Intratympanic delivery of dexamethasone palmitate-loaded lipid nanoparticles in dual viscosity hyaluronic acids hydrogel for prolonged retention and hearing loss treatment.

In this study, dexamethasone palmitate (DXP)-loaded solid lipid nanoparticles (DXP-SLNs) were incorporated into a dual-viscosity hyaluronic acids mixture-based hydrogel (DXP-SLNs DHA-gel) to prolong retention and improve hearing outcomes in ototoxic hearing loss. The optimized DXP-SLNs, formulated with DXP, stearyl alcohol, Tween 60, Span 60, and Myrj S40 at 1/1/1.2/0.2/5 (w/w ratios), showed a small particle size (125.3 nm), narrow PDI (0.289), adequate zeta potential (-24.6 mV), and high encapsulation efficiency (98.7 %). DXP-SLNs exhibited sustained in vitro drug release in artificial perilymph and mouse plasma. The DXP-SLNs DHA-gel also demonstrated favorable viscoelastic and flow properties for convenient injectability. After intratympanic administration to rats with ototoxic hearing loss, DXP-SLNs DHA-gel improved hearing ability, as demonstrated by lower auditory brainstem response thresholds at 8, 16, and 32 kHz frequencies compared to dexamethasone disodium phosphate solution (Dex-saline). Endoscopic examination revealed the biocompatibility and safety of the DXP-SLNs DHA-gel, as evidenced by recovery of the tympanic membrane without signs of inflammation or permanent perforation within 14 days. Furthermore, DXP-SLNs DHA-gel showed prolonged retention in the middle ear compared to Dex-saline (7.1 vs. < 1 day). Taken together, DXP-SLNs DHA-gel with enhanced therapeutic efficacy could be a promising intratympanic formulation for the treatment of auditory disorders.