CN116585298A - 一种偶联药物及其组合物和应用 - Google Patents
一种偶联药物及其组合物和应用 Download PDFInfo
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- CN116585298A CN116585298A CN202310801747.6A CN202310801747A CN116585298A CN 116585298 A CN116585298 A CN 116585298A CN 202310801747 A CN202310801747 A CN 202310801747A CN 116585298 A CN116585298 A CN 116585298A
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- pregabalin
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Abstract
本发明涉及普瑞巴林与十六酰胺乙醇的偶联药物、普瑞巴林与十六酰胺乙醇的药物组合物、普瑞巴林与十六酰胺乙醇偶联药物的药物组合物。同时本发明还包括使用普瑞巴林与十六酰胺乙醇偶联药物及其药物组合物治疗疼痛和神经系统疾病的方法;偶联药物或其药学上可接受的盐、组合物或偶联药物的组合物在制备预防或治疗疼痛和/或神经系统疾病的药物中的用途;本发明所提供的普瑞巴林与十六酰胺乙醇偶联药物,水中溶解度比十六酰胺乙醇显著提高。体内疼痛模型试验结果也显示,普瑞巴林与十六酰胺乙醇偶联药物的镇痛作用优于二者的组合物,再优于单一组分。同时普瑞巴林与十六酰胺乙醇偶联药物显示出更持久的镇痛作用。
Description
技术领域
本发明属于医药领域,本发明涉及普瑞巴林与十六酰胺乙醇的偶联药物、普瑞巴林与十六酰胺乙醇的药物组合物、普瑞巴林与十六酰胺乙醇偶联药物的药物组合物。
背景技术
2020年,国际疼痛学会(International Association for the Study of Pain,IASP)将疼痛定义为是一种与实际或潜在的组织损伤相关的不愉快的感觉和情绪情感体验,或与此相似的经历。疼痛可以理解为机体受到来自内外环境伤害性刺激时出现的一种伴有情绪反应的病理生理过程,常常会使患者遭受各种心理痛苦,如:惊慌、害怕、焦虑、悲伤、愤怒、烦躁、失眠等,同时它对机体的影响也是多方面的,从局部功能到整体功能,严重者还可以导致生理功能紊乱,甚至可以引发疼痛性休克。另外,疼痛亦是机体受到伤害性刺激后的一种防御反应,是多种疾病的一种症状。疼痛可根据持续时间长短分为急性疼痛和慢性疼痛;根据发病机理分为伤害性疼痛(nociceptive)、神经痛(neuropathic)及变形性伤害疼痛(nociplastic);根据疼痛强度分为轻、中及重度疼痛等。如今,疼痛已成为紧随心脑血管疾病、肿瘤之后的人类第三大健康问题。疼痛不仅给人们带来身体上的不适,而且对人们的精神、心理、体质等诸多方面产生不同程度的负面影响,直接降低了人们的生活质量。然而,尽管有大量有效且广泛使用的镇痛药,如阿片类药物、非甾体抗炎药、部分抗抑郁药物等,但这些药物伴随的安全性和副作用问题,导致其临床使用受到质疑。
镇痛机制复杂、涉及多种信号通路,包括外周敏化、中枢敏化、异位放电等。单一的镇痛药无法满足理想镇痛治疗的全部要求,因而目前临床推荐采用多模式镇痛策略。近几十年来,多模式镇痛成为临床疼痛管理的主要发展方向之一,即通过联合不同作用机制的镇痛药物和镇痛方法,阻断疼痛病理生理机制的不同时相和靶位,减少外周和中枢敏感化,取得最佳镇痛效果,同时减少镇痛药物剂量,降低药物不良反应。而药物协同作用的评估通常是通过实验来证明的,等辐射分析法是评价药物之间药理相互作用的金标准方法。该方法核心准则是选择一个效应水平,并通过实验确定单独使用药物A、单独使用药物B以及产生这种效果的组合(a,b)的剂量,产生相同效果的剂量所连接的线称为等效线,而联合后的药物作用可以a/A+b/B=γ来表示,当γ=1时,则药物之间的相互作用是相加;当γ<1时,则药物之间的相互作用是协同;当γ>1时,则药物之间的相互作用是拮抗。
普瑞巴林((S)-3-(氨甲基)-5-甲基己酸)是由辉瑞Pfizer公司开发的一种新型、高效的神经系统药物,可用于治疗与糖尿病周围神经病变相关的神经性疼痛、治疗与脊髓损伤相关的神经性疼痛、带状疱疹后遗神经痛、肌纤维痛的治疗、成人癫痫患者部分性癫痫发作的辅助治疗。普瑞巴林虽在结构上类似于抑制性神经递质γ-氨基丁酸(GABA),但普瑞巴林不直接与GABA-A或GABA-B受体结合。普瑞巴林通过结合α2δ-1亚基阻断电压门控钙通道减少钙内流,从而减少谷氨酸和感觉神经肽(P物质和CGRP)在突触上的释放。普瑞巴林还增加了EAATs(兴奋性氨基酸转运蛋白)的活性,从而导致突触内谷氨酸的可用性进一步降低。谷氨酸水平的降低进一步抑制了N-甲基-D-天门冬氨酸(NMDA,L-谷氨酸的同系物)的激活,并减少了神经元的放电,从而发挥镇痛作用、抗癫痫作用。临床前及临床研究均表明,普瑞巴林作为单一疗法或与止痛药联合使用在缓解疼痛和相关症状方面的疗效和剂量依赖性效应,但其单独使用普遍存在镇痛应答率低(40-60%)、疼痛缓解率低等不足。而且普瑞巴林的使用剂量相对较大,半衰期较短、每日需要服药2-3次,最常见的药物不良反应为头晕、嗜睡等。
十六酰胺乙醇(palmitoylethanolamide,PEA)作为类内源性脂肪酰胺,广泛存在于人体、动物内脏、鸡蛋黄、橄榄油、红花和大豆卵磷脂、花生等食物中,具有抗炎、镇痛、抗抑郁、神经保护和抗惊厥活性。PEA具有多种作用机制,主要包括1)过氧化物酶体增殖物激活受体α激动剂(PPAR-α),减少促炎症相关基因的转录,从而减少致炎物质的产生;2)激活GPR55受体,通过Gq,G12,RhoA,actin,IP(3)R等下游信号事件增加细胞内钙离子水平;3)抑制脂肪酸酰胺水解酶(FAAH),减少内源性大麻素2-花生四烯酸甘油酯和花生四烯酸乙醇胺的降解,间接作用于CB1R和CB2R;4)通过变构调节作用增强2-花生四烯酸甘油酯和花生四烯酸乙醇胺激活TRPV1通道或通过PPAR-α间接激活TRPV1通道,调控疼痛信号的传递、炎症过程的发展。临床研究表明,补充PEA可以缓解多种原因引起的慢性疼痛,且没有副作用。PEA可止痛类型包括糖尿病神经病变、化疗引起的周围神经病、坐骨神经痛、腕管综合症、骨关节炎、疱疹后遗神经痛、中风相关的神经痛、多发性硬化症、牙齿疼痛,以及阴道痛、腰背痛和慢性骨盆痛等。同时研究并显示PEA有助于减轻应激反应,从而起到抵抗压力和焦虑的重要保护作用。但是PEA的水溶性较差,严重影响其吸收速率和生物利用度。
本发明通过将普瑞巴林与十六酰胺乙醇进行偶联,所得到的偶联药物可能具有的优势包括:1):符合多模式镇痛的理念,前药进入体内释放两种不同作用机理的药物普瑞巴林与十六酰胺乙醇,不同镇痛机理间协同镇痛,可有效降低单一镇痛药物的起效剂量及剂量相关的不良反应;2):增加PEA的水溶性,增加其吸收和生物利用度。因此,研究普瑞巴林与十六酰胺乙醇偶联药物用于疼痛治疗,对临床上疼痛的预防与治疗具有重要的科学价值和社会意义。
发明内容
本发明的目的是针对现有技术的缺陷,提供一种偶联药物及其组合物和应用,以解决上述背景技术提出的问题。
为实现上述目的,本发明提供如下技术方案:一种偶联药物,偶联药物为由普瑞巴林与十六酰胺乙醇偶联得到的化合物或其药学上可接受的盐,其结构如下:
普瑞巴林通过氨基末端或通过羧酸末端与十六酰胺乙醇共价连接。
一种组合物,该组合物含有普瑞巴林与十六酰胺乙醇。
一种偶联药物的组合物,含有化合物或其药学上可接受的盐和药学可接受载体。
一种偶联药物的应用,化合物或其药学上可接受的盐、组合物或偶联药物的组合物在制备预防或治疗疼痛和/或神经系统疾病的药物中的用途。
作为本发明的一种优选技术方案,所述疼痛为急性疼痛、慢性疼痛、神经病理性疼痛、炎症性疼痛、伤害性疼痛、癌性疼痛、痛觉过敏和内脏疼痛。
作为本发明的一种优选技术方案,所述神经系统疾病为疼痛症、癫痫症、焦虑症、抑郁症、人格障碍、认知障碍、情感障碍、神经变性疾病、惊厥性疾病、帕金森氏症、阿尔茨海默氏症、精神分裂症、精神病、亨廷顿舞蹈症、头部疾病、神经变性疾病、失眠和多动腿综合征。
本发明的有益效果是:本发明的普瑞巴林和十六酰胺乙醇的组合物,在慢性疼痛中(包括炎症性疼痛、神经病理性疼痛)具有协同镇痛作用,通过不同镇痛机理互补可有效降低单一组分的起效剂量,减少普瑞巴林剂量依赖的毒副作用;本发明通过等辐射分析法,证实上述药物间的协同镇痛作用,在发挥镇痛作用的同时无明显毒副作用,具有很好的临床应用前景。
同时,体外溶解度实验表明,本发明所提供的普瑞巴林与十六酰胺乙醇偶联药物,水中溶解度比十六酰胺乙醇显著提高。体内疼痛模型试验结果也显示,普瑞巴林与十六酰胺乙醇偶联药物的镇痛作用优于二者的组合物,再优于单一组分;本发明化合物既能明显改善角叉菜胶诱导的炎症性疼痛,又能缓解紫杉醇诱导的外周神经痛,且起效剂量显著低于普瑞巴林、十六酰胺乙醇的单一有效剂量,同时镇痛作用时间也显著延长。由于这些体内药理模型与疼痛密切相关,因此本发明提供的化合物或其组合物具有制备治疗疼痛相关疾病的药物的潜力。
附图说明
图1为十六酰胺乙醇(PEA)与普瑞巴林在角叉菜胶诱导炎症疼痛模型中的协同镇痛作用示意图;
图2为十六酰胺乙醇(PEA)与普瑞巴林在紫杉醇诱导的神经痛模型中的协同镇痛作用示意图;
图3为化合物1在角叉菜胶诱导的炎症疼痛模型中结果示意图;
图4为化合物1的紫杉醇诱导神经痛模型中实验结果示意图;
图5为角叉菜胶诱导的炎症疼痛模型中,化合物1与等摩尔量普瑞巴林、PEA单药及联用的药效对比示意图;
图6为紫杉醇诱导神经痛模型中,化合物1与等摩尔量普瑞巴林、PEA单药及联用的药效对比示意图;
图7为化合物1的疲劳转棒实验结果示意图;
图8为化合物1的旷场实验结果示意图。
具体实施方式
下面结合附图对本发明的较佳实施例进行详细阐述,以使本发明的优点和特征能更易被本领域人员理解,从而对本发明的保护范围做出更为清楚明确的界定。
本发明还提供预防或治疗疾病的方法,所述方法包含将治疗有效量的本发明化合物施用给需要的受试者。所述疾病包括疼痛和/或神经系统疾病,其中所述疼痛相关疾病包括急性疼痛,如软组织及关节急性损伤疼痛,手术后疼痛,急性带状疱疹疼痛,痛风等;所述疼痛相关疾病包括慢性疼痛,如软组织及关节劳损性或退变疼痛,椎间盘源性疼痛,神经源性疼痛等;所述疼痛相关疾病包括顽固性疼痛,如三叉神经痛,疱疹后遗神经痛,糖尿病周围神经痛等;所述疼痛相关疾病包括癌性疼痛,如晚期肿瘤痛,肿瘤转移痛等。所述疼痛相关疾病包括特殊性疼痛,如顽固性心绞痛,特发性胸腹痛等。所述神经系统疾病选自癫痫症、焦虑症、抑郁症、人格障碍、认知障碍、情感障碍、神经变性疾病、惊厥性疾病、帕金森氏症、阿尔茨海默氏症、精神分裂症、精神病、亨廷顿舞蹈症、头部疾病、神经变性疾病、失眠和多动腿综合征等。在一些实施方式中,与单独施用单一部分相比,施用本发明化合物或药物组合物引起至少一种副作用减少。在其他实施方式中,与单独施用单一部分相比,施用本发明化合物或药物组合物获得提高的治疗活性。在某些实施方式中,化合物或药物组合物与其他药物联合给药。该其他药物可在施用本发明化合物或药物组合物之前、同时或之后给药。
在一些实施方式中,所述化合物可与至少一种其他治疗药物联合使用,所述其他治疗药物选自镇痛药、抗精神分裂症药、抗焦虑药、抗抑郁药、抗癫痫药、抗阿尔茨海默症药物、NMDA拮抗剂。该其他治疗药物可以在施用本发明化合物之前、同时或者之后给药。
本发明所述普瑞巴林和十六酰胺乙醇的组合物、或其偶联药物和药学上可接受的辅料制成适合于通过任何适当途径给药的形式,活性化合物优选是以单位剂量的方式,或者是以患者可以以单剂自我给药的方式。本发明提供的化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、注射液、颗粒剂、酊剂、锭剂、栓剂、再生药粉或液体制剂。
其使用方法中所用化合物或组合物的剂量通常随疾病的严重程度、患者的体重和化合物的相对功效而改变。作为一般性指导,合适的单位剂量可以是0.01~1000mg。
如本领域技术人员所熟知,药物的给药剂量依赖于多种因素,包括但并非限定于以下因素:所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等;另外,最佳的治疗方式如治疗的模式、普瑞巴林与十六酰胺乙醇偶联药物的日用量或可要用的盐的种类可根据传统的治疗方案来验证。
本发明提供的化合物还可包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如,具有本公开的结构,除了用“氘”或“氚”代替氢,或者用11C-,13C-,或者14C-富集的碳(11C-,13C-,或者14C-碳标记;11C-,13C-,或者14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针,或者可以用作疾病的体内诊断成像示踪剂,或者作为药效学、药动学或受体研究的示踪剂。氘代物通常可以保留与未氘代的化合物相当的活性,并且当氘代在某些特定位点时可以取得更好的代谢稳定性,从而获得某些治疗优势(如体内半衰期增加或剂量需求减少)。
本发明提供的化合物还包括各种氘化形式的普瑞巴林与十六酰胺乙醇偶联药物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的普瑞巴林与十六酰胺乙醇偶联化合物。在制备上述偶联化合物时可使用市售的氘代起始物质,或他们可使用常规技术采用氘代试剂合成,氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
针对药物或药理学活性剂而言,术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异,取决于受试者的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
测试方法:
本发明的化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR的测定使用Bruker AV-500核磁仪,测定溶剂为氘代氯仿(CDCl3),内标为四甲基硅烷(TMS)。化学位移(δ)单位为ppm。
HR-MS的测定使用Aglient LC-MS/MS QTOF 6530(生产商:Aglient,MS型号:QTOF6530)。
下面的实施例只是以说明为目的而不作为本发明的限制。
所有温度为摄氏温度(℃)。
A、化合物合成实施例;
实施例1:2-棕榈酰胺乙基(S)-3-(氨甲基)-5-甲基已酸酯的合成(1)
反应式:
通过普瑞巴林与二碳酸二叔丁酯反应合成中间体(1A),并进一步与十六酰胺乙醇反应生成中间体1B,最后在酸性条件下脱保护基得到目标产物。
S1):(S)-3-(((叔丁氧羰基)胺基)甲基)-5-甲基己酸(1A)的合成;
在100mL单口瓶中,加入水40mL,普瑞巴林5.0g(31.4mmol,1.0eq),搅拌下加入氢氧化钠3.13g(78.5mmol,2.5eq),滴加二碳酸二叔丁酯(Boc2O)2.74g(37.68mmol,1.2eq),滴完室温搅拌2小时后点板,已反应完。后处理:先用二氯甲烷20mL*3洗掉剩余的Boc2O,水相用浓盐酸调pH=2,再用二氯甲烷30ml*3萃取,无水硫酸钠干燥,35℃旋干,得7.2g油状物。
S2):2-棕榈酰胺乙基(S)-3-(((叔丁氧羰基)胺基)甲基)-5-甲基己酸酯(1B)的合成;
在100mL单口瓶中,加入二氯甲烷50mL,Pre-Boc 5.0g(20.4mmol,1.0eq),PEA6.1g(20.4mmol,1.0eq),EDCI 6.0g(30.6mmol,1.5eq),DMAP 0.5g(4.1mmol,0.2eq),加完后室温搅拌,2小时后点板,反应完全。后处理:加入水30mL搅拌、静置分层,水层加入30mL二氯甲挖萃取,合并有机层饱和盐酸30mL洗涤,无水硫酸钠干燥,过滤,旋干,柱层析,得产物9.5g。
S3):2-棕榈酰胺乙基(S)-3-(氨甲基)-5-甲基已酸酯(Pregabalin-PEA,化合物1)的合成;
将乙酸乙酯10mL、Pre-Boc-PEA 9.5g加入50mL反应瓶中,滴加2M HCl/EA溶液50mL,浓盐酸10mL,室温反应1天。后处理:加入水20mL,调节pH=9~10,搅拌静置分层,二氯甲烷20mL*3萃取,合并有机层饱和盐水洗,无水硫酸钠干燥,过滤,滤液蒸干,柱层析,得产物1.4g。
1H NMR(500MHz,Chloroform-d)δ8.25(br.s,3H),6.96(s,1H),4.28–4.12(m,2H),3.52(m,2H),3.13(br.s,1H),3.03(br.s,1H),2.66–2.50(m,2H),2.43–2.40(m,1H),2.25–2.22(t,J=7.6Hz,2H),1.70–1.57(m,3H),1.37–1.20(m,26H),0.961–0.86(m,9H).
13C NMR(126MHz,Chloroform-d)δ174.23,172.59,63.87,43.43,43.35,41.40,38.35,36.53,36.50,31.93,31.09,29.73,29.67,29.63,29.54,29.42,29.37,25.82,25.10,22.69,22.56,22.44,14.12.
HR-MS(ESI)m/z 441.4067([M+H]+,C23H53N2O3 +,calculated 441.4051)。
实施例2:2-棕榈酰胺乙基(S)-3-(氨甲基)-5-甲基已酸酯(Pregabalin-PEA,化合物1)的水溶性测定;
溶解度是影响药物生物利用度的最重要的性质之一,药物的溶解度与其口服在体内的吸收密切相关。本研究测试Pregabalin-PEA前药在pH 1.2磷酸缓冲液、pH 4.5醋酸缓冲液、pH 6.8磷酸缓冲液和纯水中的溶解度。
称取PEA、Pregabalin-PEA前药10mg放入试管中,分别加入纯化水、pH1.2盐酸缓冲液、pH4.5醋酸钠缓冲液、pH6.8磷酸缓冲液2ml。所有试管放入恒温摇床,37℃,100rpm,振荡1h。吸取各介质中的溶液100ul,用相应的缓冲液稀释5倍,通过0.45μm有机系过滤膜过滤并进行HPLC分析。结果如表1所示。
Pregabalin-PEA前药在pH6.8以及pH1.2的缓冲液中发生了降解,在水和pH4.5的介质中,Pregabalin-PEA前药的溶解性提高217倍以上。
表1Pregabalin-PEA(化合物1)及PEA的平衡溶解度值
B、药理方面的实施例;
实施例3:十六酰胺乙醇(PEA)与普瑞巴林在角叉菜胶诱导炎症疼痛模型中的协同镇痛作用;
炎症性疼痛是临床上最常见的病理性疼痛类型之一,角叉菜胶诱导的炎症性疼痛在镇痛药的研究中具有很高的预测价值,常被用于评估药物的抗炎症性疼痛效果。
ICR小鼠,雌性,22–30g,随机分为阴性对照组、模型组以及化合物各剂量组,每组8只。阴性对照组和模型组给与相应溶剂生理盐水,化合物各剂量组灌胃给与相应剂量化合物,给药体积为10ml/kg。小鼠被放置在高架金属网格上的测试室中,并给予至少30分钟的适应期。用微量注射器将1%角叉菜胶(20μL)注射到右后爪足底的皮下组织,等待3小时,待其足部充分肿胀,然后灌胃给予小鼠不同的化合物或生理盐水。各组分别在给药后30、60、90、120、180、240分钟测定各小鼠的机械缩足阈值。最大镇痛效应的百分比(percentage ofmaximum possible effect,%MPE)的计算公式如下:%MPE=(MWTm-MWTb)/(MWTn-MWTb)×100%,其中MWTm代表小鼠接受药物治疗后的最大机械缩足阈值,MWTb指注射角叉菜胶后的机械缩足阈值(造模后基线值),MWTn指小鼠注射角叉菜胶前的机械缩足阈值(造模前基线值)。
注射角叉菜胶3小时后,小鼠的机械性阈值明显降低。高中低剂量普瑞巴林(6、12、24mg/kg)或PEA(10、30、50mg/kg)均可剂量依赖的缓解角叉菜胶诱导的炎症性疼痛,其ED50值分别为6.72mg/kg、34.29mg/kg。二者联合给药时,剂量以两药各自的1/2ED50,1/4ED50,1/8ED50给药。等辐射分析法表明,ED50理论值Zadd=20.5mg/kg,实验算得ED50实际值Zt=12.1mg/kg,等辐射分析图中γ(ED50实际值/ED50理论值)=0.59<1,表明二者具有协同镇痛作用,其结果详见图1。
实施例4:十六酰胺乙醇(PEA)与普瑞巴林在紫杉醇诱导神经痛模型中的协同镇痛作用;
紫杉醇诱导的外周神经痛模型广泛用于评价药物的抗化疗药物引起的神经痛作用。
ICR小鼠,雌性,22–30g,随机分为阴性对照组、模型组以及化合物各剂量组,每组8只。小鼠腹腔注射紫杉醇(2mg/kg),剂量为0.1mL/10g,每日1次,连续5天(第1、2、3、4和5天14:00-16:00),第六天评估各小鼠基线机械阈值,第七天给药测试。小鼠被放置在一个高架金属网格上的测试室中,并让其适应30min。然后金属丝被提起,并对后爪施加一个线性增加的力。当动物移开爪子就会自动获得停止信号。机械刺激后的缩足阈值以克为单位自动记录下来。经过一段适应期后,每只小鼠在右后足底进行3次测试。随后,各组分别在给药后30、60、90、120、180、240分钟测定小鼠的机械缩足阈值。最大镇痛效应的百分比(percentage of maximum possible effect,%MPE)的计算公式如下:%MPE=(MWTm-MWTb)/(MWTn-MWTb)×100%,其中MWTm代表小鼠接受药物治疗后的最大机械缩足阈值,MWTb指紫杉醇造模后的机械缩足阈值(造模后基线值),MWTn指小鼠紫杉醇造模前的机械缩足阈值(造模前基线值)。
紫杉醇连续五天给药结束后,小鼠机械性疼痛阈值明显降低,表明神经痛模型造模成功。高中低剂量普瑞巴林(6、12、24mg/kg)或PEA(10、30、50mg/kg)均可剂量依赖的逆转紫杉醇诱导的神经性疼痛,其ED50值分别为7.5mg/kg、40.86mg/kg。二者联合给药时,剂量以两药各自的1/2ED50,1/4ED50,1/8ED50给药。等辐射分析法表明,ED50理论值Zadd=24.16mg/kg,实验算得ED50实际值Zt=14.8mg/kg,等辐射分析图中γ(ED50实际值/ED50理论值)=0.61<1,表明二者具有协同镇痛作用,其结果详见图2。
实施例5:Pregabalin-PEA(化合物1)在角叉菜胶诱导的炎症疼痛模型中的镇痛作用评价;
角叉菜胶诱导的炎症疼痛模型实验过程与实施例5同。
注射角叉菜胶3小时后,小鼠的机械性阈值明显降低。高中低剂量化合物3Pregabalin-PEA(3.25、6.5、13mg/kg)均可剂量依赖的缓解角叉菜胶诱导的炎症性疼痛,镇痛抑制率分别为42%、60%及75%,其ED50值为4.43mg/kg。
与实施例3中普瑞巴林(ED50=6.72mg/kg)和PEA(ED50=34.29mg/kg)相比其起效剂量明显降低,其结果详见图3。
实施例6:Pregabalin-PEA(化合物1)在紫杉醇诱导神经痛模型中的镇痛作用评价;
紫杉醇诱导神经痛模型实验过程与实施例6同。
紫杉醇连续五天给药结束后,小鼠机械性疼痛阈值明显降低,表明神经痛模型造模成功。高中低剂量化合物1Pregabalin-PEA(3.25、6.5、13mg/kg)均可剂量依赖的逆转紫杉醇诱导的神经性疼痛,镇痛抑制率分别为38%、51%及73%,其ED50值为5.54mg/kg。与实施例4中普瑞巴林(ED50=7.5mg/kg)和PEA(ED50=40.86mg/kg)相比其起效剂量明显降低,其结果详见图4。
实施例7:角叉菜胶诱导的炎症疼痛模型中,化合物1与等摩尔量普瑞巴林、PEA单药及联用的药效对比实验;
为进一步评价GABA或其类似物与类内源性大麻素前药的药效学优势,本实施例在角叉菜胶诱导的炎症疼痛模型中,对比化合物1(Pregabalin-PEA,13mg/kg)与等摩尔量普瑞巴林(4.7mg/kg)、PEA(8.8mg/kg)单药及二者联用时(4.7mg/kg普瑞巴林+8.8mg/kg PEA)的镇痛效果差异。角叉菜胶诱导的炎症疼痛模型实验过程与实施例5同。
注射角叉菜胶3小时后,小鼠的机械性阈值明显降低,表明造模成功。13mg/kg化合物3Pregabalin-PEA可显著缓解角叉菜胶诱导的炎症性疼痛,最大镇痛抑制率为75%。等摩尔剂量的普瑞巴林(4.7mg/kg)、PEA(8.8mg/kg)的最大镇痛抑制率分别为31.6%、32.7%。二者联用时(4.7mg/kg普瑞巴林+8.8mg/kg PEA)最大镇痛抑制率为51.1%。上述结果表明,化合物3(Pregabalin-PEA)对炎症性疼痛的镇痛效果显著优于单一药物、优于二者的联用,同时镇痛持续时间也大大延长,由原来的60min增加至240min以上,结果详见图5。
实施例8:紫杉醇诱导神经痛模型中,化合物1与等摩尔量普瑞巴林、PEA单药及联用的药效对比实验;
为进一步评价GABA或其类似物与类内源性大麻素前药的药效学优势,本实施例在紫杉醇诱导神经痛模型中,对比化合物1(Pregabalin-PEA,13mg/kg)与等摩尔量普瑞巴林(4.7mg/kg)、PEA(8.8mg/kg)单药及二者联用时(4.7mg/kg普瑞巴林+8.8mg/kg PEA)的镇痛效果差异。紫杉醇诱导的神经痛模型实验过程与实施例4同。
紫杉醇连续五天给药结束后,小鼠机械性疼痛阈值明显降低,表明神经痛模型造模成功。13mg/kg化合物3Pregabalin-PEA可显著缓解紫杉醇诱导的神经痛,最大镇痛抑制率为73%。等摩尔剂量的普瑞巴林(4.7mg/kg)、PEA(8.8mg/kg)的最大镇痛抑制率分别为21.3%、29.6%。二者联用时(4.7mg/kg普瑞巴林+8.8mg/kg PEA)最大镇痛抑制率为40.2%。上述结果表明,化合物3(Pregabalin-PEA)对神经痛的镇痛效果显著优于单一药物、优于二者的联用,同时镇痛持续时间也大大延长,由原来的60min增加至180min以上,结果详见图6。
实施例9:Pregabalin-PEA(化合物1)的疲劳转棒实验;
实验方法:实验前对小鼠进行筛选和训练,首先以20r/min的速度筛选出运动能力协调的老鼠,之后对筛选出的老鼠进行训练,训练两天,每天三次,每次3-5min,第一天20r/min,第二天30r/min,让小鼠适应训练强度。正式实验时,各药物单独用药或是以药效学评价最大剂量的两倍剂量联合给药,在30、60、90、120min时进行测试,转速30r/min,运行时间5min。
从图7中可以看出化合物1(26mg/kg)、普瑞巴林(50mg/kg)、PEA(100mg/kg)及联用(7.5mg/kg普瑞巴林+40.8mg/kg PEA)组均对对小鼠的运动协调能力无影响。
实施例10:Pregabalin-PEA(化合物1)的旷场实验;
采用旷场实验(Open Field Test)评价优选化合物对小鼠急性高活动的影响。急性高活动反应是中脑边缘多巴胺神经能激活的特征标志,而多巴胺神经能通路被认为和传统阿片类镇痛药物的强化和成瘾性相关。实验前,每只小鼠提前在旷场试验箱中适应30min,灌胃给药或溶媒后,继续记录210min内各小鼠的运动距离。
从图8中可以看出,240min时间范围内化合物3(26mg/kg)和溶剂组小鼠的运动距离无显著性差异,表明化合物3不具有镇静或兴奋的副作用。
实施例11:Pregabalin-PEA(化合物1)的体外肝微粒稳定性实验;
(1)、从-80℃冰箱中取出人、大鼠、小鼠肝微粒体,置于37℃水浴恒温振荡器上预温孵3min,融化待用。
(2)、称取一定量的NADPH,加入适量氯化镁溶液溶解成2mM的溶液待用。
(3)、按照下表2“实验温孵体系的构成”比例,制备温孵体系混合溶液(不含β-NADPH),以40μL/管进行分装。
表2:实验温孵体系的构成
(4)、0min样品:加入240μL内标工作沉淀剂,再加入40μL NADPH溶液(阴性对照组加入40μL氯化镁溶液)。
(5)、其他样品:加入40μL NADPH溶液启动反应(阴性对照组加入40μL氯化镁溶液),37℃水浴孵育5,15,30,60min后加入240μL含内标沉淀剂。
(6)、阳性对照组:加入40μL NADPH溶液启动反应,37℃水浴孵育5,15min后加入240μL含内标沉淀剂。
(7)、所有样品涡旋并离心。
(8)、取上清液150μL加入150μL水,涡旋混匀,LC-MS/MS进样分析。
表3:Pregabalin-PEA(化合物1)的体外肝微粒稳定性实验
结果表明化合物1在大鼠、小鼠肝微粒体中半衰期大于120min,与其在小鼠模型中展现出的长效镇痛作用吻合。化合物1在人肝微粒体中的半衰期为61.3min。
C、组合物实施例
实施例12:片剂;
成分 | 每1000片 |
各化合物 | 50g |
微粉硅胶 | 15g |
微晶纤维素 | 20g |
乳糖 | 16g |
磷酸钙 | 10g |
羟丙基甲基纤维素 | 15g |
聚乙二醇6000 | 16g |
硬脂酸镁 | 0.3g |
制备工艺:
(1):将处方量的化合物、微粉硅胶混合均匀,再加入二分之一处方量的磷酸钙,混合均匀,共粉碎至过100目筛;
(2):分别将微晶纤维素、乳糖、聚乙二醇6000、羟丙基甲基纤维素、剩余处方量的磷酸钙、硬脂酸镁过80目筛;
(3):将第一步所得与第二步过筛的处方量的微晶纤维素、乳糖、聚乙二醇、剩余处方量的磷酸钙混合均匀,再与处方量的羟丙基甲基纤维素混合均匀,用50%乙醇润湿制粒;
(4):60℃烘干第三步所得,整理,过60目筛;
(5):最后加入处方量的硬脂酸镁,压片。
以上实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。
Claims (6)
1.一种偶联药物,其特征在于:偶联药物为由普瑞巴林与十六酰胺乙醇偶联得到的化合物或其药学上可接受的盐,其结构如下:
普瑞巴林通过氨基末端或通过羧酸末端与十六酰胺乙醇共价连接。
2.一种组合物,其特征在于:该组合物含有普瑞巴林与十六酰胺乙醇。
3.一种偶联药物的组合物,其特征在于:含有权利要求1所述的化合物或其药学上可接受的盐和药学可接受载体。
4.一种普瑞巴林与十六酰胺乙醇偶联药物或其组合物的应用,其特征在于:权利要求1所述的化合物或其药学上可接受的盐、权利要求2所述的组合物或权利要求3所述偶联药物的组合物在制备预防或治疗疼痛和/或神经系统疾病的药物中的用途。
5.根据权利要求4所述的一种普瑞巴林与十六酰胺乙醇偶联药物或其组合物的应用,其特征在于:所述疼痛为急性疼痛、慢性疼痛、神经病理性疼痛、炎症性疼痛、伤害性疼痛、癌性疼痛、痛觉过敏和内脏疼痛。
6.根据权利要求4所述的一种普瑞巴林与十六酰胺乙醇偶联药物或其组合物的应用,其特征在于:所述神经系统疾病为疼痛症、癫痫症、焦虑症、抑郁症、人格障碍、认知障碍、情感障碍、神经变性疾病、惊厥性疾病、帕金森氏症、阿尔茨海默氏症、精神分裂症、精神病、亨廷顿舞蹈症、头部疾病、神经变性疾病、失眠和多动腿综合征。
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