CN111184725B - 一种防治脑梗塞的药物制剂及其制备方法 - Google Patents
一种防治脑梗塞的药物制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种防治脑梗塞的药物制剂及其制备方法，其中所述药物制剂是由如下结构式所示的化合物A、任选的用于防治脑梗塞的其它药物和药学上可接受的载体制成。本发明还提供了一种化合物A在制备用于防治脑梗塞的药物中的用途。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种防治脑梗塞的药物制剂及其制备方法。
背景技术
脑梗塞(cerebral infarction)，又称脑梗死、缺血性脑卒中(cerebral ischemicstroke)，是一种具有极高的病死率和致残率的严重威胁人类生命健康的急性脑血管疾病，通常是指因脑部血流供应障碍，引起局部缺血、缺氧，从而导致的局限性脑组织的缺血性坏死或软化。脑梗塞作为一种突发性脑部疾病，发病急促，多无明显的前驱症状，临床表现以言语障碍、半身不遂、猝然昏倒、不省人事为主要特征。
脑梗塞可以由于动脉狭窄，管腔内逐渐形成血栓而最终阻塞动脉所致。引起脑梗塞的另一常见原因是脑血管内壁上的微小栓子或心脏瓣膜的附壁血栓脱落，流动至脑动脉而发生栓塞。无论是哪种原因引起的脑梗塞，均可发生于任何年龄段，且有随着年龄增长而逐渐上升的趋势，多见于45～70岁中老年人。脑梗塞不但给人类健康和生命造成重大威胁，而且给患者、家庭及社会带来极大的痛苦和沉重的负担。
脑梗塞属疑难病症，目前在医学上一直缺乏有效的治疗措施，临床上能够用于治疗脑梗塞的手段仅有溶栓药、外科手术等少数种类，且临床使用时间窗极为短暂。鉴于脑梗塞的严重危害性，在本领域中还存在着对防治脑梗塞的药物的未满足的需求。
发明内容
本发明所要解决的技术问题是寻找防治脑梗塞的有效药物及其制备方法。
本发明的发明人基于以下预料不到的发现而完成了本发明：如以下结构式所示的N-[(4aR,7aS)-6-[5-氟-4-(1-羟基-1-甲基-乙基)-6-甲基-嘧啶-2-基]-7a-苯基-4,4a,5,7-四氢吡咯并[3,4-d][1,3]噻嗪-2-基]苯甲酰胺盐酸盐(以下简称化合物A)
具有预防和/或治疗脑梗塞的用途。基于此，发明人研究和开发了适合于防治脑梗塞的药物制剂及其制备方法。
为此，在一个方面中，本发明提供了一种防治脑梗塞的药物制剂，其中所述药物制剂是由化合物A、任选的用于防治脑梗塞的其它药物和药学上可接受的载体制成。
在一个方面中，所述药物制剂中含有用于防治脑梗塞的其它药物，所述药物选自尿激酶、肝素钠、尼莫地平、阿司匹林、丹参酮IIA中的一种或多种。
在一个方面中，所述药物制剂中不含有用于防治脑梗塞的其它药物。
在一个方面中，所述药物制剂是适用于静脉内注射的乳剂的形式，并且所述药学上可接受的载体由油酸乙酯、卵磷脂、泊洛沙姆188、吐温80、丙二醇和注射用水组成。
在一个方面中，在每100ml所述乳剂中含有：
其余为注射用水。
在一个方面中，在每100ml所述乳剂中含有：
其余为注射用水。
在一个方面中，所述药物制剂的制备方法包括以下步骤：
(1)将化合物A、卵磷脂、泊洛沙姆188、吐温80、丙二醇和占总体积50％-70％的量的注射用水在加热搅拌的条件下充分混合至完全溶解，形成水相；
(2)在水相保持加热搅拌的条件下，将油酸乙酯缓慢滴加至水相中，混合完毕后继续在加热搅拌的条件下保持10-20分钟，然后加入余量的注射用水定容，得到初乳；
(3)将初乳通过高压乳匀机乳化2-4次，先后通过0.8微米和0.22微米的微孔滤膜过滤，分装于适当的容器中，充入惰性气体，封口即得。
在一个方面中，所述步骤(1)和(2)中的加热搅拌的条件是指温度为50-70℃、搅拌速度为4000-8000转/分钟的条件。
本发明所使用的化合物A先前描述于专利文献WO2013/151832A1中。该专利文献一般地涉及作为β-位点淀粉样蛋白前体蛋白切割酶(β-site amyloid precursor protein-cleaving enzyme；BACE)的有效抑制剂的新颖的四氢吡咯并噻嗪化合物，据信所述化合物可以用于抑制BACE和抑制Aβ肽的产生，从而用于治疗阿尔茨海默氏病或用于预防轻度认知缺损至阿尔茨海默氏病的进展。在该专利文献中，化合物A的化学式、结构式和合成方法公开于实施例22中。但是，该专利文献并未提及所述化合物具有任何防治脑梗塞方面的药理学活性，而这构成了本发明的意外发现。
本发明的另一方面还提供了一种化合物A在制备用于防治脑梗塞的药物中的用途。
在一个方面中，所述药物是如上面所描述的药物制剂。
具体实施方式
下面结合具体实施例对本发明的优选实施方案及其效果进行进一步的详细描述。但是，应当理解，这些优选实施方案只是用于进一步说明本发明的特征和优点，而绝非对本发明的权利要求构成任何限制。
实施例1
本实施例所述的防治脑梗塞的药物制剂中的各组分及其用量如下表中所示：
| 组分 | 用量 |
| 化合物A | 2.5g |
| 油酸乙酯 | 20g |
| 卵磷脂 | 1.2g |
| 泊洛沙姆188 | 1.2g |
| 吐温80 | 5g |
| 丙二醇 | 2g |
| 注射用水 | 加至100ml |
该药物制剂的制备方法为：
(1)将化合物A、卵磷脂、泊洛沙姆188、吐温80、丙二醇和60mL注射用水在温度为60℃、搅拌速度为6000转/分钟的条件下充分混合至完全溶解，形成水相；
(2)在水相保持温度为60℃、搅拌速度为6000转/分钟的条件下，将油酸乙酯缓慢滴加至水相中，混合完毕后继续在温度为60℃、搅拌速度为6000转/分钟的条件下保持15分钟，然后加入余量的注射用水定容，得到初乳；
(3)将初乳通过高压乳匀机乳化3次，先后通过0.8微米和0.22微米的微孔滤膜过滤，分装于容量为10mL的安瓿中，充入氮气，封口即得。
实施例2
本实施例所述的防治脑梗塞的药物制剂中的各组分及其用量如下表中所示：
| 组分 | 用量 |
| 化合物A | 5g |
| 油酸乙酯 | 20g |
| 卵磷脂 | 1.2g |
| 泊洛沙姆188 | 1.2g |
| 吐温80 | 5g |
| 丙二醇 | 2g |
| 注射用水 | 加至100ml |
该药物制剂的制备方法为：
(1)将化合物A、卵磷脂、泊洛沙姆188、吐温80、丙二醇和60mL注射用水在温度为60℃、搅拌速度为6000转/分钟的条件下充分混合至完全溶解，形成水相；
(2)在水相保持温度为60℃、搅拌速度为6000转/分钟的条件下，将油酸乙酯缓慢滴加至水相中，混合完毕后继续在温度为60℃、搅拌速度为6000转/分钟的条件下保持15分钟，然后加入余量的注射用水定容，得到初乳；
(3)将初乳通过高压乳匀机乳化3次，先后通过0.8微米和0.22微米的微孔滤膜过滤，分装于容量为10mL的安瓿中，充入氮气，封口即得。
实施例3
本实施例所述的防治脑梗塞的药物制剂中的各组分及其用量如下表中所示：
| 组分 | 用量 |
| 化合物A | 10g |
| 油酸乙酯 | 20g |
| 卵磷脂 | 1.2g |
| 泊洛沙姆188 | 1.2g |
| 吐温80 | 5g |
| 丙二醇 | 2g |
| 注射用水 | 加至100ml |
该药物制剂的制备方法为：
(1)将化合物A、卵磷脂、泊洛沙姆188、吐温80、丙二醇和60mL注射用水在温度为60℃、搅拌速度为6000转/分钟的条件下充分混合至完全溶解，形成水相；
(2)在水相保持温度为60℃、搅拌速度为6000转/分钟的条件下，将油酸乙酯缓慢滴加至水相中，混合完毕后继续在温度为60℃、搅拌速度为6000转/分钟的条件下保持15分钟，然后加入余量的注射用水定容，得到初乳；
(3)将初乳通过高压乳匀机乳化3次，先后通过0.8微米和0.22微米的微孔滤膜过滤，分装于容量为10mL的安瓿中，充入氮气，封口即得。
实施例4
本实验的目的是利用糖氧剥夺(Oxygen and glucose deprivation,OGD)离体脑缺血模型，考察本发明的化合物A对神经元的保护作用。
本实验的实验方法如下：
参考“PC12细胞中持续性氧糖剥夺模型的建立”，《军事医学》，第35卷第3期，第189-192页，2011年3月公开的方法，利用PC12细胞建立持续性糖氧剥夺离体脑缺血模型。具体而言，将处于对数生长期的PC12细胞按照6×105个细胞/ml的密度(体积100μl/孔)接种到无菌的96孔板中，置于增湿培养箱中培养24h后取出培养板，用37℃预热的PBS清洗2次(5min/次)以除去葡萄糖。然后，向96孔板的每个孔中加入含有5×104U/ml青霉素和链霉素的无糖无血清培养基(100μl/孔，其中含有或不含有如下表1所示的供试药物)；另设对照组，向其96孔板的每个孔中加入含有葡萄糖(1.0g/L)、10％胎牛血清和5×104U/ml青霉素和链霉素的培养基(100μl/孔)。最后，将96孔板置于37℃培养箱(氧糖剥夺组的96孔板置于培养箱内的充入95％氮气和5％二氧化碳的混合气体的低氧小室)中温育30分钟。温育结束后，移除培养基，向96孔板的每孔中加入10μL的MTT(浓度为5mg/mL的PBS溶液)，并放回培养箱中继续培养3小时，然后弃去培养基，加入100μL的DMSO，于37℃水浴振荡30分钟，待生成的紫色结晶完全溶解后，用酶标仪测定波长为570纳米处的吸光度值(OD570)，并用糖氧剥夺组的OD570值占对照组的OD570值的百分比反映PC12细胞的存活率。
本实验的存活率的数据统计列于表1中。
表1不同的供试药物处理下PC12细胞的存活率
| 药物种类 | 药物浓度 | 存活率(％) |
| - | - | 26.3±4.3 |
| 尼莫地平 | 5mg/ml | 49.9±6.1 |
| 丹参酮IIA | 5mg/ml | 57.2±5.9 |
| 阿司匹林 | 5mg/ml | 43.2±7.2 |
| 化合物A | 5mg/ml | 68.2±9.7 |
注：每种供试药物设12个复孔；结果表示为均值±标准差。
通常来说，当在糖氧剥夺离体脑缺血模型中采用某种药物处理后，PC12细胞的存活率越高，则反映出该药物对于脑梗塞所致的神经细胞损伤具有更好的保护作用。从以上结果来看，化合物A对糖氧剥夺的PC12细胞具有显著的神经保护作用，且在相同浓度下该神经保护作用优于参比的其它供试药物。
实施例5
本实验的目的是利用大鼠脑缺血再灌注损伤模型考察本发明的药物制剂对脑梗塞的药理学活性。
1、实验动物
本实验采用体重为240g±10g的雄性成年SD大鼠。将动物在23-25℃室温、50％相对湿度和每12小时切换光照和黑暗的条件下适应环境两天。为大鼠提供可自由获取的清洁食物和饮用水。
2、大鼠脑缺血再灌注损伤模型的建立
将大鼠采用腹腔注射25％乌拉坦溶液进行麻醉。然后，将大鼠以侧卧位固定于手术台上，做一颈部正中切口，暴露出颈总动脉，并分离颈内动脉。然后，夹闭颈总动脉和颈内动脉，经颈外动脉主干切口将尼龙线向颈内动脉入颅方向缓慢推进，到达较细的大脑前动脉内，阻断大脑中动脉以使得局部血流完全阻断。90分钟后，拔出尼龙线，扎紧动脉残端，缝合伤口，完成大鼠脑缺血再灌注损伤模型的建立。
3、给药方案
将造模后的大鼠随机分为模型对照组、实施例1组、实施例2组、实施例3组，每组20只。另取20只麻醉后不闭塞大脑中动脉的大鼠用作假手术组。
各实验组给药方案如下：
实施例1组、实施例2组、实施例3组：造模结束后，立即通过尾静脉内注射分别给予实施例1、实施例2、实施例3的药物制剂，剂量为1.0mL/kg体重，之后每天以相同方式给药1次，连续给药3天。
模型对照组：造模结束后，立即通过尾静脉内注射给予生理盐水，之后每天以相同方式给药1次，连续给药3天。
假手术组：同模型对照组。
4、观察指标
(1)Bederson神经功能缺损评分：
实验结束当日，采用Bederson JB等人，Rat middle cerebral arteryocclusion:evaluation of the model and development of a neurologicexamination.Stroke.1986；17(3):472-476中的方法，对大鼠的行为缺陷进行神经功能缺损评分：
(2)脑缺血梗死体积和含水量的测量：
最后，断头处死除假手术组之外的各组大鼠。随机挑选5只大鼠，取全脑，称取大脑湿重，做切片。将切片置于2％氯化三苯基四氮唑(TFC)溶液中染色30min，固定，分离苍白区(梗死区)和非苍白区(正常区)，以梗死区范围重量占脑重量的百分比作为脑梗死范围。
随机挑选另外5只大鼠，取全脑，将脑组织置于110℃烘箱中干燥至恒重，称其干重，计算脑含水量。脑含水量＝(脑组织湿重－脑组织干重)/脑组织湿重×100％。
5、结果
实验统计结果参见下表1-2。
表1各组大鼠的Bederson神经功能缺损评分
| 组别 | 评分 |
| 假手术组 | 0 |
| 模型对照组 | 3.78±0.53 |
| 实施例1组 | 2.96±0.68 |
| 实施例2组 | 2.27±0.61* |
| 实施例3组 | 1.39±0.46* |
注：结果表示为均值±标准差，*表示与模型对照组比较，p<0.05。
表2各组大鼠的脑缺血梗死体积和含水量
注：结果表示为均值±标准差，**表示与模型对照组比较，p<0.05。
以上结果提示，本发明的药物制剂能够明显改善脑缺血再灌注损伤模型大鼠的神经功能缺损程度，减少脑缺血梗死体积和含水量，并且这种改善以实施例3的效果最为显著，说明本发明的药物制剂对脑梗死的药理学活性与所述药物制剂中的化合物A的含量呈现出一定的正相关关系。总之，以上结果指示，本发明所述的药物制剂可用于防治脑梗塞的用途。
Claims (1)
1.化合物A在制备用于防治脑梗塞的药物制剂中的用途，其中所述药物制剂是由化合物A和药学上可接受的载体制成，其中所述化合物A是如以下结构式所示的N-[(4aR,7aS)-6-[5-氟-4-(1-羟基-1-甲基-乙基)-6-甲基-嘧啶-2-基]-7a-苯基-4,4a,5,7-四氢吡咯并[3,4-d][1,3]噻嗪-2-基]苯甲酰胺盐酸盐
并且其中所述药物制剂是适用于静脉内注射的乳剂的形式，并且所述药学上可接受的载体由油酸乙酯、卵磷脂、泊洛沙姆188、吐温80、丙二醇和注射用水组成，并且其中所述药物制剂在每100ml所述乳剂中含有：
其余为注射用水，并且其中所述药物制剂的制备方法包括以下步骤：
(1)将化合物A、卵磷脂、泊洛沙姆188、吐温80、丙二醇和占总体积50％-70％的量的注射用水在加热搅拌的条件下充分混合至完全溶解，形成水相；
(2)在水相保持加热搅拌的条件下，将油酸乙酯缓慢滴加至水相中，混合完毕后继续在加热搅拌的条件下保持10-20分钟，然后加入余量的注射用水定容，得到初乳；
(3)将初乳通过高压乳匀机乳化2-4次，先后通过0.8微米和0.22微米的微孔滤膜过滤，分装于适当的容器中，充入惰性气体，封口即得，其中所述步骤(1)和(2)中的加热搅拌的条件是指温度为50-70℃、搅拌速度为4000-8000转/分钟的条件。
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