A pseudo-surfactant chemical permeation enhancer to treat otitis media via sustained transtympanic delivery of antibiotics.

Abstract

Chemical permeation enhancers (CPEs) represent a prevalent and safe strategy to enable non-invasive drug delivery across skin-like biological barriers such as the tympanic membrane (TM). While most existing CPEs interact strongly with the lipid bilayers in the stratum corneum to create defects as diffusion paths, their interactions with the delivery system, such as polymers forming a hydrogel, could compromise gelation, formulation stability, and drug diffusion. To overcome that challenge, we explore the differing interactions present with sodium dodecyl sulfate (SDS), an ionic surfactant and a common CPE, and methyl laurate (ML), a non-ionic counterpart with a similar length alkyl chain. Notably, we show that the use of ML effectively decouples permeation enhancement from gelation, enabling sustained delivery across TMs to treat acute otitis media (AOM) that is not possible with the use of SDS. We reveal that ML and ciprofloxacin form a pseudo-surfactant that significantly boosts transtympanic permeation. The middle ear ciprofloxacin concentration is increased by 70-fold in vivo in a chinchilla AOM model, yielding superior efficacy and biocompatibility than the previous highest-performing formulation. Beyond improved efficacy and biocompatibility, this single-CPE formulation significantly accelerates its progression toward clinical deployment. This article is protected by copyright. All rights reserved.