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With the objective to achieve prolonged drug release, especially for the treatment of diabetes mellitus, and thereby to reduce the side effects of administration of conventional dosage form, repaglinide loaded PMMA nanoparticles have been formulated. These nanoparticles have been developed by solvent evaporation method and were subjected to various studies for characterization including photon correlation spectroscopy (PCS), scanning electron microscopy (SEM) and X-ray diffraction (XRD). These studies favorably revealed that the mean particle diameter of optimized formulation was 108.3 nm and had spherical morphology with amorphous nature.Moreover, these particles were also subjected to Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermo gravimetric analysis (TGA) for compatibility analysis between drug and polymer. The results were positive and showed that, there were no interaction between drug and polymer. The optimized formulation demonstrated favorable in vitro prolonged release characteristics. Experimental in vitro release data were substituted with available mathematical models to establish the mechanism of release of repaglinide and was found to follow zero order, diffusion and erosion mechanisms.The in vivo toxicity study in albino rats showed no significant change in biochemical and pathological examinations. Hence, the designed system could possibly be advantageous in terms of prolonged release, to achieve reduced dose frequency and improve patient compliance of repaglinide.