The purpose of the present investigation was to design and compare the release characteristics of sustained-release formulations of Flurbiprofen (FLB) loaded nanoparticles (NPs) by using spray-dryer technique using Eudragit RLPO (RLPO), Eudragit RSPO (RSPO) and RLPO:RSPO 1:1 ratio. NPs Formulation were prepared by spray-dryer. Structures of nanoparticles were characterized by entrapment efficiency (EE%), dissolution study and release kinetic study with the DDSolver software program, particle size (PS), zeta potential, morphology, DSC, XRD, FTIR and H-1-NMR analyses. Cytotoxicity studies were performed on the NIH/3T3 mouse embryonic fibroblast cells. FLB-loaded NPs demonstrated nanostructural character while in vitro release study showed extended release of FLB-incorporated. The PS of the prepared FLB-NPs was affected by the polymer type and was in the range of 532 and 565 nm. Entrapment efficiency (EE %) varied from 70 to 76%, depending upon the polymer difference to drug ratio. According to the DDSolver criterion used to evaluate release kinetics, Korsmeyer-Peppas model were determined to be the most appropriate kinetic models for NPs. The results obtained in cell viability study indicate a dose and time dependent decrease in viability of NIH/3T3 for FLB and FLB-NPs. As a conclusion of this study; the effect of the polymer type on the PS, EE% and release properties of NPs has been examined and discussed in detail. According to results FLB-NPs seem to be a promising extended release drug delivery system for oral administration.