CN102416012B - 一种治疗小儿多动症的药物组合物 - Google Patents
一种治疗小儿多动症的药物组合物 Download PDFInfo
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- CN102416012B CN102416012B CN 201110363919 CN201110363919A CN102416012B CN 102416012 B CN102416012 B CN 102416012B CN 201110363919 CN201110363919 CN 201110363919 CN 201110363919 A CN201110363919 A CN 201110363919A CN 102416012 B CN102416012 B CN 102416012B
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- hyperkinetic syndrome
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- tomoxetine hydrochloride
- hyperactivity
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Abstract
本发明涉及医药领域,具体的说是涉及一种治疗小儿多动症的药物组合物。本发明所述治疗小儿多动症的药物组合物,由盐酸托莫西汀和维生素B6组成,所述盐酸托莫西汀和维生素B6的质量比为1∶0.5~1∶4,可以和常规的辅料组合制成治疗小儿多动症的药物。本发明所述治疗小儿多动症的药物组合物,盐酸托莫西汀与0.5~4倍重量的维生素B6组合,能起到协同增效作用,可显著增强NA的翻转效应,同时可促进脑部神经发育和稳定脑细胞功能,对小儿多动症起到“标本兼治”的效果。
Description
技术领域
本发明涉及医药领域,具体的说是涉及一种治疗小儿多动症的药物组合物。
背景技术
小儿多动症又称注意力缺陷多动症(ADHD),或脑功能轻微失调综合征,是一种常见的儿童行为异常疾病,造成小儿行为异常。据国外报道小儿多动症的患病率在5%~10%之间,国内调查在10%以上,早产儿患多动症的几率最高,大约在60%以上,男孩远多于女孩。小儿多动症患儿的智力正常或基本正常,但学习、行为及情绪方面有缺陷,主要表现为注意力不集中、注意短暂、活动过多、情绪易冲动、学习成绩普遍较差、在家庭及学校均难与人相处,日常生活中常常使家长和教师感到没有办法。多动症疾病危害十分严重,会对儿童的终身产生影响,造成学习困难,有的甚至被迫停学,出现人际交往困难,社会适应能力下降,攻击性行为等。然而一些儿童的多动症症状并未引起家长的重视,而被误认为“淘气”、“不听话”。由于延误了治疗时机,不仅影响了孩子的学习成绩,更对孩子的身心发育造成伤害,甚至影响到成年。
小儿多动症其严重程度分为轻度、中度、中度三类,其发病原因大概有以下几种:脑神经发育不良、脑神经递质数量不足、脑组织器质性损害、遗传因素、其他因素等。多发于儿童学龄期,患病率最高的年龄段为6-12岁。精神创伤、不良家庭环境、学习负担过重、心理压力过大、责备过多、环境中某些紧张气氛,以及母亲怀孕期和围产期出现的某些状况,如孕期患高血压、肾炎、贫血、低热、先兆流产等因也会使儿童更易患上多动症。
很多研究表明儿童注意缺陷多动症(ADH D)主要是由于中枢神经系统中多巴胺(DA)和去甲肾上腺素(NA)代谢障碍所致的轻度脑功能缺陷。目前小儿多动症的治疗药物大体可分为非中枢兴奋剂、中枢神经兴奋剂、抗忧郁剂、抗精神病药及抗癫痫剂等几类,具体的临床用药有盐酸托莫西汀、哌甲酯、右旋苯丙胺、苯异妥英、咖啡因、丙米嗪等,这些药物主要基本都是针对多动的临床症状进行干预和治疗,未有针对引起多动症的儿童因神经发育不良而进行神经发育和营养的“标本兼治”的药物。如盐酸托莫西汀是最近研制开发的适应病例范围宽、疗效好、不良反应发生率低与安慰剂组无显著性差异,其是现临床上疗效最好、用得较多的治疗小儿多动症药物。盐酸托莫西汀治疗作用与其他选择性抑制突触前胺泵对NA的再摄取效应有关,能增强NA的翻转效应,从而是改善了多动症的症状,间接促进儿童认识的完成及注意力的集中。但盐酸托莫西汀并没有解决多动症因小儿脑部神经发育问题的病因,因而在临床上的使用有很大的局限,处于“治标不治本”的尴尬状况。
发明内容
有鉴于此,本发明目的是提供一种即可解决多动症因小儿脑部神经发育问题,又能改善多动症症状,达到“标本兼治”目的的药物组合物。
为实现本发明的目的,本发明采用如下技术方案:
一种治疗小儿多动症的药物组合物,由盐酸托莫西汀和维生素B6组成,所述盐酸托莫西汀和维生素B6的质量比为1∶0.5~1∶4。
目前研究表明小儿多动症主要是由于中枢神经系统中多巴胺(DA)和去甲肾上腺素(NA)代谢障碍所致的轻度脑功能缺陷。盐酸托莫西汀是一个有效且耐受性良好的治疗儿童、青少年和成人注意缺陷多动障碍的非中枢兴奋性药物,它是强有力的突触前去甲肾上腺素转运体抑制剂,能选择性抑制突触前胺泵对去甲肾上腺素的再摄取,增强NA的翻转效应,从而改善ADHD的症状,间接促进认识的完成及注意力的集中,但盐酸托莫西汀对其他单胺类转运体或受体亲和力很弱,不能解决小儿脑部神经发育的问题,而脑神经发育不良是多动症最大的病因,因而盐酸托莫西汀在临床上的使用有很大的局限,不能从根本上治疗小儿多动症。
维生素B包括维生素B1、维生素B2、维生素B6、维生素B12、烟酸、泛酸、叶酸等。这些B族维生素是推动体内代谢,把糖、脂肪、蛋白质等转化成热量时不可缺少的物质。如果缺少维生素B,则细胞功能马上降低,引起代谢障碍,针对儿童来说可能引起发育不良的相关疾病。其中,维生素B6(Vitamin B6)又称吡哆素,是一种水溶性维生素,遇光或碱易破坏,不耐高温。一种含吡哆醇或吡哆醛或吡哆胺的B族维生素。维生素B6为人体内某些辅酶的组成成分,参与多种代谢反应,尤其是和氨基酸代谢有密切关系。脑细胞所需相关胺化合物的合成,如肾上腺素、新肾上腺素、多巴胺、酪胺、血胺素等均需要维生素B6。多巴胺是新肾上腺素的前驱物质,而血胺素又可合成褪黑激素。在脑细胞的代谢中,维生素B6的辅脢对胺基酸的脱羧基作用很重要,能稳定脑细胞的功能,因此儿童的脑部神经发育不能缺乏维生素B6。目前尚未见有含盐酸托莫西汀和维生素B6的治疗小儿多动症的药物组合物的研究及其产品。
由于小儿多动症最大的病因是脑神经发育不良,脑细胞功能不稳定。维生素B6可稳定脑细胞的功能,辅助促进脑神经发育,可解决多动症病因上的“本”问题;盐酸托莫西汀是现临床上最好的改善多动症症状的药物,可解决多动症症状上的“标”问题。通过大量的配伍筛选研究发现盐酸托莫西汀与0.5~4倍重量的维生素B6组合,能起到协同增效作用,可显著增强NA的翻转效应,同时可促进脑部神经发育和稳定脑细胞功能,对小儿多动症起到“标本兼治”的效果。
目前认为ADHD的神经生化改变主要指中枢神经系统单胺能神经递质代谢异常,且ADHD的发病不能以某一递质系统解释,而应是包括去甲肾上腺素(NE)、5-羟色胺(5-HT)等在内的多递质系统异常。在一个具体实施方案中,本发明通过对比观察本发明所述盐酸托莫西汀与维生素B6组成的组合物对ADHD动物模型自发性高血压大鼠(SHR)脑组织中NE、5-HT含量,发现本发明所述盐酸托莫西汀和维生素B6组合物可明显降低SHR大鼠脑内海马组织中NE的含量,升高额叶皮质组织中5-HT的含量,与盐酸酸托莫西汀组和空白对照组比较,P<0.05,差异有显著性意义,表明本发明所述药物组合物可以有效治疗小儿多动症,效果优于单用盐酸托莫西汀。
在一个具体实施方案中,本发明通过对大鼠脑组织神经元损伤修复的影响实验,证明本发明所述药物组合物能够保护神经元,可对脑皮质神经元损伤起到修复作用。
作为优选,本发明所述治疗小儿多动症的药物组合物,所述盐酸托莫西汀和维生素B6的质量比为1∶0.75~1∶2。
本发明还提供了所述组合物在制备具有治疗小儿多动症的药物中的应用。
本发明同时还提供了一种治疗小儿多动症的药物,由所述治疗小儿多动症的药物组合物和常规的辅料组合制成,可以进一步制备成口服药的各种固体剂型,包括片剂、胶囊、丸剂、粉剂和颗粒剂。在一些具体实施例中,为片剂和胶囊剂。在这些剂型中,药物化合物与至少一种药学上可接受的惰性赋形剂或载体混合,如填充剂、粘合剂、保湿剂、崩解剂、阻滞剂、吸收促进剂、湿润剂、吸收剂或润滑剂及它们的混合物。其中,填充剂如淀粉,乳糖,蔗糖,葡萄糖,甘露醇和硅酸;粘合剂如羧甲基纤维素,藻酸盐,明胶,聚乙烯吡咯酮,蔗糖和阿拉伯胶;保湿剂如甘油;崩解剂如琼脂,碳酸钙,土豆淀粉或木薯淀粉,海藻酸,某些硅酸盐和碳酸钠,低取代羟丙基纤维素;阻滞剂溶液如石蜡;吸收促进剂如季胺类化合物;湿润剂如十六醇和单硬脂酸甘油酯;吸收剂如白陶土和皂土;润滑剂如滑石粉,硬脂酸钙,硬脂酸镁,固体聚乙二醇,月桂硫酸钠。
具体实施方式
本发明实施例公开了一种治疗小儿多动症的药物组合物。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的产品已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的产品进行改动或适当变更与组合,来实现和应用本发明技术。
为了进一步理解本发明,下面结合实施例对本发明进行详细说明。实施例1:本发明所述药物组合物对大鼠脑组织中去甲肾上腺素含量的影响
实验动物:选用健康的雄性SHR大鼠36只,周龄为10周,体重265~295g,购自四川省医学科学院实验动物研究所。
分组与给药:将大鼠随机分为空白对照组、盐酸托莫西汀组、盐酸托莫西汀和维生素B6不同比例组,每组6只,灌胃给药。盐酸托莫西汀和维生素B6不同比例组和盐酸托莫西汀组均为10mg/kg,空白对照组等剂量的0.9%NaCl,每天上午灌服,1次/天,连续灌服14天。实验期间每日给每只大鼠15~20g饲料,水可自由获取。
检测方法:上述各组在连续灌胃14天后统一取材,先用10%水合氯醛腹腔注射麻醉大鼠,然后将大鼠断头处死,在冰台上迅速取脑并分离出海马和额叶皮质组织,将其分别称重后用锡纸包好,保存于-70℃冰箱,然后高效液相法检测去甲肾上腺素(NE)、5-羟色胺(5-HT)含量,结果见表1。使用SPSS11.5软件包进行数据整理和统计分析。计量资料方差齐者用t检验,方差不齐者用秩和检验,组间比较用单因素方差分析。
表1本发明所述药物组合物对大鼠脑组织中去甲肾上腺素含量的影响
由表1结果可见本发明所述盐酸托莫西汀和维生素B6比例1∶0.5和1∶4可明显降低SHR大鼠脑内海马组织中NE的含量,升高额叶皮质组织中5-HT的含量,与盐酸酸托莫西汀组和空白对照组比较,P<0.05,差异有显著性意义。
实施例2:本发明所述药物组合物对大鼠脑组织神经元损伤修复的影响
实验动物:Wistar大鼠,出生48小时内,购自四川省医学科学院实验动物研究所。
细胞培养:取出生48h内的Wistar大鼠,消毒,无菌条件下分离出大脑皮质,用PBS溶液冲洗2次,置于0.25%的胰蛋白酶中消化30min。用吸管弃去表面的胰蛋白酶。加入含10%胎牛血清的DMEM高糖培养液,1000r/min离心3min,吸弃上清液,制成单细胞悬液。自然沉降后将上层单细胞悬液移入另一离心管,同此法重复一遍,最终得到细胞悬液。接种于预先放入6孔培养板中,置于37℃、5%CO2培养箱中培养。
神经元损伤模型的建立及分组:神经元培养到8~10天便可以用于制备损伤模型。实验参照刘海泉等(中华眼底病杂志,2004,20(4):249-251)和黄卫东等(第四军医大学学报,2004,25:307-309)文献,分别分为对照组、损伤组、损伤加药治疗组进行试验观察,所加药物组又分为盐酸托莫西汀和维生素B6不同比例组合物组。
测定:用MAP-2免疫荧光化学鉴定神经元,并使用BR68-450DL(450定量)酶标仪测定乳酸脱氢酶(LDH),结果见表2。数据处理和统计LDH用SPSS 13.0统计软件,采用多因素方差分析。组间两两比较使用SNK方法,检验水准0.05。
表2本发明所述药物组合物对大鼠脑皮质神经元损伤后不同时间各组LDH检测(n=6,U/L)
由表2结果可见,损伤组与对照组比较有显著差异(P<0.01),各损伤加药治疗组与损伤组比较,其中盐酸托莫西汀和维生素B6比例1∶0.5和1∶4的加药组,差异有显著性意义(P<0.01),表明本发明所述药物组合物能够保护神经元,可对脑皮质神经元损伤起到修复作用。
实施例3:治疗小儿多动症的片剂
配方组成(按1000片计算)
制备方法称取盐酸托莫西汀、维生素B6、甘露醇、淀粉、硬脂酸镁、微粉硅胶,充分混合,加入适量蒸馏水搅拌制粒,过20目筛,干燥,压片,每片约0.3g。
实施例4:治疗小儿多动症的片剂
配方组成(按1000片计算)
制备方法同实施例3。
实施例5:治疗小儿多动症的胶囊剂
配方组成(按1000粒计算)
制备方法:称取盐酸托莫西汀、维生素B6、甘露醇、淀粉、硬脂酸镁、微粉硅胶,充分混合,加入适量蒸馏水搅拌制粒,过20目筛,干燥,装3号胶囊,每粒重约0.3g。
实施例6:治疗小儿多动症的片剂
配方组成(按1000片计算)
制备方法同实施例3。
实施例7:治疗小儿多动症的胶囊剂
配方组成(按1000粒计算)
制备方法同实施例5。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (5)
1.一种治疗小儿多动症的药物组合物,其特征在于,由盐酸托莫西汀和维生素B6组成,所述盐酸托莫西汀和维生素B6的质量比为1:0.5~1:4。
2.根据权利要求1所述组合物,其特征在于,所述盐酸托莫西汀和维生素B6的质量比为1:0.75~1:2。
3.权利要求1或2所述组合物在制备治疗小儿多动症的药物中的应用。
4.一种治疗小儿多动症的药物,其特征在于,由权利要求1或2所述治疗小儿多动症的药物组合物和常规的辅料组合制成。
5.根据权利要求4所述药物,其特征在于,其为片剂、胶囊剂。
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Non-Patent Citations (4)
Title |
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刘云海等.小儿多动症治疗新药:盐酸托莫西汀.《医药导报》.2004,第23卷(第5期),338-339. * |
欧阳杏娟等.盐酸文拉法辛胶囊治疗儿童多动症的疗效观察.《贵阳医学院学报》.2003,第28卷(第6期),544-545. * |
郭艳等.儿童多动症患儿家庭环境及其父母养育方式的探讨.《实用医技杂志》.2005,第12卷(第12期),3702-3703. * |
高磊等.儿童多动症及其影响因素的研究进展.《包头医学院学报》.2011,第27卷(第5期),96-98. * |
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