CN110123925A - 一种治疗脑积水的鼻用纳米乳原位凝胶及其制备方法 - Google Patents
一种治疗脑积水的鼻用纳米乳原位凝胶及其制备方法 Download PDFInfo
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Abstract
本发明涉及治疗脑积水的鼻用纳米乳原位凝胶及其制备方法,可有效解决传统口服制剂对于治疗脑部疾病靶向性较差、生物利用度较低,一定程度上限制了中医药在脑积水等症上的应用问题,其解决的技术方案是,该鼻用纳米乳原位凝胶是由以下重量计的原料药物制成:辛夷20‑100g、石菖蒲15‑75g、泽兰20‑100g、苍耳子12‑60g、苦参15‑75g、丹参15‑75g、川芎10‑50g、瓜蒂15‑75g、冰片3‑9g、芒硝10‑30g、麝香1‑3g、苏合香2‑10g、无水乙醇12.786‑63.93g、蓖麻油聚烃氧酯(35)20.586‑102.93g、油酸乙酯4.176‑20.88g、泊洛沙姆407 21‑105g和泊洛沙姆188 18‑90g,本发明具纳米乳与原位凝胶剂双重优点,不仅可以提高药物的溶解度、透皮速率,靶向作用,还可以减少药物的刺激性,是治疗脑积水药物上的创新。
Description
技术领域
本发明涉及医药,特别是一种治疗脑积水的鼻用纳米乳原位凝胶及其制备方法。
背景技术
脑积水是由于颅脑疾患使得脑脊液的产生和吸收失衡所致的颅脑内脑脊液异常增多,脑室系统扩大或蛛网膜下腔扩大的的一种病症。有资料表明脑积水在普通人群中发病率达1%~1.5%,且随人口数量的增长而递增,具有发病率高、致残率高、病死率高的特点。其分类及病因复杂,目前无统一规范化治疗方案。西医治疗严重脑积水以脑脊液分流术为主要手段,但该法不适合所有病例,且费用昂贵,存在手术失败风险,易继发感染和脑梗死;轻度脑积水则采用利尿剂、脱水剂或脑脊液分泌抑制剂等药物治疗,一般疗效不显著或仅有轻度的暂时效果,且不宜长期应用。中医对脑积水的治疗多采用内服法与外治法相结合。内服法主要有汤、丸、片等多种药物剂型,而外治法主要采用针灸、按摩等方法,但传统口服制剂对于治疗脑部疾病靶向性较差、生物利用度较低,一定程度上限制了中医药在脑积水等症上的应用,因此,发明一种治疗脑积水的中药复方外用制剂势在必行。
发明内容
针对上述情况,为解决现有技术之缺陷,本发明之目的就是提供一种治疗脑积水的鼻用纳米乳原位凝胶及其制备方法,可有效解决传统口服制剂对于治疗脑部疾病靶向性较差、生物利用度较低,一定程度上限制了中医药在脑积水等症上的应用问题。
本发明解决的技术方案是,主要以散寒祛湿、通窍逐饮、活血化瘀等作用,基于经鼻入脑通路,多配伍开窍促透药,使药物易透过血脑屏障,实现脑的靶向治疗,调节脑脊液代谢、减轻脑水肿的作用,据此,该鼻用纳米乳原位凝胶是由以下重量计的原料药物制成:辛夷20-100g、石菖蒲15-75g、泽兰20-100g、苍耳子12-60g、苦参15-75g、丹参15-75g、川芎10-50g、瓜蒂15-75g、冰片3-9g、芒硝10-30g、麝香1-3g、苏合香2-10g、无水乙醇12.786-63.93g、蓖麻油聚烃氧酯(35)20.586-102.93g、油酸乙酯4.176-20.88g、泊洛沙姆407 21-105g和泊洛沙姆188 18-90g。其制备方法包括以下步骤:
1)药物的制备:
将辛夷、石菖蒲、泽兰混合在一起,加入10倍量的水用水蒸气蒸馏法提取6h得挥发油,备用;
将苍耳子、苦参、丹参、川芎、瓜蒂混合在一起,加入10倍量浓度为70%(V/V)的乙醇回流提取3次,每次2h,合并醇提液,减压回收溶剂,浓缩得到浓缩液(1ml含2g饮片),加入浓缩液5倍量的纯化水于4℃静置沉淀24h,取上清液,浓缩至0.3g/ml(1ml含0.3g饮片),得提取物浓缩液,备用;
将麝香、苏合香研成细粉,加入无水乙醇浸渍 24h,倾取上清液,滤过,将冰片加入滤过液中,溶解,得无水乙醇混合液,备用;将芒硝配置成浓度10%(g/ml)的芒硝水溶液,备用;
2)纳米乳的制备:
将蓖麻油聚烃氧酯(35)、油酸乙酯、挥发油和无水乙醇混合液,置磁力搅拌器上搅拌至混合均匀,得混合液,将提取物浓缩液、芒硝水溶液作为水相,逐滴加入上述混合液中,得纳米乳;
3)纳米乳原位凝胶的制备:
将泊洛沙姆407、泊洛沙姆188缓慢加入不断搅拌的纳米乳中,分散均匀,于4℃溶胀完全,即得纳米乳原位凝胶。
本发明制成的纳米乳原位凝胶,属黏膜给药系统,具纳米乳与原位凝胶剂双重优点,不仅可以提高药物的溶解度、透皮速率,靶向作用,还可以减少药物的刺激性,以溶液状态给药后立即在用药部位发生相转变,形成的非化学交联的半固体制剂,与用药部位特别是黏膜组织亲和力强,滞留时间长,可显著提高疗效,增加患者的顺应性,且具有制备简单、使用方便、剂量易于控制,是治疗脑积水药物上的创新。
具体实施方式
以下结合实施例对本发明的具体实施方式作进一步详细说明。
实施例1
本发明在具体实施时,可由以下重量计的原料药物制成:辛夷20g、石菖蒲15g、泽兰20g、苍耳子12g、苦参15g、丹参15g、川芎10g、瓜蒂15g、冰片3g、芒硝10g、麝香1g、苏合香2g、无水乙醇12.786g、蓖麻油聚烃氧酯(35)20.586g、油酸乙酯4.176g、泊洛沙姆407 21g和泊洛沙姆188 18g。
实施例2
本发明在具体实施中,可由以下重量计的原料药物制成:辛夷65g、石菖蒲50g、泽兰65g、苍耳子40g、苦参50g、丹参50g、川芎30g、瓜蒂50g、冰片3g、芒硝30g、麝香1.5g、苏合香5g、无水乙醇42.62g、蓖麻油聚烃氧酯(35)68.62g、油酸乙酯13.92g、泊洛沙姆407 70g和泊洛沙姆188 60g。
实施例3
本发明在具体实施中,还可由以下重量计的原料药物制成:辛夷80g、石菖蒲60g、泽兰80g、苍耳子48g、苦参60g、丹参60g、川芎40g、瓜蒂60g、冰片6g、芒硝25g、麝香2g、苏合香8g、无水乙醇51.14g、蓖麻油聚烃氧酯(35)80.34g、油酸乙酯16.70g、泊洛沙姆407 84g和泊洛沙姆188 72g。
实施例4
本发明在具体实施中,还可由以下重量计的原料药物制成:辛夷100g、石菖蒲75g、泽兰100g、苍耳子60g、苦参75g、丹参75g、川芎50g、瓜蒂75g、冰片9g、芒硝30g、麝香3g、苏合香10g、无水乙醇63.93g、蓖麻油聚烃氧酯(35)102.93g、油酸乙酯20.88g、泊洛沙姆407 105g和泊洛沙姆188 90g。
上述实施例制备方法同发明内容。
本发明纳米乳原位凝胶由辛夷、石菖蒲、泽兰、苍耳子、苦参、丹参等药物组成,方中以辛夷、苍耳子为君,味苦性温,功能散风寒、通鼻窍,佐以苦寒之苦参,清热燥湿、利尿,苦寒之瓜蒂,外用研末吹鼻能引去湿热,咸苦性寒之芒硝,润燥软结,清火消肿,且利用渗透压原理,促使药物渗透,川芎、丹参、泽兰活血化瘀,且川芎能引药上行,共为臣药,并配伍冰片、麝香、苏合香、石菖蒲大量开窍促透药,促使药物透过血脑屏障,达到脑部靶向治疗,诸药合用共奏散寒祛湿、通窍逐饮、活血化瘀、利水消肿之功,以调节脑脊液代谢、治疗脑积水、减轻脑水肿等症,上述组份经科学、合理配伍,互相支持,有效用于脑积水的治疗,疗效好,用药安全,并经临床实验资料得到了充分证明,相关临床试验资料如下:
1 临床资料
1.1选择病例的标准
纳入病例标准:患者年龄在 45 - 75 岁;脑出血 2 周后慢性脑积水;患者及家属依从性好,并签署知情同意书。
排除病例标准:因颅内占位所致脑积水者;原发性脑萎缩者;伴发严重心、肝、肾疾病及糖尿病严重并发症者;恶性肿瘤及正在接受放化疗者。
观察病例共 60 例,随机单盲分为治疗组、对照组2组,每组各 30 例。两组在性别、年龄、病程及类型分布等方面均无显著差异,具有可比性。
1.2 诊断标准按照《各类脑血管疾病诊断要点》的相关诊断标准。且所有入选患者均采用头颅CT扫描,均示脑室系统扩大并脑间质水肿。
治疗方案
2.1对照组
采用西医内科基础治疗,参考《中国脑血管防治指南》,采用 20% 甘露醇250ml,静脉加压滴注,6-8 小时/次,同时控制血压、血糖、体温,给予营养支持、维持水、盐电解质平衡;并发肺部感染患者给予抗生素治疗,以 7天为1个疗程,共治疗2个疗程。
2.2治疗组:
在对照组治疗基础上给予纳米乳原位凝胶,每天 2 次,1次0.5 ml,7天为1个疗程,共治疗2个疗程。
观察指标与统计学方法
3.1观察指标
比较两组疗效、治疗前和治疗后第 7 天及 14 天颅内压值,同时观察治疗期间两组患者不良反应。
3.2安全性指标
一般体检项目(体温、血压、呼吸、脉搏)、血尿常规、心肝肾功能检查等,以上项目均于用药前及临床研究结束后各检查一次,随时观察不良反应。
治疗结果
两组治疗后第7天及14天较治疗前显著降低,与对照组相比,治疗组治疗后第7 天及14天颅内压均明显降低,差异具有统计学意义,总有效率为为83%。观察治疗前后两组患者一般体检项目、血尿常规检查、心功能检查等均无明显变化。两组患者未发现恶心、腹胀、乏力、便秘、低血糖等不良反应,两组治疗前后肝肾功能及血常规相关指标均无显著差异,提示两组用药期间对肝肾功能及血象均无明显影响。
表 1 两组患者疗效比较
组别 | 治愈 | 好转 | 未愈 | 总有效率 |
治疗组(30) | 15 | 10 | 5 | 83.33 % |
对照组(30) | 11 | 12 | 7 | 76.67% |
从表1可见,治疗组30例患者中,治愈15例,有效10例,无效3例,总有效率为83.33%;对照组30例患者中,治愈11例,有效12例,无效7例,总有效率为76.67%。经Ridit检验, P<0.05,两组总疗效比较差异有统计学意义。
结论
本发明鼻用纳米乳原凝胶可有效解决中药多组分经鼻给药透过血脑屏障,基于鼻腔到达神经中枢的通路,经过鼻腔给药能够绕过血脑屏障,生物利用度较高,具纳米乳与原位凝胶剂双重优点,不仅可以提高药物的溶解度、透皮速率,靶向作用,还可以减少药物的刺激性,以溶液状态给药后立即在用药部位发生相转变,形成的非化学交联的半固体制剂,与用药部位特别是黏膜组织亲和力强,滞留时间长,可显著提高疗效,增加患者的顺应性,且制备简单、使用方便、剂量易于控制,制剂中的葛根素、丹酚酸等能同步释放,累积溶出率高,能够降低颅内压,增加患者的用药顺应性,本发明配方严谨,使用方便,疗效确实,且不存在副作用,对肝肾功能、血、尿等均无明显影响,大大促进了新技术新工艺在中药领域中的应用,是治疗脑积水药物上的创新,具有实际的临床意义和推广价值。
Claims (6)
1.一种治疗脑积水的鼻用纳米乳原位凝胶,其特征在于,该鼻用纳米乳原位凝胶是由以下重量计的原料药物制成:辛夷20-100g、石菖蒲15-75g、泽兰20-100g、苍耳子12-60g、苦参15-75g、丹参15-75g、川芎10-50g、瓜蒂15-75g、冰片3-9g、芒硝10-30g、麝香1-3g、苏合香2-10g、无水乙醇12.786-63.93g、蓖麻油聚烃氧酯(35)20.586-102.93g、油酸乙酯4.176-20.88g、泊洛沙姆407 21-105g和泊洛沙姆188 18-90g。
2.根据权利要求1所述的治疗脑积水的鼻用纳米乳原位凝胶,其特征在于,由以下重量计的原料药物制成:辛夷20g、石菖蒲15g、泽兰20g、苍耳子12g、苦参15g、丹参15g、川芎10g、瓜蒂15g、冰片3g、芒硝10g、麝香1g、苏合香2g、无水乙醇12.786g、蓖麻油聚烃氧酯(35)20.586g、油酸乙酯4.176g、泊洛沙姆407 21g和泊洛沙姆188 18g。
3.根据权利要求1所述的治疗脑积水的鼻用纳米乳原位凝胶,其特征在于,由以下重量计的原料药物制成:辛夷65g、石菖蒲50g、泽兰65g、苍耳子40g、苦参50g、丹参50g、川芎30g、瓜蒂50g、冰片3g、芒硝30g、麝香1.5g、苏合香5g、无水乙醇42.62g、蓖麻油聚烃氧酯(35)68.62g、油酸乙酯13.92g、泊洛沙姆407 70g和泊洛沙姆188 60g。
4.根据权利要求1所述的治疗脑积水的鼻用纳米乳原位凝胶,其特征在于,由以下重量计的原料药物制成:辛夷80g、石菖蒲60g、泽兰80g、苍耳子48g、苦参60g、丹参60g、川芎40g、瓜蒂60g、冰片6g、芒硝25g、麝香2g、苏合香8g、无水乙醇51.14g、蓖麻油聚烃氧酯(35)80.34g、油酸乙酯16.70g、泊洛沙姆407 84g和泊洛沙姆188 72g。
5.根据权利要求1所述的治疗脑积水的鼻用纳米乳原位凝胶,其特征在于,由以下重量计的原料药物制成:辛夷100g、石菖蒲75g、泽兰100g、苍耳子60g、苦参75g、丹参75g、川芎50g、瓜蒂75g、冰片9g、芒硝30g、麝香3g、苏合香10g、无水乙醇63.93g、蓖麻油聚烃氧酯(35)102.93g、油酸乙酯20.88g、泊洛沙姆407 105g和泊洛沙姆188 90g。
6.权利要求1-5任一项所述的治疗脑积水的鼻用纳米乳原位凝胶的制备方法,其特征在于,包括以下步骤:
1)药物的制备:
将辛夷、石菖蒲、泽兰混合在一起,加入10倍量的水用水蒸气蒸馏法提取6h得挥发油,备用;
将苍耳子、苦参、丹参、川芎、瓜蒂混合在一起,加入10倍量浓度为70%的乙醇回流提取3次,每次2h,合并醇提液,减压回收溶剂,浓缩得到浓缩液,加入浓缩液5倍量的纯化水于4℃静置沉淀24h,取上清液,浓缩至0.3g/ml,得提取物浓缩液,备用;
将麝香、苏合香研成细粉,加入无水乙醇浸渍 24h,倾取上清液,滤过,将冰片加入滤过液中,溶解,得无水乙醇混合液,备用;将芒硝配置成浓度10%的芒硝水溶液,备用;
2)纳米乳的制备:
将蓖麻油聚烃氧酯(35)、油酸乙酯、挥发油和无水乙醇混合液,置磁力搅拌器上搅拌至混合均匀,得混合液,将提取物浓缩液、芒硝水溶液作为水相,逐滴加入上述混合液中,得纳米乳;
3)纳米乳原位凝胶的制备:
将泊洛沙姆407、泊洛沙姆188缓慢加入不断搅拌的纳米乳中,分散均匀,于4℃溶胀完全,即得纳米乳原位凝胶。
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