Purpose Currently the difficulty in the development of drug-loaded microspheres is the preparation technology, which are not suitable for industrialization due to their intermittent operation and difficult to control process, resulting in low encapsulation efficiency and wide particle size distribution.An Ultra-fine Particle Process System (UPPS) was initially developed by our group, which can continuously manufacture micron-sized spherical particle with a simple and reproducible operation to control mechanical parameters.The purpose of this study was to develop and validate risperidone-loaded PLGA-MPs (RIS-PLGA-MPs) used as a long-acting delivery system which was prepared by UPPS.Methods PLGA microspheres were prepared by UPPS and the optimal parameters as follow:rotating disc speed 4000 rpm;fluid feed speed 3rpm;PLGA (Mw=43000) concentration 4%.The surface morphology of the microspheres which release in medium at 1h, 1d, 7d, 14d and 21 d observed by SEM.In vitro release data were fitted in kinetics equations and morphology studies were used to explore the release mechanism of RIS-PLGA-MS.Further the pharmacokinetic study of RIS-PLGA-MS was performed on Beagles, 5-HTP induce head twitch test and catalepsy study in mice was employed to investigate the pharmacodynamics of the RIS-PLGA-MPs.Results The morphology and particle size of microspheres prepared by UPPS were summed up and a simple model diagram was proposed for formation of microspheres with UPPS.The characterization showed that drug content in PLGA microspheres had significant effect on appearance and vivo release.CLSM results showed that the saturated solubility of the drug in PLGA solution affected the drug distribution within the microspheres.The speed of rotating disc and fluid feed was in direct proportion to the release rate of microspheres.The pharmacokinetic results in Beagles showed that optimized RIS-PLGA-MPs possessed sustained properties without release delay, maintaining plasma RIS concentration higher than 20ng/ml for 10 days.The pharmacodynamics results in mice demonstrated that the microspheres could sustained inhibit the efficacy of 5-HTP till 11d.RIS-PLGA-MPs group compared to RIS solution group had a lower EPS incidence in the catalepsy test.Conclusion RIS-PLGA-MS produced by UPPS showed good characteristics such as high drug loading and high entrapment efficiency, narrow particle size distribution, low toxic residues and sustained release.The UPPS is suitable for large-scale manufacture of microspheres by regulating rotating disk speed, fluid feed speed and other parameters.