CN114557960A - 一种治疗蛛网膜下腔出血的药物及其应用 - Google Patents
一种治疗蛛网膜下腔出血的药物及其应用 Download PDFInfo
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Abstract
本发明涉及一种治疗蛛网膜下腔出血的药物,其特征在于所述药物为注射液,所述注射液中含有尼莫地平、磷脂和聚乙二醇,所述磷脂选自DPPC、DPPE和DOPE中的一种或者多种的组合,所述注射液以乙醇和水的组合作为混合溶剂。本发明采用乙醇/水的混合溶剂制备尼莫地平注射液,通过加入特定磷脂,使得尼莫地平的血药浓度时间得以延长,并且能够有效提高治疗蛛网膜下腔出血的疗效。与现有治疗蛛网膜下腔出血的药物相比,具有给药方式简单,治疗效果好以及副作用小等优点。
Description
技术领域
本发明属于医药技术领域,具体涉及一种治疗蛛网膜下腔出血的药物及其应用。
背景技术
蛛网膜下腔出血(subarachnoid hemorrhage,SAH)指脑底部或脑表面的病变血管破裂,血液直接流入蛛网膜下腔引起的一种临床综合征,又称为原发性蛛网膜下腔出血,约占急性脑卒中的10%,是一种非常严重的常见疾病。世界卫生组织调查显示中国发病率约为2.0/10万人年,亦有报道为每年6-20/10万人。还可见因脑实质内、脑室出血、硬膜外或硬膜下血管破裂,血液穿破脑组织流入蛛网膜下腔,称为继发性蛛网膜下腔出血。
SAH典型临床表现为突然发生的剧烈头痛、恶心、呕吐和脑膜刺激征,伴或不伴局灶体征。剧烈活动中或活动后出现爆裂性局限性或全头部剧痛,难以忍受,呈持续性或持续进行性加重,有时上颈段也可出现疼痛。其始发部位常与动脉瘤破裂部位有关。常见伴随症状有呕吐、短暂意识障碍、项背部或辖制疼痛、畏光等。绝大多数病例发病后数小时内出现脑膜刺激征,以颈强直最明显,Kernig征、Brudzinski征可阳性。眼底检查可见视网膜出血、视乳头水肿,约25%的患者可出现精神症状,如欣快、谵妄、幻觉等。还可有癫痫发作、局灶神经功能缺损体征如动眼神经麻痹、失语、单瘫或轻偏瘫、感觉障碍等。部分患者,尤其是老年患者头痛、脑膜刺激征等临床表现常不典型,而精神症状较明显。中脑周围蛛网膜下腔出血的患者症状较轻,CT表现为中脑或脑桥周围脑池积血,血管造影未发现动脉瘤或其他异常,一般不发生再出血或迟发型血管痉挛等情况,临床预后良好。
中国专利申请CN109419801A公开了左旋奥拉西坦在制备预防或治疗蛛网膜下腔出血后早期脑损伤药物的应用。机理研究结果表明,左旋奥拉西坦对蛛网膜下腔出血后的早期脑损伤的作用机制可能与抑制神经元的凋亡和坏死有关,具体可能涉及线粒体途径或caspase途径的SAH后细胞凋亡路径从而起到神经保护作用。此外,左旋奥拉西坦在减轻SAH后的血脑屏障通透性、减轻脑水肿并改善SAH后的神经行为功能缺损方面同样作用明显。
中国授权专利CN103768045B公开了富马酸二甲酯在制备治疗蛛网膜下腔出血后早期脑损伤药物的应用。富马酸二甲酯能够激活Keap1-Nrf2-ARE信号通路,降低了SAH后的EBI脑损伤,减弱EBI发展,同时改善皮质细胞凋亡、神经坏死、脑水肿、血脑屏障损伤,为临床治疗SAH后的EBI提供新的方法。
虽然现有技术中公开了大量可以治疗蛛网膜下腔出血的药物,但是临床上使用最多的仍然是尼莫地平注射液。尼莫地平通过对与钙通道有关的神经元受体和脑血管受体的作用,保护神经元,稳定神经元的功能,改善脑血流,增加脑的缺血耐受力。尼莫地平能明显地降低蛛网膜下腔出血患者的缺血性神经损伤及死亡率。然而,在临床上使用时,尼莫地平需以1~2mg/h的速度慢速滴注,否则病人无法耐受其副作用,即10mg药物所需滴注时间一般需至少5小时,使用时与葡萄糖或生理盐水混合滴注或用特殊的三通输液器与葡萄糖或生理盐水同时滴注,混合液直接输入病人体内。因此,如何制备在体内维持时间长的尼莫地平注射液成为一个新的挑战。
中国授权专利CN101485632B公开了一种尼莫地平脂质微球注射液,按尼莫地平0.08%、注射用卵磷脂0.5%~2.3%、注射用大豆油2%~8%、注射用中链脂肪酸2%~8%、甘油1%~3%、吐温-800.1%~0.2%、油酸钠0.03%~0.05%、注射用水加至100%的质量配比制成。其制备方法包括制备油相、制备水相、制备初乳、匀化、罐装步骤。在本发明的配比中,采用注射用大豆油与注射用中链脂肪酸制备成油相,尼莫地平为脂溶性药物,在油相中溶解度较好,注射用大豆油为主要成分的脂质微球既具有溶剂特性,无毒性,将脂溶性药物引入并溶于乳剂颗粒,随脂质油滴进行代谢、缓慢释放从而维持有效的血药浓度,降低了药物的毒副作用,增加了尼莫地平药物的溶解度、稳定性,提高了载药量,减少了药物的水解。
然而,上述注射液配方复杂,其对于尼莫地平克服血脑屏障不利,由此导致其对于治疗蛛网膜下腔出血的效果有待进一步改进。因此,本发明的目的在于克服上述现有技术的缺陷,提供治疗蛛网膜下腔出血的药物及其应用,该药物在不使用油性溶剂以及表面活性剂的情况下,仍然能够缓慢释放尼莫地平从而维持有效的血药浓度。
发明内容
基于上述背景技术,本发明所要解决的技术问题在于提供一种治疗蛛网膜下腔出血的药物及其应用。为了实现本发明的发明目的,拟采用如下技术方案:
本发明一方面涉及一种治疗蛛网膜下腔出血的药物,其特征在于所述药物为注射液,所述注射液中含有尼莫地平、磷脂和聚乙二醇,所述磷脂选自DPPC、DPPE和DOPE中的一种或者多种的组合,所述注射液以乙醇和水的组合作为混合溶剂。本发明采用乙醇/水的混合溶剂制备尼莫地平注射液,通过加入特定磷脂,使得尼莫地平的血药浓度时间得以延长,并且能够有效提高治疗蛛网膜下腔出血的疗效。
在本发明的一个优选实施方式中,所述注射液中还含有枸橼酸钠和枸橼酸的缓冲体系。
在本发明的一个优选实施方式中,所述尼莫地平、磷脂和聚乙二醇的重量比为1:800~1000:80~120。本发明通过采用上述优选的比例,有助于发挥磷脂和尼莫地平的协同作用。
在本发明的另一个优选实施方式中,所述乙醇和水的重量比为1:8-10。本发明通过降低注射液中乙醇的含量,有助于降低乙醇所导致的副作用。
在本发明的另一个优选实施方式中,所述注射液中不含有油性溶剂和/或除了聚乙二醇以外的表面活性剂。
在本发明的一个优选实施方式中,所述磷脂为DOPE。
本发明另一方面还涉及上述药物的制备方法,其特征在于将磷脂的水分散液与尼莫地平注射液进行超声混合,所述尼莫地平注射液中含有尼莫地平、聚乙醇、枸橼酸钠、枸橼酸、乙醇和水。
在本发明的一个优选实施方式中,所述磷脂水分散液通过将磷脂溶解于氯仿中,减压旋转蒸发在玻璃容器内壁形成膜,然后水,超声分散形成脂质体。
本发明另一方面还涉及上述药物在制备治疗蛛网膜下腔出血的药物中的应用。
在本发明的一个优选实施方式中,所述药物为注射剂。
在本发明的一个优选实施方式中,所述药物用于降低脑含水率和/或提高神经功能。
有益效果
本发明采用乙醇/水的混合溶剂制备尼莫地平注射液,通过加入特定磷脂,使得尼莫地平的血药浓度时间得以延长,并且能够有效提高治疗蛛网膜下腔出血的疗效。与现有治疗蛛网膜下腔出血的药物相比,具有给药方式简单,治疗效果好以及副作用小等优点。而且,本发明的药物在不使用油性溶剂以及表面活性剂的情况下,仍然能够缓慢释放尼莫地平从而维持有效的血药浓度。
附图说明
图1为实验组和阳性对照组中尼莫地平药物动力学实验结果。
具体实施方式
为了进一步理解本发明,下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
如无特殊说明,本发明实施例中所涉及的试剂均为市售产品,均可以通过商业渠道购买获得。
实施例1:
(一)试剂:市售尼莫地平注射液(每毫升注射液含0.2mg尼莫地平,200mg乙醇,170mg聚乙二醇,枸橼酸钠和枸橼酸,注射用水),二棕榈酰磷脂酰胆碱(DPPC)、二棕榈酰基磷脂酰乙醇胺(DPPE)和1,2-二油酸甘油-3-磷脂酰乙醇胺(DOPE)购自Sigma-Aldrich公司。
(二)制备药物:
(1)分别将100mgDPPC、DPPE和DOPE溶解于氯仿中,减压旋转蒸发在玻璃容器内壁形成膜,然后分别加入5mL去离子水,超声分散形成脂质体。
(2)将脂质体与尼莫地平注射液按照体积比1:1超声混合,形成待测药物。
药效学实验
(1)实验动物
健康雄性SD大鼠(体重240~280g)共计50只,由陕西省人民医院实验动物中心提供。通风,饲养温度平均25℃,湿度40%~50%。自由摄食、饮水。
(2)大鼠蛛网膜下腔出血模型的建立
大鼠SAH模型建立:采用异氟醚吸入麻醉方式麻醉大鼠。动物取仰卧位,标记颈前部长约2.0cm切口,逐层切开,分离出左侧颈总动脉、颈内动脉及颈外动脉,电凝细小分支血管,迷你动脉夹临时阻断颈外动脉,5-0尼龙丝线结扎并剪断,临时阻断颈总动脉及颈内动脉,颈外动脉远端切一小口,牵拉颈外动脉,使其尾侧与颈内动脉成一直线。用头端锐利的4-0可吸收缝线从小口处由颈外动脉穿入颈内动脉,直到术者感到有突破感,再向前推进约3mm,表示穿刺线已穿破血管分叉处的血管壁。所有动物术后自由获得食物和水并单独饲养。SAH的严重程度根据量表予以量化。量表以颅底基底池6支血管中蛛网膜下腔出血量为依据。0级:无蛛网膜下腔血;1级:轻度蛛网膜下腔血;2级:中度蛛网膜下腔血;3级:重度蛛网膜下腔血,血栓覆盖了节段内所有动脉。将所有6支血管评分相加,总分18分。选择了中、重度的SAH模型(评分≥8分)作为建模成功的动物,共计30只。
(3)实验分组
实验设计:在这项研究中,建模成功大鼠被随机分为5组,每组6只:(1)阴性对照组(注射生理盐水),(2)阳性对照组(注射市售尼莫地平注射液),(3)DPPC组(注射含DPPC的尼莫地平注射液),(4)DPPE组(注射含DPPE的尼莫地平注射液),(5)DOPE组(注射含DOPE的尼莫地平注射液)。(2)-(5)组中每只大鼠在SAH建模成功后10min内通过尾静脉注射15μg的尼莫地平,阴性对照组注射与阳性对照组等体积的生理盐水
(4)实验结果
A、神经功能评分:在建模成功后24h,根据改良Garcia法评分。评分原则:从自发性活动、四肢运动对称、前脚伸展、攀登、对双侧躯干的接触反应以及触须反应6个方面进行神经功能评分,每项最低为0分,最高为3分,满分为18分,得分越高表示运动神经功能障碍越轻微,反之则越严重。评分采用双盲法,实验结果如表1所示。实验结果表明,加入特定磷脂的尼莫地平注射液相比于阳性对照组,能够更显著的提高神经功能评分,其中,DOPE组的提高程度最明显。
表1神经功能评分结果
B、脑水含量测定:在建模成功后48h处死大鼠。完整取出整脑,立即分成左半球、右半球、小脑和脑干。用精度为0.1mg的天平分别称量脑组织(湿重)。然后,将样品置于烤箱(105℃)中烘干24h,再次分别称重(干重)。脑含水量计算公式:脑含水量(%)=[(湿重-干重)/湿重]×100%,实验结果如表2所示。实验结果表明,加入特定磷脂的尼莫地平注射液相比于阳性对照组,能够更显著的降低脑含水量,其中,DOPE组的下降程度最明显。
表2脑含水量(%)
C、血药浓度变化:每小时检测血浆中活性成分尼莫地平的含量,实验结果如图1所示。实验结果显示,DPPC、DPPE和DOPE都能够在一定程度上延长尼莫地平半衰期,起到缓释的效果,其中,DOPE缓释效果最好。
以上描述了本发明优选实施方式,然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (10)
1.一种治疗蛛网膜下腔出血的药物,其特征在于所述药物为注射液,所述注射液中含有尼莫地平、磷脂和聚乙二醇,所述磷脂选自DPPC、DPPE和DOPE中的一种或者多种的组合,所述注射液以乙醇和水的组合作为混合溶剂。
2.根据权利要求1所述的药物,所述注射液中还含有枸橼酸钠和枸橼酸的缓冲体系。
3.根据权利要求1所述的药物,所述尼莫地平、磷脂和聚乙二醇的重量比为1:800~1000:80~120。
4.根据权利要求1所述的药物,所述乙醇和水的重量比为1:8-10。
5.根据权利要求1所述的药物,所述注射液中不含有油性溶剂和/或除了聚乙二醇以外的表面活性剂。
6.根据权利要求1所述的药物,所述磷脂为DOPE。
7.权利要求1-6任意一项所述药物的制备方法,其特征在于将磷脂的水分散液与尼莫地平注射液进行超声混合,所述尼莫地平注射液中含有尼莫地平、聚乙醇、枸橼酸钠、枸橼酸、乙醇和水。
8.根据权利要求7所述的制备方法,所述磷脂水分散液通过将磷脂溶解于氯仿中,减压旋转蒸发在玻璃容器内壁形成膜,然后水,超声分散形成脂质体。
9.权利要求1-6任意一项所述药物的在制备治疗蛛网膜下腔出血的药物中的应用。
10.根据权利要求9所述的应用,所述药物用于降低蛛网膜下腔出血患者的脑含水率和/或提高蛛网膜下腔出血患者的神经功能。
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