Abstract: As a novel amide local anesthetic, ropivacaine (ROP) is widely used in postoperative pain management. However, ROP has a short half-life (t1/2=1.8 h), and multiple doses in clinical is needed to meet the demand for analgesia, resulting in poor patient compliance. In this study, ROP-PLGA microspheres were prepared by using the premix membrane emulsification technique combined with the double emulsion-solvent evaporation method. Finally, the uniform microspheres with particle size of 7.831 μm and Span value of 0.874 were prepared under 1.5% (w/v) of PVA in external aqueous phase, 1:7.5 of volume ratio of oil phase-external aqueous phase (O/W2), 300 r/min of stirring rate of pre-double emulsion as well as 10 kPa of trans-membrane pressure. Additionally, factors such as the pH of external water phase, PLGA concentration in oil phase and internal water phaseoil phase volume ratios (W1/O) on the effect of encapsulation efficiency (EE) and the drug loading (DL) were investigated based on response surface method (RSM). The optimal formulation and process parameters designed by RSM were as follow: the pH of the external water phase was 11, PLGA concentration in oil phase was 15%(w/v), internal water phaseoil phase volume ratios (W1/O) were 1:10. Moreover, the model predicted the DL of 17.6 μg/mg and the EE of 53.89% were predicted by RSM model. In the meanwhile, repeatability test showed that the DL was (18.0±0.5) μg/mg and the EE was (55.7±2.69)%. Eventually, the relative error was insignificant (less than 7%), which meant the model was reliable. In vitro release profile showed that the cumulative release of ropivacaine loaded microspheres at three and five days was about 50% and 70% respectively, which indicated that the prepared ROP-PLGA microspheres had a stable sustained release effect and microsphere bioformulation had great potential in the field of sustained release of local anesthetics.

Key words: ropivacaine hydrochloride, the premix membrane emulsification, double emulsion method, microsphere, response surface method

摘要： 作为一种新型酰胺类局部麻醉药，罗哌卡因(ROP)被广泛用于术后的疼痛管理中。ROP半衰期短(t1/2=1.8 h)，临床上为满足患者的镇痛需求，常需多次给药，导致患者顺应性差。采用复乳溶剂挥发法结合快速膜乳化技术制备ROP-PLGA微球，最终在外水相PVA浓度1.5%(w/v)、油相与外水相(O/W2)体积比1:7.5、复乳液搅拌速率300 r/min、过膜压力10 kPa条件下得到粒径为7.831 μm，Span值为0.874的均一PLGA微球。基于响应面法设计实验考察了外水相pH、油相PLGA浓度、内水相与油相(W1/O)体积比等因素对微球包埋率及载药量的影响，模型优化的条件：外水相pH为11、油相PLGA浓度为15% (w/v)、内水相与油相(W1/O)体积比1:10。模型预测载药量为17.6 μg/mg，包埋率53.89%，重复性验证实验测得载药量(18.0±0.5) μg/mg，包埋率(55.7±2.69)%，相对误差小于7%，证明模型可靠。体外释放结果显示，3天累计释放率约为50%，5天累计释放率约为70%，表明制备的ROP-PLGA微球具有平稳的缓释作用，微球制剂在局麻药缓释领域具有巨大的潜力。

关键词: 盐酸罗哌卡因, 快速膜乳化, 复乳法, 微球, 响应面法