Biodistribution and transport of intratympanically administered drugs in the inner ear using a porcine ex-vivo chamber model.

Effective pharmacotherapy for hearing loss remains a significant challenge because of the blood-labyrinth barrier, which limits systemic drug access and often necessitates local intratympanic (IT) administration. However, the distribution of drugs after IT injection between the vestibular system and cochlea is unclear. Although the round window membrane is the main recognized entry route, in this study, we explored alternative pathways, namely the oval window (OW) and the thin apical otic capsule, using an ex vivo porcine model to assess their permeability to different solvent vehicles. We demonstrated that the route of entry is critically on the solvent composition and additives; in particular, reconstituting dexamethasone-fluorescein in dimethyl sulfoxide enhanced permeability through the OW by 42-fold compared to that with methanol, establishing the OW as a pathway for this solvent type rather than the RWM. Furthermore, we identified the thin apical otic capsule as a third drug-entry route in young pigs. Surgical sealing of this pathway in vivo, which reduces perilymph drug levels, underscores its importance in human translational studies. In summary, we developed a robust ex vivo multi-barrier model integrated with FluidSim to predict the inner ear drug biodistribution.