Drug Nanocrystal-Loaded Thermo-Reversible Hydrogels of Dexamethasone Palmitate for Intratympanic Drug Delivery

Intratympanic (IT) injection of corticosteroids is a standard clinical treatment for sensorineural hearing loss; however, achieving both biocompatibility and efficient cochlea drug delivery remains a significant challenge. Herein, we engineered a novel drug nanocrystal (NS)-loaded thermo-reversible hydrogel (NS-TG) system of dexamethasone-21-palmitate (DEX-P), a lipophilic prodrug of dexamethasone (DEX), for improved IT delivery. NSs with a mean diameter of 835.0 nm were fabricated using a dual centrifugation process with polyvinyl alcohol as the stabilizer. The NS-TG system, comprising NSs in a 19% (w/v) Poloxamer 407 hydrogel, exhibited rapid gelation (2-3 min) and a 31-fold increase in drug solubility (1.57 ± 0.02 mg/mL) compared to NS alone, through micellar solubilization. In vitro cytotoxicity assays in HEI-OC1 cells revealed that NS-TG is highly biocompatible, maintaining cell viability, whereas the commercial lipid emulsion (Lipothason^®) induced significant cytotoxicity. In vivo pharmacokinetic evaluation in mice revealed that IT NS-TG provided superior cochlear drug absorption compared to DEX-SP solutions and DEX-P NS, despite showing lower absorption than the lipid emulsion. These findings suggest that the DEX-P NS-TG system, pending further investigation, could serve as a promising platform for cochlear steroidal delivery, offering an optimal balance between delivery efficiency and local safety for treating inner ear diseases.