Abstract: OBJECTIVE To optimize the preparation technology of mestinon poly (lactic acid) nanoparticle (MTPNP) by using central composite design and response surface methodology. METHODS The MTPNP was prepared by double emulsion solvent evaporation method and evaluated by entrapment efficiency and drug loading. The single factor method was firstly used to investigate preparation technology, and a circumscribed central composite design (CCD) approach was chosen to properly formulate MTPNP. The binomial equations were fitted to the data of overall desirability. Response surface methodology was used to select and predict optimum conditions. RESULTS The optimum conditions for the preparation of MTPNP selected by response surface optimization were: mestinon was 49.20 mg, the PLA concentration was 3.31%, the PVA concentration was 3.41%. Under the optimal conditions, the entrapment efficiency and drug loading capacity was (51.98±1.28) and (7.01±0.31) % (n=3), respectively, and compared with the predict results of quadratic model were less than 2%. CONCLUSION Central composite design-response surface methodology can be used as a quick and accurate method to optimize the preparation technology of MTPNP, and has a good predictability.