摘要This study aimed to prepare poly(D,L-lactic-co-glycolic acid)microspheres(PLGA-Ms)by a modified solid-in-oil-in-water(S/O/W)multi-emulsion technique in order to achieve sustained release with reduced initial burst and maintain efficient drug concentration for a prolonged period of time.Composite PLGA microspheres containing exenatide-encapsulated lecithin nanoparticles(Ex-NPs-PLGA-Ms)were obtained by initial fabrication of exenatide-loaded lecithin nanoparticles(Ex-NPs)via the alcohol injection method,followed by encapsulation of Ex-NPs into PLGA microspheres.Compared to Ms prepared by the conventional water-in-oil-in-water(W/O/W)technique(Ex-PLGA-Ms),Ex-NPs-PLGA-Ms showed a more uniform particle size distribution,reduced initial burst release,and sustained release for over 60 d in vitro.Cytotoxicity studies showed that Ms prepared by both techniques had superior biocompatibility without causing any detectable cytotoxicity.In pharmacokinetic studies,the effective drug concentration was maintained for over 30 d following a single subcutaneous injection of two types of Ms formulation in rats,potentially prolonging the therapeutic action of Ex.In addition,administration of Ex-NPs-PLGA-Ms resulted in a more smooth plasma concentration-time profile with a higher area under the curve(AUC)compared to that of Ex-PLGA-Ms.Overall,Ex-NPs-PLGA-Ms prepared by the novel S/O/W method could be a promising sustained drug release system with reduced initial burst release and prolonged therapeutic efficacy.