复合三联抗结核药聚乳酸-羟基乙酸缓释微球的制备及体外释药特性

Preparation of composite HRZ/PLGA slow-release microspheres and its drug release characteristics in vitro

目的 :制备复合异烟肼(H)、利福平(R)、吡嗪酰胺(Z)的聚乳酸-羟基乙酸(HRZ/PLGA)缓释微球,观察其理化性质和体外缓释特性。方法:以PLGA(450mg)为载体,避光条件下称取H(40mg)、R(60mg)、Z(125mg),采用复乳-溶剂挥发法制备HRZ/PLGA缓释微球,应用扫描电镜观察微球的形态特征;应用高效液相色谱法(HPLC)测定其载药量、包封率;采用溶出法、HPLC于3h、6h、12h、1d、2d、3d、6d、9d、12d、15d、20d、25d、30d、40d、50d测定H、R、Z三种药物的浓度,观察其是否均大于10倍最低抑菌浓度(MIC),计算其日均释药率、累计释药率。结果:HRZ/PLGA微球在电镜下观察呈圆球形,平均粒径为10.3±4.7μm;H、R、Z三种药物的载药量分别为(18.02±0.36)%、(22.46±0.24)%、(21.68±0.37)%,包封率分别为(54.79±1.13)%、(72.35±0.39)%、(67.21±0.68)%;体外缓释试验显示微球缓释前12d左右,三种药物的累计缓释度均超过了50%,日均释药率分别为5.05%、4.89%、6.86%;第12天后三药的缓释基本趋于稳定,日均释药率分别为0.17%、0.26%、0.16%;三种药物缓释到50d时均大于10倍MIC。结论:HRZ/PLGA微球具有优良的载药及药物缓释效果,是一种理想的复合抗结核药物缓释系统。

Objectives：To prepare the compound isoniazid（H）,rifampicin（R） and pyrazinamide（Z）/polylactic acid-glycolic acid （PLGA）（HRZ/PLGA） sustained release microspheres,and to investigate the physical and chemical properties and slow-release characteristics in vitro.Methods：By using PLGA as the carrier,the HRZ/PLGA microspheres were prepared by emulsifying-solvent evaporation technique under dark conditions,H （40mg）,R（60mg）,Z（125mg）,PLGA（450mg）.The characteristics of HRZ/PLGA microspheres were observed under scanning electron microscopy （SEM）.The drug-loading and encapsulation rate was evaluated by High performance liquid chromatography（HPLC） in simulated body fluid.The H,R,Z drugs concentration were detected by stripping and HPLC at 3h,6h,12h,1d,2d,3d,6d,10d,12d,15d,20d,25d,30d,40d,50d,respectively,in simulated body fluid in vitro and whether greater than minimal inhibitory concentrations（MIC） of 10 times or not was also observed,the average daily release rate and cumulative release rate were calculated by fitted mathematical equations in vitro.Results：HRZ/PLGA microspheres presented as round ball under the SEM,the average particle size was 10.3±4.7μm,drug loading of H,R,Z was （18.02±0.36）％,（22.46±0.24）％,（21.68±0.37）％ respectively,encapsulation rate was （54.79±1.13）％,（72.35±0.39）％,（67.21± 0.68）％ respectively.In vitro the HRZ/PLGA microspheres of cumulative sustained release of three drugs were more than 50％ before 12d,the average daily release rate was 5.05％,4.89％,6.86％.And at the first 12d,the three drugs of release were basically stable,the average daily release rate was 0.17％,0.26％,0.16％ respectively.Three drugs concentrations were ten times greater than the MIC even at 50 days.Conclusions：With perfect drug loading and slow release effect,HRZ/PLGA microsphere is an ideal anti-TB drug slow-release complex.