CN105596321A - 一种治疗帕金森病的复方药物组合物及其应用 - Google Patents
一种治疗帕金森病的复方药物组合物及其应用 Download PDFInfo
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Abstract
本发明公开了一种治疗帕金森病的复方药物组合物及其应用,所述复方药物组合物包含以下组分:药物A和左旋多巴,其中药物A与左旋多巴的摩尔比为1:10-10:1,其中药物A为茜素及其前体药物中的一种或至少两种混合物,所述茜素及其前体药物可抑制左旋多巴等儿茶酚类药物的体内代谢,因此可作为儿茶酚类药物的增效剂,所述茜素及其前体药物用于制备治疗帕金森病的复方药物组合物,具有安全、高效、口服成药性好等特征,具有良好的应用前景。
Description
技术领域
本发明涉及一种治疗帕金森病的复方药物组合物及其应用,具体涉及一种包含安全、高效的儿茶酚-O-甲基化转移酶抑制剂—茜素及其前体药物的复方药物组合物及其应用。
背景技术
帕金森症(PD)是脑内多巴胺不足导致的一种慢性中枢神经系统退化性失调症。患病后,患者的动作机能、语言能力等严重受损,并伴有痛疼,肢体僵直、震颤等症状导致患者的生活质量严重下降。该病的发病率高达1.6%,而且随着年龄的增加,患病的风险也在增加。我国是世界上PD患者最多的国家,目前已有患者170万。此外,随着我国老龄化社会的来临,PD带来的医疗、家庭、社会等问题越发广泛和严峻,患者的生活质量受到巨大影响。
目前,治疗帕金森症(PD)最有效的治疗手段为多巴胺替代疗法,即通过前体药物左旋多巴(L-dopa)在患者脑中转变为多巴胺,以补充患者脑中多巴胺的不足。值得注意的是,L-dopa只有到达大脑才能发挥作用,但由于L-dopa在外周组织中极易被代谢,单独使用时几乎没有药效。儿茶酚-O-甲基转移酶Catechol-O-methyltransferase,COMT)介导的甲基化是L-dopa发生的一条主要代谢途径,国内外临床研究已证实COMT酶抑制剂与L-dopa联用确能显著增强L-dopa的疗效。因此,高效的COMT酶抑制剂是临床帕金森症治疗的一类重要药物。
儿茶酚-O-甲基转移酶(COMT)是一种镁离子依赖型酶,其以SAM作为甲基供体催化儿茶酚类底物的甲基化,生成相应的O-甲基化儿茶酚。COMT酶参与了体内大量内源性儿茶酚(如多巴胺等神经递质)及外源性儿茶酚类化合物(如黄酮、香豆素及左旋多巴等)的代谢。理想的COMT酶抑制剂不仅需要安全、有效,且具有良好的口服成药性及适宜的药代行为,可保证其可达到作用靶点且在体内具有一定的持效时间。利用强效外周COMT酶抑制剂提高L-dopa的口服生物利用度并延长L-dopa的作用时间是临床治疗帕金森症的首选。因此,新型安全、强效儿茶酚甲基化转移酶抑制剂的开发对于帕金森症的治疗至关重要。
然而,目前已上市的COMT酶抑制剂(如托卡朋、恩托卡朋)在体内的抑制活性偏低、代谢半衰期短、连续使用易引发肝、肾毒性等诸多缺陷,而帕金森症患者则需要频繁用药,长期使用托卡朋、恩托卡朋等现有COMT酶抑制剂后会引发严重的不良反应。因此开发新型安全高效的COMT抑制剂一直是帕金森症治疗药物研发的重心。
发明内容
本发明针对已有COMT酶抑制剂存在多种缺陷(如体内抑制活性偏低,连续使用易引发肝、肾毒性等),在前期工作的基础上,通过系列化合物的结构-药效、结构-安全性、结构-ADME属性的多维属性评估和优化,研发了上述新型儿茶酚-O-甲基化转移酶强效抑制剂—茜素及其前体药物,茜素及其前体药物可抑制左旋多巴等儿茶酚类药物的体内代谢,因此可作为儿茶酚类药物的增效剂,所述茜素及其前体药物用于制备治疗帕金森病的复方药物组合物,具有安全、高效、口服成药性好等特征,具有良好的应用前景。
本发明提供了一种包含上述新型儿茶酚-O-甲基化转移酶强效抑制剂—茜素及其前体药物的复方药物组合物,可用于治疗帕金森病。
本发明所述的治疗帕金森病的复方药物组合物包含以下组分:药物A和左旋多巴,药物A与左旋多巴的摩尔比为1:10-10:1,其中药物A为茜素及其前体药物中的一种或至少两种混合物,所述茜素及其前体药物的结构如下:
其中,R1与R2分别为氢、脂肪烷基、或酰基。
优选的:所述酰基包含乙酰基、丙酰基、丁酰基、苯甲酰基和琥珀酰基。
所述药物A与左旋多巴的摩尔比优选为2:1-5:1。
所述茜素及其前体药物,作为儿茶酚-O-甲基化转移酶强效抑制剂,具有良好的口服成药性,所述复方药物组合物可制成为口服剂型。所述口服剂型包括普通片剂、缓释片、胶囊剂和滴丸。
本发明还公开了上述治疗帕金森病的复方药物组合物在制备治疗帕金森病药物中的应用。所述复方药物组合物可有效提高血中左旋多巴的药物浓度进而缓解患者脑中多巴胺不足的症状。
本发明的有益效果:
(1)安全性高:本发明所述的复方药物组合物包含的茜素及其前体药物,具有良好的口服安全性,其小鼠口服LD50>2g/kg,同时对人体主要脏器细胞亦无明显毒性,且不会经CYP酶代谢激活产生活性中间体,亦不会与生物大分子形成毒性加合物;
(2)高效:本发明所述的复方药物组合物包含的茜素及其前体药物,作为一种新型的COMT酶强效抑制剂,体外COMT抑制活性评估显示所述茜素及其前体药物的EC50值可达1μM左右,体内研究显示其与L-dopa联用后,相对于托卡朋,L-dopa的AUC最高可增加47%;
(3)良好的药代行为:所述茜素及其前体药物具有较好的口服生物利用度,体内代谢半衰期可达1.5-2h,超过多数儿茶酚药物的体内半衰期,所述茜素及其前体药物原型在体内驻留时间较长;
(4)代谢产物仍保留活性:茜素在人体内的主要代谢产物在体内仍可发挥儿茶酚药物增效剂的用途。
附图说明
图1茜素及其前体药物的结构通式。
图2茜素对人COMT酶抑制剂的浓度依赖性抑制图。
图3茜素对人COMT酶抑制剂的抑制类型图。
具体实施方式
实施例1
茜素及其前体药物对人肝COMT酶的抑制活性测定:
以左旋多巴(L-dopa)-O-甲基化反应为探针反应,借助人肝细胞浆体外孵育体系,测定茜素及其前体药物对人COMT酶的抑制活性EC50,具体实验流程如下:
(1)200微升体外代谢反应体系中,加入5mM氯化镁,2mM二硫苏糖醇,150uM底物L-dopa,人肝细胞浆蛋白浓度为1mg/ml,抑制剂终浓度范围为0.05μM-50μM,于37℃条件下预孵3分钟;
(2)向反应体系中加入S-腺苷蛋氨酸(终浓度为0.2mM),起始反应;于37℃条件下反应30分钟后,加入200μL乙腈,剧烈震荡后,终止反应;
(3)采用高速冷冻离心机,在20,000×g的条件下,高速离心上述体系20分钟后,取上清,进行LC-MS/MS检测分析;定量检测左旋多巴的主要甲基化代谢产物3-甲氧基左旋多巴(采用MRM模式,离子对[M-H]+m/z212.2>195.1),通过检测单位时间内甲基化代谢产物的生成速率定量检测COMT酶的活性。
如图2所示,茜素对人COMT酶呈现出底物依赖性和浓度依赖性的抑制,其半数抑制浓度EC50值为0.9μM。在此基础上,我们还测定了另外五种茜素前体药物对人COMT酶的抑制活性,其EC50值如表1所示,从中可以看出茜素及部分前体药物对人COMT酶有较强的抑制活性。此外,我们还通过Lineweaver–Burk及二次作图发现茜素是COMT酶的非竞争性抑制剂,如图3所示。
表1茜素及其前体药物对COMT酶的抑制活性
实施例2
茜素的小鼠口服急性毒性评估:
选取昆明小鼠(购于大连医科大学实验动物中心),雌雄各半,体重19-22g。将小鼠随机分组,每组20只,雌雄各半。茜素混悬于0.5%CMC-Na中,浓度为1g/L。实验组包括茜素不同剂量组(0.2~2g/kg)以及0.5%CMC-Na空白对照组。连续观察给药后小鼠的行为状态直至14天,并于第14天对不同给药组小鼠进行大体解剖并观察内脏情况。最大剂量组(2g/kg)给药组小鼠中只有3例死亡,其他剂量组均无死亡例。对死亡个体进行解剖并未发现肝、肾等主要器官的明显病变。实验结果提示小鼠口服茜素的LD50值大于2.0g/kg,属于无毒级别。
实施例3
茜素与L-dopa合用的大鼠整体药代学研究:
选择18只Wistar大鼠,雌雄各半,按体重(180-220g)随机分为3组,6只/组开展单独口服L-dopa及同时口服茜素与L-dopa的整体药代学研究,并与阳性对照(托卡朋)对L-dopa药动学影响进行对比。分别在采集给药前血浆及给药后5、10、15、30、45、60、90、120、180、240分钟的大鼠血浆样品0.5ml左右,置于预先肝素化的1.5ml尖底棕色离心管中,4000×g离心10分钟后,分离血浆后加入等体积的甲醇沉淀蛋白并高速离心(20,000×g),取上清保存于-80℃冰箱待测。采用LC-MS测定各样品中L-dopa的血药浓度,应用DAS2.0软件对血药浓度数据进行处理,并计算药动学参数。结果表明,相对于阳性对照(托卡朋),茜素能显著提高大鼠血浆中L-dopa水平,其AUC增大了47%,同时体内代谢半衰期延长了1.5倍,以上结果显示茜素发挥了L-dopa增效剂的作用。
Claims (6)
1.一种治疗帕金森病的复方药物组合物,其特征在于:它包含以下组分:药物A和左旋多巴,其中药物A与左旋多巴的摩尔比为1:10-10:1,其中药物A为茜素及其前体药物中的一种或至少两种混合物,所述茜素及其前体药物的结构如下:
其中,R1与R2分别为氢、脂肪烷基、或酰基。
2.根据权利要求1所述的治疗帕金森病的复方药物组合物,其特征在于:所述酰基包含乙酰基、丙酰基、丁酰基、苯甲酰基和琥珀酰基。
3.根据权利要求1所述的治疗帕金森病的复方药物组合物,其特征在于:所述药物A与左旋多巴的摩尔比为2:1-5:1。
4.根据权利要求1所述的治疗帕金森病的复方药物组合物,其特征在于:所述复方药物组合物为口服剂型。
5.根据权利要求4所述的治疗帕金森病的复方药物组合物,其特征在于:所述口服剂型包括普通片剂、缓释片、胶囊剂和滴丸。
6.权利要求1-5任一权利要求所述的治疗帕金森病的复方药物组合物在制备治疗帕金森病药物中的应用。
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WO2019224300A3 (en) * | 2018-05-24 | 2020-02-06 | Eth Zurich | Tomm6-interacting extracts and compounds for use in the treatment and prophylaxis of nervous system diseases, atherosclerosis, hepatitis b infection and human papilloma virus (hpv) infection |
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