不同处方喷昔洛韦微乳体外特性及小鼠体内分布研究

In Vitro Release and in Vivo Distribution in Mice of Penciclovir-loaded Microemulsions with Different Formulation and Process

目的探讨微乳处方(表面活性剂种类及用量)及制备工艺对喷昔洛韦微乳体内分布的影响。方法考察Cremophor EL自发微乳(PCV-ME6)、Cremophor EL均质微乳(PCV-MEho)和去氧胆酸钠微乳(PCV-MEde)此3种载喷昔洛韦微乳的粒径分布、zeta电位、体外释放及在小鼠体内分布特征。结果各载药微乳粒径均小于100nm,zeta电位在-3mV至0mV之间;各载药微乳均延缓了喷昔洛韦的体外释放,其中PCV-MEde与喷昔洛韦溶液(PCV-S)相比释放呈现显著差异(f2<50);PCV-MEde使喷昔洛韦肾脏消除明显变慢,AUC为PCV-S的3.5倍。PCV-MEde在各组织和血浆的AUC也均明显大于其它微乳和PCV-S。结论表面活性剂种类对喷昔洛韦的体内分布有显著影响。PCV-MEde静注后,表面活性剂去氧胆酸钠与磷脂发生相互作用,结合形成脂质囊泡。喷昔洛韦由于被包裹在亲水内核,从而改变了喷昔洛韦的释放和体内过程。而微乳制备工艺引起药物的体内过程的差异,可能是由于表面活性剂用量小造成微乳粒径较大所致。

OBJECTIVE To study the effect of various surfactants and various preparing process on in vivo distribution of penciclovir-loaded microemulsions. METHODS Drop sizes, zeta potential and in vitro release and in vivo distribution of three penciclovir-loaded microemulsions were investigated. They are Cremophor EL microemulsion by self-emulsifying （PCV-ME6）, Cremophor EL microemulsion by homogenizing （PCV-MEho）, sodium deoxycholate microemulsion by self-emulsifying （PCV-MEde）. RESULTS Drop sizes of all penciclovir-loaded microemulsions were smaller than 100 nm, zeta potential between -3 mV and 0 mV. In vitro release of all penciclovir-loaded microemulsions were delayed, but only PCV-MEde showed evident difference from that of penciclovir solution （PCV-S） with f2 less than 50. PCV-MEde obviously increased penciclovir concentration in the brain and decelerated the clearance of penciclovir from kidney with AUC 3.5 folds higher than PCV-S. AUCs of PCV-MEde in plasma and other tissues also were distinctly higher than those of PCV-S and other penciclovir-loaded microemulsions. CONCLUSION What surfactants we choose greatly affect in vivo disposition of penciclovir. The microstructure of PCV-MEde might have changed during dilution after iv administration. A reassembly could take place between lecithin and sodium deoxycholate due to their strong interaction, which resulted in formation of lipid vesicles. Penciclovir is then solubilized into hydrophilic core of lipid vesicles and its release and disposition were changed. The different in vivo disposition of microemulsions made by self-emulsifying and homogenizing （PCV-ME6 ＆ PCV-MEho） likely depended on less surfactant content of the later which is related to bigger drop sizes.