基于响应面法对制备高包埋率ROP-PLGA微球的影响因素分析  

Analysis of preparation factors of ROP-PLGA microspheres with high encapsulation efficiency based on response surface method

作　　者：文康 韦祎[1] 马光辉[1,2] Kang WEN;Yi WEI;Guanghui MA(State Key Laboratory of Biochemical Engineering,Institute of Process Engineering,Chinese Academy of Sciences,Beijing 100190,China;School of Chemical Engineering,University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]中国科学院过程工程研究所生化工程国家重点实验室,北京100190 [2]中国科学院大学化学工程学院,北京100049

出　　处：《过程工程学报》2021年第1期83-91,共9页The Chinese Journal of Process Engineering

基　　金：国家重大科技专项(编号:2017ZX09201004014)。

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(t_(1/2)=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/W_(2))体积比1:7.5、复乳液搅拌速率300 r/min、过膜压力10 k Pa条件下得到粒径为7.831μm,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17.6μg/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。As a novel amide local anesthetic,ropivacaine(ROP)is widely used in postoperative pain management.However,ROP has a short half-life(t_(1/2)=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 7.831μm 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/W_(2)),300 r/min of stirring rate of predouble emulsion as well as 10 k Pa of trans-membrane pressure.Additionally,factors such as the p H 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 p H 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 17.6μg/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.

关 键 词：盐酸罗哌卡因 快速膜乳化 复乳法 微球 响应面法 

分 类 号：R944.27[医药卫生—药剂学]