A Pseudo-Surfactant Chemical Permeation Enhancer to Treat Otitis Media via Sustained Transtympanic Delivery of Antibiotics.

Chemical permeation enhancers (CPEs) represent a prevalent and safe strategy to enable noninvasive 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, can compromise gelation, formulation stability, and drug diffusion. To overcome this challenge, differing interactions between CPEs and the hydrogel system are explored, especially those with sodium dodecyl sulfate (SDS), an ionic surfactant and a common CPE, and those with methyl laurate (ML), a nonionic counterpart with a similar length alkyl chain. Notably, the use of ML effectively decouples permeation enhancement from gelation, enabling sustained delivery across TMs to treat acute otitis media (AOM), which is not possible with the use of SDS. Ciprofloxacin and ML are shown to 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.

Engineering the Structure and Rheological Properties of P407 Hydrogels via Reverse Poloxamer Addition.

Aqueous solutions of poloxamer 407 (P407), a commercially available and nontoxic ABA triblock polymer (PEO-PPO-PEO), undergo a solution-to-gel transition with increasing temperature and are promising candidates for injectable therapeutics. The gel transition temperature, modulus, and structure are all dictated by polymer concentration, preventing independent tuning of these properties. Here, we show that addition of BAB reverse poloxamers (RPs) to P407-based solutions dramatically alters the gelation temperature, modulus, and morphology. Gelation temperature and RP localization within the hydrogel are dictated by RP solubility. Highly soluble RPs increase gelation temperature and incorporate primarily into the micelle corona regions. Alternatively, RPs with low aqueous solubility decrease gelation temperature and associate within the micelle core and core-corona interface. These differences in RP localization have significant implications for the hydrogel modulus and microstructure. The ability to tune gelation temperature, modulus, and structure through RP addition allows for the design of thermoresponsive materials with specific properties that are unobtainable with neat P407-based hydrogels.