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Silver sulfadiazine has been frequently used as an antibacterial agent for topical treatment of partial thickness burn wounds. In this study, we present the preparation of silver sulfadiazine microsponges by w/o/w emulsion solvent evaporation method. Formulation variables were optimized by using 3 2 factorial design. The optimized microsponges were characterized by FTIR, DSC, PXRD, particle size analysis, SEM analysis and mercury intrusion porosimetry studies. Viscosity, texture analysis and ex vivo drug deposition study of optimized microsponge loaded gel were also evaluated. The safety of the optimized gel was assessed by MTT assay using epidermal keratinocyte (HaCaT) and mouse embryonic fibroblast (NIH-3T3) cell lines. In vitro antibacterial studies were carried out to compare the antibacterial inhibitory efficiency of the optimized gel against the commercial product. The efficacy of the optimized gel was evaluated by the partial thickness (second degree) burn wound model in mice. Optimized microsponge loaded gel enhanced the drug retaining capacity in the skin layers, by 3 fold higher to that of a commercial product. The antibacterial inhibitory efficiency of optimized gel was similar to the commercial product against the Staphylococcus aureus and Pseudomonas aeruginosa. Optimized gel showed reduced frequency of application, no skin irritation, low cytotoxicity on dermal cell lines and enhanced wound contraction., (Copyright © 2016 Elsevier B.V. All rights reserved.)