Thesis Advisor马光辉, 吴有斌, 韦祎
Degree Grantor中国科学院大学
Degree Name硕士
Degree Discipline生物工程

盐酸罗哌卡因(Ropivacaine,ROP)通过与神经膜上的Na+通道结合,从而可逆地、暂时地阻断神经冲动传导,且在酰胺类局麻药中毒性较低,因此在临床上应用广泛。但ROP半衰期较短(t1/2=1.8 h),单次注射给药仅能满足2-4 h的镇痛效果,而临床上术后3-5天内需要持续镇痛。为了突破ROP自身的限制,本论文拟通过两种方法制备粒径均一、载药量高和释放行为理想的ROP缓释微球,具体研究内容包括以下三个方面:(1)采用W/O/W复乳法结合快速膜乳化技术的“前载药”模式,同时采用响应面法对制备微球过程中的各影响因素进行分析和优化,最终制备得到粒径为8.368 μm,Span值为0.852,载药量为1.76%的均一ROP-PLGA微球,与模型预测值的偏差小于7%。另外,体外释放结果表明前载药模式制备的载药微球0.5 h突释为1.45%,5天累积释放率约为70%,具有平稳的缓释作用。(2)为解决微球载药量偏低的问题,利用多孔PLGA微球“自愈合”特性,采用“后载药”模式,通过对多孔微球的优化和愈合条件考察,最终多孔微球在44℃下愈合2.5 h,得到粒径为38.158 μm,Span值为0.688,载药量为8.72%,0.5 h突释率为33.21%,3天累积释放率达到90%以上的多孔自愈合ROP-PLGA微球。(3)为评价制备的多孔自愈合ROP-PLGA微球的药效和安全性,构建了SD大鼠的坐骨神经阻滞模型。药效学结果显示ROP-PLGA微球给药组具有最长的感觉和运动神经阻滞时间;坐骨神经、主要脏器的H&E切片均未观察到炎症反应的发生,血液生化各项指标正常,说明ROP-PLGA微球制剂生物安全性良好。综上所述,本论文采用复乳法结合快速膜乳化技术的“前载药”模式制备了粒径均一的ROP-PLGA微球,释放较为平稳。采用多孔微球自愈合的“后载药”模式制备了载药量较高的多孔自愈合 ROP-PLGA微球,并成功建立了合理有效的动物实验模型,为其临床应用奠定基础。 ;Ropivacaine Hydrochloride (ROP) reversibly and temporarily blocks nerve impulse conduction by binding to Na+ channels on the nerve membrane, and has been widely used clinically based on its relatively low toxicity compared to other amide local anesthetics. However, ROP has a short half-life (t1/2=1.8 h), and a single injection can only satisfy the analgesic effect of 2-4 hours, while continuous analgesia is needed within 3-5 days after surgery. In order to break through the limitation of ROP, in this study, ROP-PLGA microspheres with uniform particle size, high drug load and sustained release behavior were prepared by two different methods. It includes the following three aspects:(1) ROP-PLGA microspheres were prepared by the premix membrane emulsification technique combined with W/O/W double emulsion solvent evaporation, which was called “pre-loading” mode. The response surface method (RSM) was used to analyze and optimize the factors affecting the preparation of ROP-PLGA microspheres. Finally, ROP-PLGA microspheres with particle size of 8.368 μm, Span value of 0.852 and drug loading of 1.76% were prepared and the deviation from the model was less than 7%. In addition, in vitro release results showed that the burst release of ROP-PLGA microspheres prepared by “pre-loading” mode at first 0.5 hour was only 1.45%, and the cumulative release rate was about 70% at 5 days.(2) In order to solve the problems of low drug loading of ROP-PLGA microspheres, porous PLGA microspheres with "self-healing" characteristics were prepared, which was called “post-loading” mode. Finally, the porous self-healing ROP-PLGA microspheres were obtained under healed at 44℃ for 2.5 hours, with particle size of 38.158 μm, Span value of 0.688, drug loading of 8.72%, the burst release at first 0.5 hour was 33.21% and accumulated release rate at 3 days reached more than 90%.(3) To evaluate the efficacy and safety of the prepared porous self-healing ROP-PLGA microspheres, the sciatic nerve block model of SD rats was established. The pharmacodynamic results showed that porous self-healing ROP-PLGA microspheres showed the longest sensory and motor nerve block time. H&E section showed that after 7 days of injection of porous self-healing ROP-PLGA microspheres, no inflammatory reaction was observed in the sciatic nerve and main organs on the side of the drug administration, and the blood biochemical indicators were normal, suggesting the satisfactory biological safety of porous self-healing ROP-PLGA microspheres.In summary, based on "pre-loading" mode, ROP-PLGA microspheres with uniform particle size were prepared by double emulsion method combined with the premix membrane emulsification technique, which showed relatively stable release behavior. In addition, based on “post-loading” mode, porous self-healing ROP-PLGA microspheres with high drug loading were obtained by using the self-healing properties of porous microspheres. The most important achievement is that a reasonable and effective animal experimental model was successfully established, which layed a foundation for its clinical application. 

Document Type学位论文
Recommended Citation
GB/T 7714
文康. 两种载药模式制备盐酸罗哌卡因微球及其药效学评价[D]. 中国科学院大学,2020.
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