Intratympanic dexamethasone microcrystal-loaded porous PLGA microspheres containing lipoic acid for combined delivery to the inner ear.

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

Methods: 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.

Results: 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.

Conclusions: 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.