尼非韦罗微乳热敏原位凝胶相变性和体外释药行为

In vitro drug release and phase transition of nifeviroc microemulsion thermosensitive in situ gel

目的以尼非韦罗(nifeviroc,NFVR)为模型药物制备一种微乳-热敏原位凝胶(microemulsion thermosensitive in situ gel,ME-TISG),并对该凝胶的制剂学性质进行考察。方法用温控(75℃)相图方法制备尼非韦罗微乳(nifeviroc microemulsion,NFVR/ME),并将其载入泊洛沙姆407(Poloxamer 407,P407)形成的凝胶中,用动态激光散射粒度仪及透射电子显微镜测定其粒径、ζ电位及形态,利用高级旋转流变仪对凝胶流变学进行研究;采用无膜溶出模型研究在频率100 r·min-1下,NFVR/ME的释放与凝胶溶蚀之间的关系。结果不同浓度NFVR/ME的平均粒径为36.30~38.25 nm,且呈圆整均一球体,ζ电位-7.15^-7.22 mV,相转变温度为29.5℃,胶凝温度为34.5℃,NFVR/ME-TISG在低温(<25℃)时为牛顿流体,黏度很小;随着温度升高,黏弹性增大,在35~37℃表现出典型的假塑性流体特征,复数黏度随着剪切速率的升高而逐渐减小,呈现剪切变稀现象。ME中NFVR的释放率受控于凝胶的溶蚀速率,二者呈现良好的线性关系(R2=0.98),遵循零级动力学特征,这种由溶蚀控制药物释药的方式可以避免突释效应。结论热敏原位凝胶是一种具有应用前景的新型阴道释药系统。

Objective To prepare a kind of microemulsion thermosensitive in situ gel(ME-TISG) with nifeviroc(NFVR)as a model drug, and to explore its pharmaceutical properties. Methods Nifeviroc microemulsion(NFVR/ME) were prepared by temperature(75℃) control phase diagram and loaded into P407 gel. The particle size, ζ potential and morphology of the ME were analyzed by ZetePALS Zeta Potential Analyzer and Transmission Electron Microscope, and the rheology property was determined by Senior rotary rheometer. The correlation between NFVR/ME release and gel dissolution under a frequency of 100 r·min-1 was studied using non-membrane model. Results Average particle size of different concentration NFVR/ME was 36.30-38.25 nm and ζ potential was-7.15--7.22 mV. It showed that the micromorphology of ME was in round flat sphere shape. Sol-gel transition temperature and gelation temperature of the TISG was 29.5℃ and 34.5℃ respectively. NFVR/ME-TISG appeared to be newtonian fluid at low temperature(<25℃) with low viscosity. The viscosity of ME increased as temperature rose and it showed a typical pseudoplastic fluid characteristics as to 35-37℃. The complex viscosity decreased gradually with the increase of shear rate, suggesting a shear-thinning behavior. In vitro release rate of NFVR was controlled by gel dissolution rate with good linear relationship(R2=0.98), following the zero order kinetics. Such gel dissolution-controlling drug release mode can avoid burst release effect. Conclusion ME-TISG is a promising new vaginal drug delivery system.