: Clobetasol propionate (CP) is a potent corticosteroid used for skin conditions but often causes side effects due its systemic absorption. To improve its solubility and reduce it side effects (like skin irritation, skin atrophy, hypopigmentation and steroidal acne), Microsponge (Msg) has been employed as a unique three-dimensional particle that can encapsulate hydrophilic and lipophilic drugs. This study aims to develop and evaluate CP Msg-loaded hydrogels. Two Clobetasol-loaded ethylcellulose-based Msg formulas were prepared using the quasi-emulsion solvent diffusion method, then they were incorporated into Carbopol hydrogel. Two ratios of Carbopol 940 (1% and 1.5% w/w) were used. The prepared hydrogel were assessed for appearance, pH, drug content, spreadability, extrudability, rheology, and in vitro release. The optimum hydrogel was compared to generic CP cream available locally and plain hydrogel. The results showed that both Msg formulas had good product yield, entrapment efficiency and highly porous micron size. The four prepared hydrogels revealed acceptable characterization including; pH ranged between 5.6and 6, drug content (98.8- 100%) and % extrudability (80.7-92%) with pseudoplastic flow type. The hydrogel formula (F2Ha 1%) containing (1:1 weight ratio of CP: ethylcellulose) with (1%w\w Carbopol) was chosen as the optimized formula since it showed the highest spreadablility and approximately 43% of CP was released at 8 hours. The ex-vivo data including; the highest deposition in stratum corneum and epidermal/ dermis with the flux, permeability coefficient and lag time of F2Ha were low, compared to plain hydrogel and marketed cream. Based on the study՚s finding, we concluded that CP Msg-loaded Carbopol hydrogel is a proper drug delivery system for topical application with minimized systemic absorption
