CN102406594A - 一种姜黄素鼻用凝胶剂及其制备方法和应用 - Google Patents
一种姜黄素鼻用凝胶剂及其制备方法和应用 Download PDFInfo
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- CN102406594A CN102406594A CN2011103942152A CN201110394215A CN102406594A CN 102406594 A CN102406594 A CN 102406594A CN 2011103942152 A CN2011103942152 A CN 2011103942152A CN 201110394215 A CN201110394215 A CN 201110394215A CN 102406594 A CN102406594 A CN 102406594A
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Images
Abstract
本发明属于药物制剂技术领域，具体涉及一种姜黄素鼻用凝胶剂，该凝胶剂含有：姜黄素（Curcumin）或其药学上可以接受的盐、凝胶基质和药剂学上可接受的辅料。其中姜黄素的浓度为0.1%-5%（w/w），即每1g凝胶中含姜黄素1-50mg。本发明提供的姜黄素鼻用凝胶剂克服了口服姜黄素吸收差，生物利用度低的缺点，制备工艺简单，并能延长药物在鼻腔的滞留时间，增加药物吸收，提高药物在中枢神经系统中的量。
Description
一、技术领域
本发明属于药物制剂技术领域，具体涉及一种姜黄素的鼻用凝胶剂及其制备方法和在制备姜黄素之适应症药物中的应用。
二、背景技术
姜黄素(curcumin)是从姜科姜黄属植物姜黄、莪术、郁金等的根茎中提取出来的一种脂溶性酚类色素，具有抗炎、抗氧化、抗癌等药理作用，可以改善癌症、糖尿病、代谢性疾病、自身免疫疾病、动脉粥样硬化、关节炎、中风、外周神经病、肠炎和脑外伤等多种疾病症状。但是由于姜黄素水溶性差，在体外容易被氧化，且目前没有稳定性较好的药物剂型，给药困难。目前已上市或报道的姜黄素制剂主要有：乳化剂（200510042547.9，200780008293.6，200910101327.7，201010214085.5）、固体分散剂（200510035060.8）、脂质体（200610026576.0，200810155819.X，200910009097.1，201010561666.6）、纳米微粒（200610125179.9，200810159648.8，200910201403.1，201010528014.2）、缓释剂（200610154913.4）、注射剂（200310116734.8）。这些制剂的常用给药途径有口服、肌肉注射和静脉注射，其中肌肉注射和静脉注射需要专业人员完成，不适宜于自主用药，而口服给药虽然使用方便，但往往起效较慢，且生物利用度较低。因此，本领域需要提供一种安全、有效、使用方便、生物利用度高的姜黄素制剂。
三、发明内容
本发明所要解决的问题是提供一种鼻用姜黄素凝胶制剂及其制备方法和在制备治疗姜黄素之适应症药物中的应用。
本发明所述的姜黄素鼻用凝胶制剂含姜黄素，凝胶基质，以及药学上可接受的辅料，如pH调节剂、保湿剂、防腐剂、增溶剂等，其用量为药剂学上所规定的常规用量。
本发明鼻用凝胶剂，其中姜黄素或其药学上可接受的盐的重量是凝胶剂总重量的5-10%，凝胶基质的重量是凝胶剂总重量的0.1-40%。
本发明所述的普通水凝胶选自以下几类物质：Gellan胶、卡波姆、聚卡波菲、纤维素类衍生物、壳聚糖或脱乙酰壳多糖、透明质酸钠、聚乙烯醇、聚氧乙烯、海藻酸钠或黄原胶、果胶、魔芋胶角叉菜胶、西黄耆胶等。卡波姆可以是卡波姆934P、卡波姆940、卡波姆941、卡波姆974P，聚卡波菲可以是NoveonAA-1、NoveonCA-1、NoveonCA-2，纤维素类衍生物包括有甲基纤维素、羧甲基纤维素钠和羟丙甲基纤维素。其中，Gellan树胶其浓度为0.1%~5%，卡波姆其浓度为0.2~1.5%，纤维素类衍生物其浓度为2~6%，壳聚糖浓度为0.2~10%，透明质酸钠的浓度为0.2~15%，聚乙烯醇的浓度为0.2~15%，聚氧乙烯的浓度为0.5~10%，海藻酸钠的浓度为0.2~7%，黄原胶浓度为0.2~6%。
本发明所述的温敏凝胶，即在冷藏或室温下为自由流动的液体，而在体温时可逆的形成澄明的凝胶，选自下述一种或几种材料：泊洛沙姆407、泊洛沙姆188、N-异丙基丙烯酰胺共聚物、聚乙二醇-PLGA嵌段共聚物、乙基羟乙基纤维素、木聚糖等。其中泊洛沙姆407的浓度为15~30%，N-异丙基丙烯酰胺共聚物的浓度为20~40%，聚乙二醇-PLGA嵌段共聚物浓度为15~40%，乙基羟乙基纤维素浓度为0.1~10%，木聚糖浓度为0.1~10%。
本发明所述的鼻用凝胶剂包括下述一种或多种增溶剂：（1）环糊精类：β-环糊精，羟并集-β-环糊精，甲基-β-环糊精等；（2）醇类：乙醇、聚乙二醇、丙二醇、二乙二醇二甲基醚、正丁醇、异丙醇等；（3）聚山梨酯类：聚山梨醇酯-20、聚山梨醇酯-40、聚山梨醇酯-60、聚山梨醇酯-80等；（4）蓖麻油类：聚氧乙烯（40）氢化蓖麻油、聚氧乙烯（40）蓖麻油等；（5）、胆酸盐类：牛磺胆酸盐、胆酸盐、肝胆酸盐、鹅去氧胆酸盐及去氧胆酸盐等；（6）脂肪酸及其酯类：癸酸酯、辛酸酯、月桂酸酯等；（7）、糖苷类：皂苷；（8）、聚氧乙烯醚类：聚氧乙烯烷基醚、聚氧乙烯-4-月桂醇醚、聚氧乙烯-2-鲸蜡醇醚、聚氧乙烯-5-辛醚、聚氧乙烯-10-辛醚、聚氧乙烯-5-月桂基醚、聚氧乙烯-9-月桂基醚、聚氧乙烯-10-月桂基醚等；（9）、聚氧乙烯酯类：聚氧乙烯（8）硬脂酸酯、聚氧乙烯（12）硬脂酸酯、聚氧乙烯（24）硬脂酸酯、聚氧乙烯（100）硬脂酸酯等；（10）、其他具有促进吸收的物质：牛磺双氢褐霉素钠、甘草酸、甘草次酸、α-环糊精、溶血磷脂酰胆碱等。
本发明中的渗透压调节剂为氯化钠、葡萄糖、乳糖、甘露糖、甘露醇和山梨醇中的一种或数种。
本发明中的pH调节剂为盐酸、磷酸、硫酸、醋酸、硼酸、柠檬酸、氢氧化钠、氢氧化钾、单乙醇胺、双异丙醇胺、三乙醇胺、碳酸氢钠和碳酸氢钾中的一种或数种。
本发明中的防腐剂为苯扎溴铵、苯扎氯铵、苯甲酸、苯甲酸盐、三氯叔丁醇、苯甲醇、醋酸洗必泰、依地酸二钠、硫柳汞和尼泊金酯中的一种或数种。
本发明中的鼻用姜黄素凝胶剂的制备方法，按以下步骤制备：（1）称取处方量的凝胶基质、防腐剂和pH调节剂，充分溶胀/溶解；（2）称取处方量的姜黄素与溶剂和增溶剂混合，充分溶解；（3）将上述两步所得溶液均匀混合后定容。
本发明与现有技术相比具有延长药物滞留时间、增加药物吸收、刺激性小、制备简单、使用方便、给药剂量准确等优点，是一种安全、有效、患者乐于接受的顺应性高的给药剂型。
四、附图说明
图1为SD大鼠使用不同姜黄素剂型后的脑组织药时曲线 五、具体实施方式
1、普通水凝胶制备
制备步骤：
（1）称取处方量的凝胶基质、防腐剂和pH调节剂，充分溶胀/溶解，其中凝胶基质的重量是凝胶剂总重量的0.1%-5%，防腐剂的重量是凝胶剂总重量的0.01%-1%，pH调节剂的重量是凝胶剂总重量的0.01%-1%；（2）称取处方量的姜黄素与溶剂和/或增溶剂混合，充分溶解，其中姜黄素的重量是凝胶剂总重量的0.1%-5%，溶剂和/或增溶剂的体积为凝胶剂总体积的5%-40%；（3）将上述两步所得溶液均匀混合后定容。
处方1：
姜黄素 0.5g
卡波姆934P 1g
乙醇 10ml
PEG400 10ml
苯扎溴铵 0.02g
生理盐水 加至100ml
处方2：
姜黄素 0.5g
羟丙基甲基纤维素 2g
乙醇 10ml
PEG400 10ml
苯扎溴铵 0.02g
生理盐水 加至100ml
处方3：
姜黄素 0.5g
泊洛沙姆407 25g
乙醇 10ml
PEG400 10ml
苯扎溴铵 0.02g
生理盐水 加至100ml
处方4：
姜黄素 0.5g
海藻酸钠 2g
乙醇 10ml
PEG400 10ml
苯扎溴铵 0.02g
生理盐水 加至100ml
2、温敏型凝胶制备
制备步骤：
（1）称取处方量的凝胶基质、防腐剂和pH调节剂，充分溶胀/溶解，其中凝胶基质的重量是凝胶剂总重量的0.1%-10%，防腐剂的重量是凝胶剂总重量的0.01%-1%，pH调节剂的重量是凝胶剂总重量的0.01%-1%；（2）称取处方量的姜黄素与溶剂和/或增溶剂混合，充分溶解，其中姜黄素的重量是凝胶剂总重量的0.1%-5%，溶剂和/或增溶剂的体积为凝胶剂总体积的5%-30%；（3）将上述两步所得溶液均匀混合后定容。
处方：
姜黄素 0.5g
泊洛沙姆407 20g
泊洛沙姆188 2g
乙醇 10ml
PEG400 10ml
苯扎溴铵 0.02g
生理盐水 加至100ml
3、药效实验
（1）60只SD大鼠，随机分为4组，即姜黄素静脉注射组、姜黄素溶液鼻滴组、姜黄素普通水凝胶组和姜黄素温敏凝胶组。每组15只(共5个时间点，每个时间点3只)，给药前禁食12h，试验期间可自由饮水。试验前称重，以10%水合氯醛进行麻醉，待大鼠麻醉后，分别进行尾静脉注射或用微量注射器经鼻给药分别于给药后10、30、60、90、120 min心脏采血，离心分离血浆，置于-80℃冰箱保存；同时迅速开颅，取其全脑，用生理盐水荡洗，去除血污，用滤纸吸干水分，-80℃冰箱保存待测。
（2）血浆样品冰箱取出后，以大黄素为内标，乙酸乙酯进行萃取，HPLC测定姜黄素含量。大鼠全脑精密称重后，加入生理盐水匀浆，取一定体积的脑组织样品与大黄素溶液混合均匀后，乙酸乙酯进行萃取，HPLC测定姜黄素含量。
（3）实验结果
使用不同姜黄素剂型后的脑组织药时曲线，结果见附图1。结果表明，相比姜黄素普通溶液，姜黄素普通水凝胶和温敏凝胶均具有增加脑部药物吸收的功效。
Claims (7)
1.一种鼻用姜黄素凝胶剂，其特征在于，含有姜黄素，凝胶基质以及药学上可接受的辅料；其中姜黄素的重量是凝胶剂总重量的0.1%-5%，凝胶基质的重量是凝胶剂总重量的0.1%-40%，有普通水凝胶和温敏型凝胶两种。
2.根据权利要求1所述的鼻用姜黄素凝胶剂，其特征在于普通水凝胶基质为下述辅料的一种或数种：Gellan胶、卡波姆、聚卡波菲、羧甲基纤维素钠、甲基纤维素、羟丙基纤维素、泊洛沙姆407、泊洛沙姆188、N-异丙基丙烯酰胺共聚物、醋酸纤维素钛酸酯、丙烯酸聚合物、海藻酸钠、黄原胶、阿拉伯胶、西黄耆胶、卡拉胶、文莱胶。
3.根据权利要求1所述的鼻用姜黄素凝胶剂，其特征在于温敏型凝胶基质为下述温敏型凝胶辅料中的一种或数种：泊洛沙姆407、泊洛沙姆188、N-异丙基丙烯酰胺共聚物、聚乙二醇-PLGA嵌段共聚物、乙基羟乙基纤维素、木聚糖。
4.根据权利要求1所述的鼻用姜黄素凝胶剂，其特征在于药学上可接受的辅料为渗透压调节剂、pH调节剂、相变温度调节剂、促透剂、稳定剂和/或防腐剂。
5.根据权利要求1所述的鼻用姜黄素凝胶剂的制备方法，其特征在于普通水凝胶的制备由以下步骤组成：（1）称取处方量的凝胶基质、防腐剂和pH调节剂，充分溶胀/溶解，其中凝胶基质的重量是凝胶剂总重量的0.1%-5%，防腐剂的重量是凝胶剂总重量的0.01%-1%，pH调节剂的重量是凝胶剂总重量的0.01%-1%；（2）称取处方量的姜黄素与溶剂和/或增溶剂混合，充分溶解，其中姜黄素的重量是凝胶剂总重量的0.1%-5%，溶剂和/或增溶剂的体积为凝胶剂总体积的5%-40%；（3）将上述两步所得溶液均匀混合后定容。
6.根据权利要求1所述的鼻用姜黄素凝胶剂的制备方法，其特征在于温敏型凝胶的制备由以下步骤组成：（1）称取处方量的凝胶基质、防腐剂和pH调节剂，充分溶胀/溶解，其中凝胶基质的重量是凝胶剂总重量的0.1%-10%，防腐剂的重量是凝胶剂总重量的0.01%-1%，pH调节剂的重量是凝胶剂总重量的0.01%-1%；（2）称取处方量的姜黄素与溶剂和/或增溶剂混合，充分溶解，其中姜黄素的重量是凝胶剂总重量的0.1%-5%，溶剂和/或增溶剂的体积为凝胶剂总体积的5%-30%；（3）将上述两步所得溶液均匀混合后定容。
7.权利要求1所述的鼻用姜黄素凝胶剂在制备姜黄素之适应症药物中的应用。
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