Permeation enhancers for intratympanically-applied drugs studied using fluorescent dexamethasone as a marker

Hypothesis: Entry of locally applied drugs into the inner ear can be enhanced by chemical manipulations. Background: Perilymph drug concentrations achieved by intratympanic applications are well below the applied concentration due to limited entry through the round window (RW) membrane and stapes. Chemical manipulations to increase entry permeability could increase the effectiveness of drug therapy with local applications. Methods: Dexamethasone-fluorescein (F-dex) was used as an entry marker. F-dex was applied to the RW niche of Guinea pigs as a 20 μL bolus of 1 mM solution. After a 1 hour application, 10 samples of perilymph were collected sequentially from the lateral semicircular canal, allowing F-dex distribution throughout the perilymph to be quantified. Entry was also measured with the applied solution additionally containing dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), saponin, caprate, benzyl alcohol (BA) or poloxamer 407 (P407). Combinations of saponin or BA with P407 were also compared. Results: In control experiments, F-dex entered the inner ear slowly at both the RW and stapes. The total F-dex recovered in all 10 samples from each animal averaged 2.1 pMoles for controls, 1.71 pMoles for 17% P407, 3.70 pMoles for caprate, 8.04 pMoles for DMSO, 16.32 pMoles for NMP, 31.0 pMoles for saponin, and 67.3 pMoles for 4% BA. Entry with DMSO, NMP, saponin and 4% BA were all significantly higher than the controls (one-way ANOVA). Conclusion: These studies confirm that entry of drugs into the ear can be markedly enhanced with the use of chemical permeation-enhancing agents.