甘草次酸—白蛋白复合微粒的制备与评价

发布时间：2018-03-22 11:35

本文选题：甘草次酸　切入点：牛血清白蛋白　出处：《宁夏医科大学》2016年硕士论文　论文类型：学位论文

【摘要】：目的基于甘草次酸保肝药效明确但水溶性差、生物利用度低,本课题旨在制备粒径均匀、载药量和包封率较高、缓释且具有一定肝靶向性能的甘草次酸-白蛋白复合微粒,提高生物利用度,以期增强疗效。方法以粒径及初步稳定性为评价指标,优选反溶剂沉淀法制备甘草次酸纳米混悬液的工艺参数;分别以药物纳米混悬液和白蛋白纳米粒为基础进一步复合制粒,以粒径和突释率为指标优选复合微粒制法;采用氯化锌为凝聚剂、戊二醛为交联剂,将上述所得甘草次酸-白蛋白纳米粒组装为复合微粒;考察稳定剂种类、白蛋白浓度及固化剂用量对纳米粒/微粒粒径大小及其分布、载药量和包封率的影响,采用单因素实验法逐步优化处方。所得复合微粒经透射电镜观察粒径和形态,X-射线衍射(XRD)分析药物晶型,差示扫描热分析(DSC)及红外光谱法(FTIR)考察药物与载体之间的相互作用;测定其体外释放度,并对释药数据进行拟合、探讨释药机理;研究复合微粒经小鼠尾静脉注射的药代动力学和组织分布特征,并与注射液比较。结果1以TPGS-SDS为复配稳定剂,PVPK30为空间稳定剂,采用反溶剂沉淀-超声辅助法制得的甘草次酸纳米混悬液,粒径较小且分布均匀(54 nm,PDI=0.370),90天内放置稳定性良好。2甘草次酸纳米混悬液、甘草次酸-白蛋白纳米粒进一步交联即可得到甘草次酸-白蛋白复合微粒,而后者包封率较高、缓释效果更佳。当白蛋白浓度为7.5 mg/mL,加入25%氯化锌(10μL/mg BSA)和0.1%戊二醛量(4μL/mg BSA)分别交联1h后,所得微粒粒径较均匀(2μm),载药量(30.2±1.18)%、包封率(75.0±2.36)%最佳,体外0.5 h突释28.1%、后期缓慢释放且8 h释放达70%以上,释药行为符合Higuchi模型。DSC、XRD及FTIR测定结果表明甘草次酸被BSA包裹并高度分散于微粒骨架中。3与甘草次酸溶液相比,甘草次酸-白蛋白复合微粒经小鼠尾静脉注射后,达峰浓度与半衰期差异不明显,但微粒组的MRT0-24值和药时曲线下面积分别是溶液组的2.35倍和2.8倍,延长了药物在血液中的滞留时间,相对生物利用度有所提高。组织分布结果显示,微粒在肝脏的相对摄取率大于1,在心、脾、肺、肾、脑的总靶向系数分别为3.75、2.11、3.11、2.82、8.53,表明微粒能够选择性地浓集于肝部,具有一定的肝靶向功效,同时降低了其他组织的药物浓度。结论采用简便的反溶剂沉淀-化学交联法所得复合微粒粒径均匀、载药量和包封率较高、具有一定缓释及肝靶向性、生物利用度提高。这为肝靶向新剂型研究提供参考,并为开发新型甘草次酸制剂产品奠定了基础。
[Abstract]:The purpose of glycyrrhetinic acid hepatoprotective activity based on clear but poor water solubility and low bioavailability, this paper aims at the preparation of uniform particle size, entrapment efficiency and the release rate is higher, and has a certain liver targeting glycyrrhetinic acid - properties of albumin nanoparticles, improve the bioavailability, to enhance the curative effect. With the particle size and preliminary stability as the evaluation index, the optimum parameters of anti solvent precipitation preparation of glycyrrhetinic acid nanosuspension; with drug nanosuspensions and albumin nanoparticles based composite granulation, with particle size and burst rate index. The composite particles preparation method using zinc chloride as coagulant;, glutaraldehyde as crosslinking agent, the obtained glycyrrhetinic acid - albumin nanoparticles assembled into composite particles; effects of stabilizers, albumin concentration and dosage of the curing agent of nanoparticles / particle size and size distribution, drug loading and encapsulation The rate of effect, using single factor experiment method and gradually optimize the prescription. The composite particles by transmission electron microscope to observe the particle size and morphology, X- ray diffraction (XRD) analysis of drug crystal, differential scanning calorimetry (DSC) and infrared spectroscopy (FTIR) study the interaction between drug and carrier; Determination of in vitro release and then fitting the drug release data, to investigate the drug release mechanism of composite particles; after tail vein injection on the pharmacokinetics and tissue distribution characteristics, and compared. Results 1 injection with TPGS-SDS composite stabilizer PVPK30, space stabilizer, anti solvent precipitation by ultrasonic assisted method biogastrone acid nanosuspension, small particle size and uniform distribution (54 nm, PDI=0.370,.2) placed good stability within 90 days of glycyrrhetinic acid nano suspension, glycyrrhetinic acid - albumin nanoparticles can be further crosslinked to glycyrrhetinic acid albumin complex The latter particles, high entrapment efficiency, release effect is better. When the concentration of albumin was 7.5 mg/mL, adding 25% zinc chloride (10 L/mg BSA) and 0.1% glutaraldehyde amount (4 L/mg BSA) respectively after 1h cross-linking, the particles with uniform particle size (2 m), drug loading (30.2 + 1.18)%, the encapsulation rate (75 + 2.36)%, 0.5 in vitro h burst release of 28.1% and 8 h, the slow release formulation of more than 70%, the drug release behavior with the Higuchi model of.DSC, XRD and FTIR results showed that glycyrrhetic acid by BSA package and highly dispersed on.3 and glycyrrhetinic acid solution particle skeleton compared with glycyrrhetinic acid albumin composite particles by mice after intravenous injection, the peak concentration and the half-life was not significantly different, but the value of MRT0-24 and particle area under the concentration time curve is respectively 2.35 times and 2.8 times solution group, prolong the retention time of the drug in the blood, the relative bioavailability was improved tissue distribution of nodes. The results showed that the particles in the liver, the relative uptake rate of more than 1, in the heart, spleen, lung, kidney, brain to the total target coefficient was 3.75,2.11,3.11,2.82,8.53, showed that the particles can be selectively enriched in the liver, has liver targeting effect, and reduce the other tissue drug concentration. Conclusion the simple anti solvent precipitation and chemical crosslinking of the composite particles with uniform particle size, drug loading and encapsulation rate is high, has a certain release and liver targeting and bioavailability enhancement. The liver targeting dosage form of reference, and laid the foundation for the development of the new glycyrrhetinic acid preparation products.

【学位授予单位】：宁夏医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R943

【相似文献】