(626f) Thermo-Sensitive Block Copolymers for the Local Delivery of Antibiotics

Hydrogel with reverse thermal gelation has been an important tool in drug delivery. Some of them, such as poloxamer 407 (P407), have been approved by the FDA for topical applications. Despite the clinical importance of P407, the assembly of P407 in the presence of therapeutics and other bioactive molecules has not been well understood. That deficiency in the literature deterred the rational design of thermo-sensitive hydrogels and limited their facile incorporation into clinical practice. We have bridged this gap by elucidating the effects of some of the most common molecules delivered using P407 (chemical permeation enhancers, antibiotics, and anesthetics) on the gelation mechanism of P407. We also provided a path forward to overcoming the detrimental interactions and rendering the gelation more robust in the presence of small molecules, achieved by chemically modifying P407.

As a proof-of-principle, the chemically modified P407 was used to treat otitis media (OM), the most common reason for antimicrobial prescription in US children. Our current treatment option, the requisite 7-10 day course of oral antibiotics, can be challenging to deliver in children, entailing potential systemic toxicity and encouraging selection of antibiotic-resistant bacteria. Building upon the modified P407, we developed a drug delivery system which, when applied once to the tympanic membrane (TM) through the external auditory canal, delivers an entire course of antimicrobial therapy to the middle ear. The pentablock copolymer was designed to flow easily during application then form a hydrogel on the TM. Chemical permeation enhancers within the drug delivery system then assisted flux of the antibiotic (ciprofloxacin) across the TM. This drug delivery system successfully treated OM from non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae in a chinchilla animal model. Biocompatibility was excellent, and ciprofloxacin was undetectable in blood (i.e. no systemic antibiotic exposure).