CN108653305B - 以胞内渗透压为靶点治疗脑水肿的药物组合 - Google Patents
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- CN108653305B CN108653305B CN201810479838.1A CN201810479838A CN108653305B CN 108653305 B CN108653305 B CN 108653305B CN 201810479838 A CN201810479838 A CN 201810479838A CN 108653305 B CN108653305 B CN 108653305B
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Abstract
本发明涉及一种治疗脑水肿的药物组合物及其制备方法。该复方药物组合物的活性成分包括番泻苷A、斑蝥素或其衍生物、尼莫地平或硝苯地平、马来酸桂哌齐特和依达拉奉。本发明通过细胞实验,寻找能降低脑细胞内胶体渗透压和晶体渗透压从而治疗脑水肿的活性药物及其组合,为临床提供新的药用用途。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种治疗脑水肿的药物组合物及其制备方法。
背景技术
脑水肿是一种由外源性或内源性致病因素刺激的高危病理状态,表现为脑实质内液体异常增加,脑容量增大,颅内压升高。颅内压的升高能导致脑组织缺血、缺氧,造成神经细胞不可逆的功能损伤,甚至发生脑疝以至死亡。根据发生机制,脑水肿分为4种类型:1)血管源性脑水肿;2)细胞毒性脑水肿;3)间质性脑水肿;4)渗透压性脑水肿。若同时合并两种机制以上,称之为混合性脑水肿。血管源性脑水肿的主要机制为静脉压力升高、紧密连接蛋白分解、血脑屏障破坏,最终渗出液及细胞外液进入脑实质;细胞毒性水肿的主要机制为ATP离子泵破坏、细胞内的Na+堆积,造成细胞内渗透压升高;间质性脑水肿的主要机制为脑脊液回流不畅、脑室内脑脊液压力过高,脑室表面结构及通透性改变,脑脊液经过室管膜向脑室周围白质渗出;渗压性脑水肿的主要机制为各种原因导致的细胞外液渗透压降低,水分向脑细胞内转移。综上所述,脑细胞与其细胞外液之间的渗透压差异常,是脑水肿发生的重要机制。
临床上用于治疗脑水肿的药物繁多,机制复杂,但是大多数药物所起作用有限,疗效不确切。按照功能可以分为:1)渗透性药物,代表药物有甘露醇、甘油果糖、白蛋白、高渗盐水、吡拉西坦等;2)非渗透性药物,如七叶皂甙钠等;3)肾上腺皮质激素,如地塞米松等;4)利尿剂,如呋塞米等;5)钙离子通道拮抗剂,如尼莫地平、硝苯地平等;6)降低脑细胞代谢药物,如巴比妥类药等;7)自由基清除剂,如维生素C等;8)神经内分泌治疗,代表药物有阿片受体拮抗剂、兴奋性氨基酸拮抗剂、凝血酶抑制剂、促甲状腺素释放激素类似物、脑素钠、胰蛋白酶抑制剂、神经节苷脂等;9)水通道蛋白调节剂等。此外,中医药在治疗脑水肿方面有着明确的疗效,具有调节渗透压、抗自由基、改善微循环及激素样等方面作用。
渗透压是包括细胞内液在内的体液的重要物理特性之一,分为晶体/离子渗透压和胶体渗透压。晶体渗透压是低分子物质,如无机离子、尿素、葡萄糖等所形成的渗透压;胶体渗透压是高分子物质,如蛋白质等所产生的渗透压。多种离子相关因素被认为至关重要的参与了神经星形胶质细胞胞内渗透压力的调节和水的进出,是细胞毒性和渗透压性水肿的重要调控机制。同时,当细胞内存在大量游离的蛋白质颗粒时,能构成直径为1-100nm的胞浆分散介质,形成胶体溶液,产生及其相关的胶体渗透压。这一胞内力学现象,与血浆胶体渗透压极为类似。微丝或微管结构的解聚,能诱导肌球蛋白和微管蛋白颗粒的大量生成,继而导致胞内渗透压的增加,诱导中间纤维丝GFAP牵拉张力上调以及细胞体积的增大,成为细胞内渗透压增加、细胞容积膨胀和水肿发生的重要调控机制。
Cofilin是代表性肌动蛋白解聚因子,stathmin1是常见微管蛋白解聚因子。Profilin是小分子肌动蛋白结合因子,能诱导肌球蛋白与微丝聚合延伸。微管相关蛋白家族(MAP)能与微管结合,促进微管组装和稳定性。因此,肌球蛋白和微管蛋白颗粒在胞内的分布受微丝和微管解聚和聚合的调节。据此,我们开发了以抑制肌球蛋白和微管蛋白颗粒解聚和促进其聚合的组合药物,降低胞内胶体渗透压升高,抑制水肿及脑水肿的发生。
发明内容
脑水肿的发生机制复杂,临床上用于治疗脑水肿的药物种类繁多,但是多数药物疗效不确切。本发明针对脑水肿发生的关键病理机制——脑细胞与其细胞外液之间的渗透压差异常,以脑细胞内的胶体渗透压和晶体渗透压为治疗靶点,筛选出治疗脑水肿的最佳药物组合。
本发明的首要目的在于提供一种具有治疗脑水肿作用的复方药物组合物;该复方药物组合物由番泻苷A(Sennoside A)、斑蝥素(Cantharidin)或其衍生物、尼莫地平(Nimodipine)或硝苯地平(Nifedipine)、马来酸桂哌齐特(CinepazideMaleate)和依达拉奉(Edaravone)组成,其中依达拉奉为选择性改善脑损伤药物。
本发明的另一目的在于提供一种上述具有治疗脑水肿作用的复方药物组合物的制备方法。
本发明的再一目的在于提供一种上述具有治疗脑水肿作用的复方药物组合物的应用。
为实现上述目的,本发明提供的技术方案是:
一种具有治疗脑水肿作用的复方药物组合物,该复方药物组合物的活性成分包括番泻苷A、斑蝥素或其衍生物、尼莫地平或硝苯地平、马来酸桂哌齐特和依达拉奉。
进一步的,所述复方药物组合物的浓度分别为:番泻苷A(10-100μM)、斑蝥素或其衍生物(1-5μM)、尼莫地平或硝苯地平(5-30μM)、马来酸桂哌齐特(1-100μM)和依达拉奉(5-100μM)。
优选的,所述复方药物组合物的浓度分别为:番泻苷A(100μM)、斑蝥素或其衍生物(2μM)、尼莫地平或硝苯地平(30μM)、马来酸桂哌齐特(7.5μM)和依达拉奉(50μM)。
该复方药物组合物还含有药物上可接受的载体。
所述的具有治疗脑水肿作用的复方药物组合物的制备方法,包括以下步骤:
(1)在无菌操作间中按照浓度比例称取各原料,备用;
(2)将番泻苷A、斑蝥素或其衍生物、尼莫地平或硝苯地平、马来酸桂哌齐特研磨成粉末后在25-35℃温度下混合均匀,得混合物A;
(3)将依达拉奉研磨成粉末后在30-35℃温度下混合均匀,得混合物B;
(4)将上述混合物A、混合物B混合均匀,放入5-15℃温度下静置20-30min,即得复方药物组合物;
(5)复方药物组合物放入2-8℃温度下保存。
该复方药物组合物有注射剂、散剂、片剂、颗粒剂、胶囊剂、溶液剂和混悬剂共七种基本剂型,在该复方药物组合物制作成不同剂型时还添加有赋形剂、增塑剂、溶剂、成膜材料。
本发明保护所述的复方药物组合物在治疗水肿中的应用。
进一步的,所述应用为包括人在内的哺乳动物的脑水肿。
进一步的,所述应用为包括人在内的哺乳动物的除脑水肿以外的机体其他组织水肿。
进一步的,使用复方药物组合物治疗之后,可以选择性给予适量高渗溶液辅助治疗,有利于维持细胞容积的稳定。
与现有技术相比,本发明的有益效果是:
本发明在对脑细胞内胶体渗透压和晶体渗透压产生机制的研究中发现,通过抑制微丝和微管解聚、稳定微丝和微管、阻滞钙通道等方法,可以降低脑细胞内胶体渗透压和晶体渗透压,从而有效的减轻脑水肿。其中,番泻苷A是Cofilin抑制剂;斑蝥素或其衍生物是PP2A选择性抑制剂,也是Stathmin抑制剂;尼莫地平、硝苯地平和马来酸桂哌齐特是钙离子内流抑制剂,能抑制PP2B,也能抑制Stathmin活性;依达拉奉是自由基还原剂,能保护缺血缺氧诱导的细胞损伤。
本发明通过细胞实验,寻找能降低脑细胞内胶体渗透压和晶体渗透压,从而治疗脑水肿的活性药物及其组合,为临床提供新的药用用途。本发明以降低脑细胞内胶体渗透压和晶体渗透压为治疗靶点用于脑水肿的药物及治疗方法尚未见文献报道。
将番泻苷A、斑蝥素或其衍生物、尼莫地平或硝苯地平、马来酸桂哌齐特和依达拉奉组合给药,特别是其浓度分别为100μM、2μM、30μM、7.5μM和50μM时,具有更好地治疗脑水肿的效果。
附图说明
图1:浓度范围为10-100μM的番泻苷A降低细胞内胶体渗透压和晶体渗透压的效果示意图。
图2:浓度范围为2.5-50μM的斑蝥素降低细胞内胶体渗透压和晶体渗透压的效果示意图。
图3:浓度范围为2.5-50μM的尼莫地平降低细胞内胶体渗透压和晶体渗透压的效果示意图。
图4:浓度范围为5-100μM的依达拉奉降低细胞内胶体渗透压和晶体渗透压的效果示意图。
图5:浓度范围为1-100μM的马来酸桂哌齐特降低细胞内胶体渗透压和晶体渗透压的效果示意图。
图6:两种药物联用降低细胞内胶体渗透压和晶体渗透压的效果示意图。
图7:三种药物联用降低细胞内胶体渗透压和晶体渗透压的效果示意图。
图8:三种及四种药物联用降低细胞内胶体渗透压和晶体渗透压的效果示意图。
图9:五种药物联用降低细胞内胶体渗透压和晶体渗透压的效果示意图。
具体实施方式
下面结合具体实施例对本发明作进一步说明。
实施例1
一种具有治疗脑水肿作用的复方药物组合物,包括以下重量份数(Mol)的原料组成:番泻苷A 100份、斑蝥素2份、尼莫地平30份、马来酸桂哌齐特7.5份和依达拉奉50份。
一种具有治疗脑水肿作用的复方药物组合物的制备方法,包括以下步骤:
(1)在无菌操作间中按照浓度比例称取各原料,备用;
(2)将番泻苷A、斑蝥素、尼莫地平、马来酸桂哌齐特研磨成粉末后在25-35℃温度下混合均匀,得混合物A;
(3)将依达拉奉研磨成粉末后在30-35℃温度下混合均匀,得混合物B;
(4)将上述混合物A、混合物B混合均匀,放入5-15℃温度下静置20-30min,即得复方药物组合物;
(5)复方药物组合物放入2-8℃温度下保存;
(6)用胶囊填充机进行填充,制备得胶囊。
上述一种具有治疗脑水肿作用的复方药物组合物可以用于治疗成年人脑水肿。
实施例2
一种具有治疗脑水肿作用的复方药物组合物,包括以下重量份数(Mol)的原料组成:番泻苷A 50份、去甲斑蝥素2份、尼莫地平20份、马来酸桂哌齐特10份和依达拉奉10份。
一种具有治疗脑水肿作用的复方药物组合物的制备方法,包括以下步骤:
(1)在无菌操作间中按照浓度比例称取各原料,备用;
(2)将番泻苷A、去甲斑蝥素、尼莫地平、马来酸桂哌齐特研磨成粉末后在25-35℃温度下混合均匀,得混合物A;
(3)将依达拉奉研磨成粉末后在30-35℃温度下混合均匀,得混合物B;
(4)将上述混合物A、混合物B混合均匀,放入5-15℃温度下静置20-30min,即得复方药物组合物;
(5)复方药物组合物放入2-8℃温度下保存。
上述一种具有治疗脑水肿作用的复方药物组合物可以用于治疗昆明小鼠脑水肿。
实施例3
一种具有治疗脑水肿作用的复方药物组合物,包括以下重量份数(Mol)的原料组成:番泻苷A 75份、斑蝥素2份、硝苯地平25份、马来酸桂哌齐特5份和依达拉奉15份。
一种具有治疗脑水肿作用的复方药物组合物的制备方法,包括以下步骤:
(1)在无菌操作间中按照浓度比例称取各原料,备用;
(2)将番泻苷A、斑蝥素、硝苯地平、马来酸桂哌齐特研磨成粉末后在25-35℃温度下混合均匀,得混合物A;
(3)将依达拉奉研磨成粉末后在30-35℃温度下混合均匀,得混合物B;
(4)将上述混合物A、混合物B混合均匀,放入5-15℃温度下静置20-30min,即得复方药物组合物;
(5)复方药物组合物放入2-8℃温度下保存。
上述一种具有治疗脑水肿作用的复方药物组合物可以用于治疗恒河猴脑水肿。
对比例1
一种具有治疗脑水肿作用的复方药物组合物,包括以下重量份数(Mol)的原料组成:番泻苷A100份、斑蝥素2份和依达拉奉50份。
一种具有治疗脑水肿作用的复方药物组合物的制备方法,包括以下步骤:
(1)在无菌操作间中按照浓度比例称取各原料,备用;
(2)将番泻苷A、斑蝥素研磨成粉末后在25-35℃温度下混合均匀,得混合物A;
(3)将依达拉奉研磨成粉末后在30-35℃温度下混合均匀,得混合物B;
(4)将上述混合物A、混合物B混合均匀,放入5-15℃温度下静置20-30min,即得复方药物组合物;
(5)复方药物组合物放入2-8℃温度下保存;
(6)用胶囊填充机进行填充,制备得胶囊
上述一种具有治疗脑水肿作用的复方药物组合物可以用于治疗成年人脑水肿。
对比例1中未添加尼莫地平和马来酸桂哌齐特。
对比例2
一种具有治疗脑水肿作用的复方药物组合物,包括以下重量份数(Mol)的原料组成:番泻苷A 100份、斑蝥素2份、尼莫地平30份、马来酸桂哌齐特7.5份和依达拉奉10份。
一种具有治疗脑水肿作用的复方药物组合物的制备方法,包括以下步骤:
(1)在无菌操作间中按照浓度比例称取各原料,备用;
(2)将番泻苷A、斑蝥素、尼莫地平、马来酸桂哌齐特研磨成粉末后在25-35℃温度下混合均匀,得混合物A;
(3)将依达拉奉研磨成粉末后在30-35℃温度下混合均匀,得混合物B;
(4)复方药物组合物放入2-8℃温度下保存。
上述一种具有治疗脑水肿作用的复方药物组合物可以用于治疗昆明小鼠脑水肿。
对比例2中未在5-15℃温度下静置20-30min。
八、主要药效试验
本发明具有降低脑细胞胶体渗透压和晶体渗透压、治疗脑细胞缺血损伤的作用,用于治疗包括人在内的哺乳动物的脑水肿疾病。以下通过主要药效学实验对本发明进一步说明。
1.番泻苷A、斑蝥素、尼莫地平、马来酸桂哌齐特和依达拉奉分别对谷氨酸(Glutamic acid)诱导的神经胶质细胞水肿模型中胶体渗透压和晶体渗透压的影响
使用浓度为1mM的谷氨酸刺激神经胶质细胞2小时,制造水肿模型。接着分别给予不同浓度梯度的药物,15分钟后,在4℃条件下,离心沉淀细胞,弃上清培养基,保留细胞沉淀,采用超速破碎15-30秒。40,000g离心15min,吸取上清,即细胞质(20-40μl)。分别测量其胶体渗透压和晶体渗透压。
结果表明,番泻苷A在较低剂量(10μM)时表现出显著的降晶体渗透压作用,当浓度较高(100μM)时也可以表现出降胶体渗透压的作用,但此时晶体渗透压下降不明显;斑蝥素有较强的肝肾毒性,故用量宜低,在较低剂量(2μM)时表现为降胶体渗透压的作用,晶体渗透压与对照组基本持平;尼莫地平在30μM时显著地降低晶体渗透压,胶体渗透压也有明显下降;马来酸桂哌齐特在10μM时显著地降低晶体渗透压和胶体渗透压,但是在与其他四药联用时,马来酸桂哌齐特的最佳浓度为7.5μM;依达拉奉在50μM时显著地降低胶体渗透压,晶体渗透压也有明显下降。
2.番泻苷A、斑蝥素、尼莫地平、马来酸桂哌齐特和依达拉奉联合使用对谷氨酸诱导的神经胶质细胞水肿模型中胶体渗透压和晶体渗透压的影响。
结果表明,两药联用,番泻苷A(100μM)和尼莫地平(30μM)能有效降低晶体和胶体渗透压。注释:番泻苷A(Sen);尼莫地平(NMDP);斑蝥素(Can,2μM)
结果表明,三药联用,番泻苷A(100μM)、尼莫地平(30μM)和斑蝥素(2μM)能有效降低晶体和胶体渗透压。注释:番泻苷A(Sen);尼莫地平(NMDP);斑蝥素(Can)
结果表明,四药联用,番泻苷A(100μM)、尼莫地平(30μM)、斑蝥素(2μM)和依达拉奉(50μM)能有效降低晶体和胶体渗透压,同时对缺血诱导的脑细胞损伤有一定的保护作用。注释:番泻苷A(Sen);尼莫地平(NMDP);斑蝥素(Can);依达拉奉(ED)。
结果表明,五药联用,番泻苷A(100μM)、尼莫地平(30μM)、马来酸桂哌齐特(7.5μM)、斑蝥素(2μM)和依达拉奉(50μM)能有效降低晶体和胶体渗透压,同时对缺血诱导的脑细胞损伤有一定的保护作用。注释:番泻苷A(Sen);尼莫地平(NMDP);马来酸桂哌齐特(CM);斑蝥素(Can);依达拉奉(ED)。
以上所述,仅是本发明的较佳实施例,并非对本发明作任何形式上的限制,任何熟悉本专业的技术人员,在不脱离本发明技术方案范围内,依据本发明的技术实质,对以上实施例所作的任何简单的修改、等同替换与改进等,均仍属于本发明技术方案的保护范围之内。
Claims (10)
1.一种具有治疗脑水肿作用的复方药物组合物,其特征在于:该复方药物组合物的活性成分包括番泻苷A、斑蝥素、尼莫地平或硝苯地平、马来酸桂哌齐特和依达拉奉;所述复方药物组合物的浓度分别为:番泻苷A 10-100μM、斑蝥素1-5μM、尼莫地平或硝苯地平5-30μM、马来酸桂哌齐特1-100μM和依达拉奉5-100μM。
2.根据权利要求1所述的具有治疗脑水肿作用的复方药物组合物,其特征在于:所述复方药物组合物的浓度分别为:番泻苷A 100μM、斑蝥素2μM、尼莫地平或硝苯地平30μM、马来酸桂哌齐特7.5μM和依达拉奉50μM。
3.根据权利要求1所述的具有治疗脑水肿作用的复方药物组合物,其特征在于:该复方药物组合物还含有药物上可接受的载体。
4.权利要求1所述的具有治疗脑水肿作用的复方药物组合物的制备方法,包括以下步骤:
在无菌操作间中按照浓度比例称取各原料,备用;
将番泻苷A、斑蝥素、尼莫地平或硝苯地平、马来酸桂哌齐特研磨成粉末后在25-35℃温度下混合均匀,得混合物A;
将依达拉奉研磨成粉末后在30-35℃温度下混合均匀,得混合物B;
将上述混合物A、混合物B混合均匀,放入5-15℃温度下静置20-30min,即得复方药物组合物;
复方药物组合物放入2-8℃温度下保存。
5.根据权利要求4所述的具有治疗脑水肿作用的复方药物组合物,其特征在于:该复方药物组合物有注射剂、散剂、片剂、颗粒剂、胶囊剂、溶液剂和混悬剂。
6.根据权利要求4所述的具有治疗脑水肿作用的复方药物组合物,其特征在于:
在该复方药物组合物制作成不同剂型时还添加有增塑剂、溶剂、成膜材料。
7.权利要求1所述的复方药物组合物作为制备治疗脑水肿药物的应用。
8.根据权利要求7所述的复方药物组合物作为制备治疗脑水肿药物的应用,其特征在于:应用于哺乳动物的脑水肿。
9.根据权利要求8所述的复方药物组合物作为制备治疗脑水肿药物的应用,其特征在于:应用于人的脑水肿。
10.根据权利要求7所述的复方药物组合物作为制备治疗脑水肿药物的应用,其特征在于:使用复方药物组合物治疗之后,选择性给予适量高渗溶液,平衡细胞内外渗透压差,改善脑水肿治疗效果。
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