The present investigation aims at developing models by response surface methodology (FCCCD) followed by the scale-up method in preparing control release microsponge particles loaded with 5- fluorouracil, a drug used to treat actinic keratosis and colon cancer, and producing a new Dermal Delivery System. The polymer-based (ethyl cellulose and eudragit RS 100) microsponge particles were prepared by the w/o/w double emulsification method. The optimized product was formed with the combination of independent variables levels: polymer (600 mg), stirring speed (1198 rpm) and surfactant (2% w/v), yielding responses as yield (~63.6257%), the average size of particles (~151.563 µm), entrapment efficiency (~75.319 %) and drug release in 8hr (~75.75%), with desirability value of 0.737. The products showed similar responses as obtained in scale-up work. FT-IR, DSC and SEM studies confirmed the drug's compatibility with polymers and porous morphology. Finally, gel embedded optimised product showed shear-thinning rheological property, ideal for drug release from the thixotropic gel.