异常性疼痛效力(%MPE)的ED50值和95%置信区间(95%CI)。
通过所谓的固定比例的联合药物的理论加性ED50值与实验测定的ED50值的统计学比较,进行结果的分析(按Tallarida RJ,Porreca F,and Cowan A.的等辐射分析,用等辐射测量图(isobologram)进行药物-药物和位点-位点相互作用的统计学分析(Statisticalanalysis of drug-drug and site-site interactions with isobolograms).Life Sci1989;45:947-61,其通过引用结合到本文中,并形成本发明公开的一部分)。
结果:
盐酸他喷他多(0.1、0.316、1、3.16和10mg/kg i.v.)显示同侧后爪的缩回阈值呈剂量依赖性增加,并且由给药后30分钟相对于对照值的峰值作用计算出:效力为94%MPE,ED50值(95%置信区间)为1.65(1.20-2.35)mg/kg i.v.。
(S)-普加巴林(0.1、3.16和10mg/kg i.v.)显示同侧后爪的缩回阈值呈现剂量依赖性增加,并且由给药后30分钟相对于对照值的峰值作用计算出:效力为67%MPE,ED50值(95%置信区间)为4.20(3.37-5.43)mg/kg i.v.。
盐酸他喷他多和(S)-普加巴林显示活性差异,基于给药后30分钟的ED50值,该差异总计达2.5因数。在剂量0.1mg/kg+0.25mg/kg;0.3mg/kg+0.75mg/kg;1mg/kg+2.5mg/kgi.v.盐酸他喷他多+(S)-普加巴林下,分别测试固定比例为1:2.5(盐酸他喷他多:(S)-普加巴林)的联合药物。这些联合药物显示同侧后爪的缩回阈值呈剂量依赖性增加。测试的最高剂量联合药物显示完全效力(full efficacy)为89%MPE。活性通过ED50值(95%置信区间)定量,由给药后30分钟相对于对照值的峰值作用计算出ED50值为0.83(0.74-0.92)mg/kgi.v.。
等辐射分析的结果总结在下表1中。
表1:
盐酸他喷他多和(S)-普加巴林的试验ED50值以及盐酸他喷他多与(S)-普加巴林之间相互作用的等辐射分析:
p:统计显著性水平
本发明联合药物的实验ED50值(95%置信区间)0.83(0.74-0.92)mg/kg i.v低于理论加性ED50值(95%置信区间)2.91(2.28-3.54)mg/kg i.v.,且与加性线相比具有统计学显著性(p<0.001)。因此,盐酸他喷他多和(S)-普加巴林的相互作用为协同性的。
对侧爪缩回阈值的分析显示,10mg/kg i.v.的盐酸他喷他多和(S)-普加巴林具有显著的防感受伤害作用,而在本发明联合药物的最高剂量下,未看到明显的防感受伤害作用。因此,盐酸他喷他多和(S)-普加巴林的协同抗异常性疼痛活性导致减少的防感受伤害副作用。
Claims (12)
1.一种联合药物,所述联合药物包含作为组分的:
(a)盐酸加成盐形式的式(I’)的(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚
其为控释形式;和
(b)(S)-普加巴林或由其形成的盐。
2.根据权利要求1所述的联合药物,其特征在于组分(a)和(b)按给予患者后所述联合药物将发挥协同作用的重量比存在。
3.一种药用组合物,所述组合物包含根据权利要求1或权利要求2所述的联合药物和任选的一种或多种助剂。
4.一种剂型,所述剂型包含根据权利要求1或权利要求2所述的联合药物和任选的一种或多种助剂。
5.根据权利要求4所述的剂型,其特征在于其适用于经口、静脉内、动脉内、腹膜内、皮内、透皮、鞘内、肌内、鼻内、透粘膜、皮下或直肠给药。
6.根据权利要求4所述的剂型,其特征在于组分(b)按控释形式存在。
7.根据权利要求4-6中任一项所述的剂型,其特征在于所述剂型还包含咖啡因。
8.根据权利要求1或权利要求2所述的联合药物在制备药物中的用途,所述药物用于治疗疼痛。
9.根据权利要求8所述的用途,其特征在于所述疼痛选自炎性疼痛、神经性疼痛、急性疼痛、慢性疼痛、内脏痛、偏头痛和癌性疼痛。
10.根据权利要求1或权利要求2所述的联合药物在制备药物中的用途,所述药物用于在哺乳动物中治疗疼痛。
11.根据权利要求10所述的用途,其特征在于所述联合药物的组分(a)和组分(b)同时或序贯给予哺乳动物,其中组分(a)在组分(b)之前或之后给予,和其中组分(a)或(b)通过相同或不同的给药途径给予所述哺乳动物。
12.根据权利要求10或11所述的用途,其特征在于所述疼痛选自炎性疼痛、神经性疼痛、急性疼痛、慢性疼痛、内脏痛、偏头痛和癌性疼痛。
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