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Donepezil free base was encapsulated into carboxyl terminal PLGA matrix to obtain high drug loading and encapsulation efficiency. The formulation which sustained release for one week both in vitro and in vivo was designed in order to fulfill various clinical demands. A good correlation between in vitro and in vivo data was obtained. AbstractThe purpose of this study was to develop a PLGA microspheres-based donepezil (DP) formulation which was expected to sustained release DP for one-week with high encapsulation efficiency (EE). DP derived from donepezil hydrochloride was encapsulated in PLGA microspheres by the O/W emulsion-solvent evaporation method. The optimized formulation which avoiding the crushing of microspheres during the preparation process was characterized in terms of particles size, morphology, drug loading and EE, physical state of DP in the matrix and in vitro and in vivo release behavior. DP microspheres were prepared successfully with average diameter around 30 μm, drug loading of 15.92 ± 0.31% and EE up to 78.79 ± 2.56%. Scanning electron microscope image showed it has integrated spherical shape with no drug crystal and porous on its surface.Differential scanning calorimetry and X-ray diffraction results suggested DP was in amorphous state or molecularly dispersed in microspheres. The Tg of PLGA was increased with the addition of DP. The release profile in vitro was characterized with slow but continuous release lasted for about one week and fitted well with First-order model, which suggested the diffusion governing release mechanism. After single-dose administration of DP microspheres via subcutaneous injection in rats, the plasma concentration of DP reached peak concentration at 0.50 d, and then declined gradually, but was still detectable at 15 day. A good correlation between in vitro and in vivo data was obtained.The results suggest the potential use of DP microspheres for treatment of Alzheimer's disease over long periods.