CN108524490A - 一种预防和治疗脑中风的药物组合物 - Google Patents
一种预防和治疗脑中风的药物组合物 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
本发明公开一种预防和治疗脑中风的药物组合物,属于医药技术领域。本发明所述药物组合物由灯盏乙素苷元和高车前素组成,其中,灯盏乙素苷元的质量百分比为50~90%,高车前素的质量百分比为10~50%,该组合物与符合药用要求的辅料制成各种剂型的药物。本发明所制成的药物组合对治疗和预防脑中风具有更好的疗效,优于灯盏乙素和单体给药,生物利用度高、用量小,且能快速进入靶器官发挥药效。
Description
技术领域
本发明涉及一种预防和治疗脑中风的药物组合物,属于医药技术领域。
背景技术
脑中风是一种常见的脑血管疾病,是世界第二大死亡原因,也是致残的主要原因。脑中风的主要特征是具有很高的死亡率、复发率、发病率、致残率,所以医学界把它同冠心病、癌症并列为威胁人类健康的三大疾病之一。本病常留有后遗症,且极易复发,是威胁人类生命和生活质量的重大疾患。
市场上已经存在多种治疗和预防脑中风的药物均有一定的局限性。(1)以阿司匹林为代表的西药最为普遍,但西药长期使用副作用较为明显,长期治疗效果不佳,普遍价格昂贵。(2)以灯盏乙素为主要成分的药物,虽安全性高、副作用小,但此类药物生物利用度低、用量大、起效慢、在作用的靶器官含量极低。
发明内容
本发明要解决的技术问题为:以灯盏乙素为主要成分的药物生物利用度低、用量大、起效慢、作用在靶器官含量极低的问题。
本发明的目的在于提供一种用于治疗和预防脑中风的药物组合物,该组合物生物利用度高,起效快速,且安全性好,副作用小,治疗和预防脑中风效果更佳;该药物组合物由灯盏乙素苷元和高车前素组成,其中,灯盏乙素苷元的质量百分比为50~90%,高车前素的质量百分比为10~50%。
本发明所述组合物与符合药用要求的辅料制成各种剂型的药物,所述剂型包括片剂、胶囊剂、散剂、颗粒剂、滴丸剂、口服液、注射剂、粉针剂、栓剂、透皮贴剂、软膏剂。
本发明药用辅料为常规辅料包括乳糖、葡萄糖、预胶化淀粉、微晶纤维素、淀粉、糖粉、糊精、甘露醇、山梨醇、无机盐类(如硫酸钙二水物、磷酸三钙、磷酸氢钙、碳酸钙等)、乙醇、羟丙甲基纤维素、聚维酮、淀粉浆、胶浆、交联羧甲基纤维素钠、羧甲基淀粉钠、羟丙基淀粉、低取代羟丙基纤维素、干淀粉、硬脂酸、滑石粉、氢化植物油、聚乙二醇、微粉硅胶、十二烷基硫酸镁(钠)、维生素A、维生素C、维生素E、维生素D、二甲亚砜、氮酮等其中之一或多成分不同比例组合。
本发明的有益效果
(1)本发明所制成的药物与现有的西药相比,长期使用西药治疗和预防脑中风的患者易产生副反应和耐药性,使用本发明所述药物基本无毒副反应,增加了药物的安全性,减少了不良反应发生率,改善患者用药的顺应性;本发明所制成的药物与灯盏乙素为主要成分的药物相比,避免了肝脏首过效应和肠胃灭火效应,提高了生物利用度;使用量小,安全性顺应性提高;易通过血脑屏障,快速进入靶器官,起效时间缩短。
(2)本发明以灯盏乙素苷元和高车前素为主要成分的药物组合,具有改善心脑缺血、抑制血小板和血栓形成、改善微循环、抗炎、清除自由基、抗氧化、促进血管再生的作用;生物利用度高;易通过血脑屏障,快速进入靶器官发挥疗效,用量少;副作用小、安全性高、顺应性好,是长期治疗和预防脑中风的有效药物。
具体实施方式
下面结合具体实施例对本发明作进一步详细说明,但本发明的保护范围并不限于所述内容。
一种治疗和预防脑中风的药物组合物,按质量百分比称量灯盏乙素苷元与高车前素,配制药物组合物;
药物组合物A:灯盏乙素苷元25%,高车前素75%;
药物组合物B:灯盏乙素苷元50%,高车前素50%;
药物组合物C:灯盏乙素苷元75%,高车前素25%;
将灯盏乙素苷元、高车前素、灯盏花素、药物组合物A、药物组合物B、药物组合物C,分别溶于含20%聚乙二醇的生理盐水,配成药物,取适量给大鼠灌胃。
取39只健康 SD大鼠,雄性,体重200g~230g,术前禁食12h,自由饮水;随机分成13组,每组三只,给药前做MCAO模型,称量大鼠体重,给药组按照100mg/kg的剂量灌胃给药,提前一周给予每组不同的前处理。
(1)假手术组:仅手术暴露右侧颈总动脉及颈内动脉,再缝合,不做缺血处理。
(2)空白组:造模后,用含20%聚乙二醇的生理盐水灌胃。
(3)高车前素组:造模再灌住后,用高车前素灌胃。
(4)药物组合A组:造模再灌住后,用药物组合A灌胃。
(5)药物组合B组:造模再灌住后,用药物组合B灌胃。
(6)药物组合C组:造模再灌住后,用药物组合C灌胃。
(7)灯盏乙素苷元组:造模再灌住后,用灯盏乙素苷元灌胃。
(8)灯盏花素组:造模再灌住后,用灯盏花素灌胃。
实验结果:
**p<0.01,*p<0.05与空白组对比;##p<0.01与假手术组对比;◆p<0.05与灯盏乙素苷元对比
神经缺损评分:
根据Bederson方法,再灌住12h后进行神经功能缺损评估;假手术组大鼠无神经系统症状。空白(MCAO)组有明显的神经功能缺损(P<0.01);大鼠不能正常自由行动。灯盏乙素苷元对脑神经保护作用优于灯盏乙素(P<0.05)。灯盏乙素苷元占中量百分比为75%的药物影响优于灯盏乙素苷元单体给药(P<0.05)。
大脑梗死体积:
采用TTC染色测定脑梗死体积,神经功能缺损评分后,将处死的大鼠大脑转移到−20℃冻结为固体,然后切成2mmol/L厚的冠状切片;选择五个切片在2%TTC溶液,37℃染色30min;正常大脑的区域可被染为红色,但梗死区不被染色,呈淡色。计算梗死率(%)=A0/A*100%,其中,A0是梗死的重量,A是整个脑的重量。
假手术组大鼠无梗死体积;相比之下,假手术组和MCAO模型组差异显著(P<0.01),MCAO模型组大鼠,大脑的大部分地区不能被染成红色;灯盏乙素苷元的影响优于灯盏乙素(P<0.05),且灯盏乙素苷元的质量百分比为75%的药物影响优于灯盏乙素苷元单体给药(P<0.05)。
灯盏乙素、灯盏乙素苷元、高车前素清除DPPH自由基的能力对比:
灯盏花素(含98%灯盏乙素)、灯盏乙素苷元、高车前素分别用甲醇配制0.02mmol/L,0.05mmol/L,0.1mmol/L,0.2mmol/L,0.5mmol/L五个不同浓度备用;分别取等量配置好的溶液加入DPPH自由基溶液中,避光反应 30min,采用酶标仪测定反应后的吸光值;每个浓度平行测定三次;将样品溶液换为纯甲醇即为空白。
组合物质配比表:
实验结果表明,灯盏乙素苷元的清除DPPH自由基能力强于灯盏乙素,灯盏乙素苷元清除DPPH自由基的能力最强,高车前素几乎无清除DPPH自由基的能力。
灯盏乙素、灯盏乙素苷元、高车前素清除ABTS自由基能力对比:
灯盏花素(含98%灯盏乙素)、灯盏乙素苷元、高车前素分别用甲醇配制0.02mmol/L,0.05mmol/L,0.1mmol/L,0.2mmol/L,0.5mmol/L五个不同浓度备用;分别取等量配置好的溶液加入ABTS自由基溶液中,避光反应 30min,采用酶标仪测定反应后的吸光值;每个浓度平行测定三次;将样品溶液换PBS为空白。
组合物质配比表:
实验结果表明,灯盏乙素与灯盏乙素苷元清除ABTS自由基能力相差不大,而高车前素几乎无清除ABTS自由基的能力。
对灯盏花素(含98%灯盏乙素)、灯盏乙素苷元、高车前素三种化合物的抗凝血活性进行比较;健康SD大鼠股动脉采血,与3.8 %的枸橼酸钠充分混合均匀,3000r/min离心,分离出上层贫血小板血浆。
凝血酶原时间(PT)的测定,用血凝仪测定PT值,记录血浆凝固的时间。
活化部分凝血酶原(APTT)的测定,用血凝仪测定APTT值,记录血浆凝固的时间。
血浆纤维蛋白原( FIB) 的测定,用血凝仪测定FIB值,记录血浆中纤维蛋白原的含量。
凝血酶时间( TT) 的测定,用血凝仪测定TT值,记录血浆凝固的时间。
注:与空白对照组比较,**P<0.01,*P<0.05
以上结果表明,灯盏花素,灯盏乙素苷元均具有较好的抗凝血活性,而高车前素无明显抗凝血活性。灯盏乙素苷元与灯盏乙素作用效果相同,通过减少细胞凋亡发挥其脑神经保护作用,但其治疗效果明显优于灯盏乙素;灯盏乙素苷元与高车前素组合药物的治疗作用优于灯盏乙素苷元单体给药,高车前素虽活性相对较低,但易透过血脑屏障,更有助于灯盏乙素苷元易通过血脑屏障,起到协同作用,提高药物组合的治疗效果。
Claims (2)
1.一种用于治疗和预防脑中风的药物组合物,其特征在于:由灯盏乙素苷元和高车前素组成,其中,灯盏乙素苷元的质量百分比为50~90%,高车前素的质量百分比为10~50%。
2.根据权利要求1所述用于治疗和预防脑中风的药物组合物,其特征在于:将所述组合物制成各种剂型的药物,剂型包括片剂、胶囊剂、散剂、颗粒剂、滴丸剂、口服液、注射剂、粉针剂、栓剂、透皮贴剂、软膏剂。
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