CN109602724A - 一种牛蒡子苷元口服纳米制剂及其制备方法 - Google Patents
一种牛蒡子苷元口服纳米制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种牛蒡子苷元口服纳米制剂及其制备方法，牛蒡子苷元口服纳米制剂由牛蒡子苷元和辅料组成，所述辅料为a‑环糊精和PLGA2000‑PEG2000，其制备方法为将a‑环糊精溶于水中，制得溶液A；将PLGA2000‑PEG2000加入到溶液A中，充分搅拌至PLGA2000‑PEG2000溶解，制得溶液B；将牛蒡子苷元加入至溶液B中，搅拌至牛蒡子苷元溶解，即得牛蒡子苷元口服纳米制剂。本发明制备的牛蒡子苷元口服纳米制剂载药量高、稳定性好、制备流程无有机溶剂，制备工艺适于规模化生产，大幅度提高了牛蒡子苷元口服生物利用度。
Description
技术领域
本发明涉及中药制剂领域，具体地说，涉及一种牛蒡子苷元口服纳米制剂及其制备方法。
背景技术
牛蒡子苷元(CAS号:7770-78-7)是从牛蒡子中提取分离制得的活性成分，具有改善阿尔茨海默氏症和抗肿瘤等药效，但其水溶性较差，口服生物利用度较低，严重限制了牛蒡子苷元的开发与临床应用。
a-环糊精是由6个葡萄糖单位经糖键连接成环形结构的糊精，它是葡萄糖基转移酶作用于淀粉糖浆的产物，在医药食品领域具有广泛的应用。
PLGA2000-PEG2000是聚乳酸-羟基乙酸共聚物(poly(lactic-co-glycolicacid)， PLGA)的聚乙二醇(PEG)化衍生物，是平均分子量2000的PLGA与平均分子量2000 的PEG的嵌段聚合物，是一种具有较好生物相容性的药用辅料。 PLGA2000-PEG2000难溶于水，一般在制剂过程采用氯仿等有机溶剂溶解应用。
纳米载体可以增加难溶性药物的表观溶解度，改善药物的口服吸收与药效。但是一般的纳米制剂制备工艺复杂，往往需要使用难以完全除尽的有机溶剂，而且载药量偏低，多数在1-5％，限制了应用。
发明内容
本发明的目的是提供一种制备工艺简单、制备流程无有机溶剂、载药量大和能够有效提高牛蒡子苷元口服生物利用度的纳米制剂及其制备方法。
为了解决现有技术存在的缺陷，发明人通过大量实验，首次发现：a-环糊精与PLGA2000-PEG2000形成的混合胶束系统可以增溶牛蒡子苷元形成稳定的纳米制剂，口服给药后能够大幅度增加牛蒡子苷元的生物利用度。
将a-环糊精与PLGA2000-PEG2000合用作为辅料，制备牛蒡子苷元纳米制剂时，为了形成载药量和包封率高，粒径均一和稳定性良好的牛蒡子苷元口服纳米制剂，发明人对不同质量比例的牛蒡子苷元与两种辅料、不同质量比例的a- 环糊精与PLGA2000-PEG2000进行试验。研究发现，牛蒡子苷元与辅料的质量比为1︰4-1︰6，a-环糊精与PLGA2000-PEG2000的质量比为1︰1-1︰2时，牛蒡子苷元口服纳米制剂的平均粒径范围为20-200nm，多分散系数(PDI)较低，稳定性较好。当牛蒡子苷元、a-环糊精与PLGA2000-PEG2000的质量比为1︰2︰2 时效果最优。
因此本发明所述的牛蒡子苷元口服纳米制剂的技术方案为：辅料由a-环糊精和PLGA2000-PEG2000组成，牛蒡子苷元与辅料的质量比为1︰4-1︰6，a-环糊精与PLGA2000-PEG2000的质量比为1︰1-1︰2，牛蒡子苷元口服纳米制剂的平均粒径范围为20-200nm；牛蒡子苷元、a-环糊精与PLGA2000-PEG2000的质量比优选为1︰2︰2。
本发明公开了一种牛蒡子苷元口服纳米制剂的制备方法，包括如下步骤：
a.将a-环糊精溶于水中，制得溶液A；
b.将PLGA2000-PEG2000加入到溶液A中，充分搅拌至PLGA2000-PEG2000 溶解，制得溶液B；
c.将牛蒡子苷元加入至溶液B中，搅拌至牛蒡子苷元溶解，即得牛蒡子苷元口服纳米制剂。
本发明所述的牛蒡子苷元口服纳米制剂有如下优点：
(1)相对于现有技术，本发明在制备过程中不使用任何毒性溶剂，不存在环境污染和残留溶剂毒性等问题。
(2)a-环糊精在水相体系能够显著增溶PLGA2000-PEG2000，避免了溶剂回收程序，简化了制备工艺，易于商业化生产。
(3)牛蒡子苷元溶解度和口服生物利用度大幅度提高。
附图说明
图1为本发明所述的牛蒡子苷元口服纳米制剂的透射电镜图。
具体实施方式
实施例1
称取a-环糊精100mg加入20ml蒸馏水中，搅拌使其完全溶解，将100mg PLGA2000-PEG2000加入到上述a-环糊精溶液中，磁力搅拌至完全溶解，称取牛蒡子苷元原料药50mg加入至a-环糊精-PLGA2000-PEG2000溶液体系中，磁力搅拌至牛蒡子苷元完全溶解形成透明溶液，即得牛蒡子苷元口服纳米制剂。测得平均粒径为22.3nm，PDI为0.06，包封率为99.7％，载药量为20％；室温放置2年，牛蒡子苷元含量与粒径分布无显著变化。
实施例2
称取a-环糊精100mg加入50ml蒸馏水中，搅拌使其完全溶解，将150mg PLGA2000-PEG2000加入到上述a-环糊精溶液中，磁力搅拌至完全溶解，称取牛蒡子苷元原料药62.5mg加入至a-环糊精-PLGA2000-PEG2000溶液体系中，磁力搅拌至牛蒡子苷元完全溶解形成透明溶液，即得牛蒡子苷元口服纳米制剂。测得平均粒径为158.5nm，PDI为0.16，包封率为98.3％，载药量为19％；室温放置2年，牛蒡子苷元含量与粒径分布无显著变化。
实施例3
称取a-环糊精100mg加入100ml蒸馏水中，搅拌使其完全溶解，将200mg PLGA2000-PEG2000加入到上述a-环糊精溶液中，磁力搅拌至完全溶解，称取牛蒡子苷元原料药75mg加入至a-环糊精-PLGA2000-PEG2000溶液体系中，磁力搅拌至牛蒡子苷元完全溶解形成透明溶液，即得牛蒡子苷元口服纳米制剂。测得平均粒径为193.0nm，PDI为0.12，包封率为98.0％，载药量为19％；室温放置2年，牛蒡子苷元含量与粒径分布无显著变化。
实施例4
称取a-环糊精100mg加入20ml蒸馏水中，搅拌使其完全溶解，将100mg PLGA2000-PEG2000加入到上述a-环糊精溶液中，磁力搅拌至完全溶解，称取牛蒡子苷元原料药40mg加入至a-环糊精-PLGA2000-PEG2000溶液体系中，磁力搅拌至牛蒡子苷元完全溶解形成透明溶液，即得牛蒡子苷元口服纳米制剂。测得平均粒径为26.2nm，PDI为0.09，包封率为99.0％，载药量为17％；室温放置1年，牛蒡子苷元含量与粒径分布无显著变化。
实施例5
称取a-环糊精60mg加入10ml蒸馏水中，搅拌使其完全溶解，将60mg PLGA2000-PEG2000加入到上述a-环糊精溶液中，磁力搅拌至完全溶解，称取牛蒡子苷元原料药20mg加入至a-环糊精-PLGA2000-PEG2000溶液体系中，磁力搅拌至牛蒡子苷元完全溶解形成透明溶液，即得牛蒡子苷元口服纳米制剂。测得平均粒径为30.0nm，PDI为0.08，包封率为99.3％，载药量为14％；室温放置1年，牛蒡子苷元含量与粒径分布无显著变化。
实施例6
称取a-环糊精100mg加入50ml蒸馏水中，搅拌使其完全溶解，将100mg PLGA2000-PEG2000加入到上述a-环糊精溶液中，磁力搅拌至完全溶解，称取牛蒡子苷元原料药50mg加入至a-环糊精-PLGA2000-PEG2000溶液体系中，磁力搅拌至牛蒡子苷元完全溶解形成透明溶液，即得牛蒡子苷元口服纳米制剂。测得平均粒径为21.2nm，PDI为0.07，包封率为99.5％，载药量为20％；室温放置2年，牛蒡子苷元含量与粒径分布无显著变化。
实施例7
牛蒡子苷元纳米制剂口服生物利用度研究
取SD大鼠18只，体重为220g±20g，随机分成三组，每组6只，给药前禁食12 小时，自由饮用生理盐水。给药前称重标号，三组大鼠分别按照100mg/kg的剂量灌胃给予牛蒡子苷元原料药、牛蒡子苷元口服纳米制剂(按实施例1制备)和牛蒡子苷元口服纳米制剂(按实施例3制备)，分别于给药后0、15、30、60、 90、120、240、300、480、720和1440min后眼眶取血0.5mL，并置于1％肝素钠浸润干燥后的离心管中，将血液以3000rpm离心15min取上层血浆。用移液枪精密吸取血浆样品100μL，加入内标厚朴酚溶液(20μg/mL)50μL混合30s后，用 1mL醋酸乙酯涡旋提取5min，14000r/min离心15min，取上层萃取液，再重复上述步骤一遍，将萃取液合并，用氮气吹干，残留物加入100μL流动相溶解后进样20μl，用UPLC进行测定。记录各个时间点样品峰与内标峰的面积As、Ai，以 R＝As/Ai代入标准曲线方程计算测定浓度。通过计算，牛蒡子苷元原料药及制剂的药代动力学参数如下表。牛蒡子苷元口服纳米制剂能够显著增加牛蒡子苷元口服生物利用度，其中按实施例1制备的制剂效果最好。
表1牛蒡子苷元原料药及制剂药代动力学参数表
Claims (6)
1.一种牛蒡子苷元口服纳米制剂，其特征为：由牛蒡子苷元和辅料组成，所述辅料为a-环糊精和PLGA2000-PEG2000。
2.如权利要求1所述的牛蒡子苷元口服纳米制剂，其特征为：牛蒡子苷元与辅料的质量比为1︰4-1︰6。
3.如权利要求2所述的牛蒡子苷元口服纳米制剂，其特征为：a-环糊精与PLGA2000-PEG2000的质量比为1︰1-1︰2。
4.如权利要求3所述的牛蒡子苷元口服纳米制剂，其特征为：牛蒡子苷元、a-环糊精与PLGA2000-PEG2000的质量比为1︰2︰2。
5.如权利要求1-4任一权利要求所述的牛蒡子苷元口服纳米制剂，其特征为：牛蒡子苷元口服纳米制剂的平均粒径范围为20-200nm。
6.一种牛蒡子苷元口服纳米制剂的制备方法，包括如下步骤：
a.将a-环糊精溶于水中，制得溶液A；
b.将PLGA2000-PEG2000加入到溶液A中，充分搅拌至PLGA2000-PEG2000溶解，制得溶液B；
c.将牛蒡子苷元加入至溶液B中，搅拌至牛蒡子苷元溶解，即得牛蒡子苷元口服纳米制剂。
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| US20100136129A1 (en) * | 2007-04-20 | 2010-06-03 | Instituto Científico Y Tecnológico De Navarra, S.A | Nanoparticles comprising a cyclodextrin and a biologically active molecule and uses thereof |
| CN102008454A (zh) * | 2010-12-03 | 2011-04-13 | 上海交通大学 | 包载黄豆苷元的plga纳米颗粒及其制备方法 |
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| US20100136129A1 (en) * | 2007-04-20 | 2010-06-03 | Instituto Científico Y Tecnológico De Navarra, S.A | Nanoparticles comprising a cyclodextrin and a biologically active molecule and uses thereof |
| CN102008454A (zh) * | 2010-12-03 | 2011-04-13 | 上海交通大学 | 包载黄豆苷元的plga纳米颗粒及其制备方法 |
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