To develop a sustained-release codelivery system for intratympanic administration of dexamethasone (DEX) and lipoic acid (LA).

DEX microcrystals (MCs) were prepared via precipitation, while LA-loaded porous PLGA microspheres (LPMPs) were fabricated using a double emulsion–solvent evaporation method. DEX MCs were physically perfused into LPMPs via negative pressure to form a combined system (DEX MCs+LPMPs). Physicochemical properties, in vitro drug release, pharmacokinetics, and biocompatibility were evaluated. Guinea pigs were used for intratympanic injections of DEX MCs, LPMPs, or DEX MCs+LPMPs.

The DEX MCs+LPMPs system enabled simultaneous release of both drugs, with DEX exhibiting superior pharmacokinetics (sustained perilymph concentrations up to 7 days) compared to DEX MCs alone. LA release from LPMPs demonstrated prolonged kinetics without burst release. SEM confirmed DEX MCs were localized within/on LPMPs and adhered to the round window membrane (RWM). Histological analysis revealed normal cochlear morphology and no inflammatory response, confirming biocompatibility.

This novel codelivery system combining microcrystals and porous microspheres achieves sustained dual-drug release, enhances therapeutic efficacy, and offers a promising strategy for managing hearing loss via intratympanic administration.