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The aim of the present work was to develop novel hydrogels for delivering sertaconazole based on cyclodextrins and various biocompatible polysaccharides. Sertaconazole is an antifungal agent very effective for treatment of Candida albicans infections. However its poor aqueous solubility is still a challenging issue for developing suitable formulations. Complexation with cyclodextrins is a very attractive route to overcome this limitation, simultaneously enhancing its antifungal effectiveness. Hydroxypropyl-cyclodextrin (HP CD) hydrogels prepared by direct cross-linking in presence of methylcellulose (MC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMCNa), or dextran were transparent and swelled in water without dissolving, which enables the formation of microenvironments very rich in cyclodextrin cavities responsible for hosting the drug and control its release rate. HP CD hydrogels showed a high capability to load sertaconazole (with partition coefficients from 22 to 470) while still combining high water affinity (superabsorbency), versatile biomechanical properties (hardness and compressibility) and sustained release behavior (up to 4 days). Importantly, sertaconazol-loaded hydrogels showed effectiveness against Candida albicans in culture medium. HP CD-polysaccharide hydrogels could be useful as sertaconazole delivery systems for the treatment of mucosal infections.