Extended local anesthesia enabled by flavonoid permeation enhancers

Prolonged local anesthesia remains a major challenge in clinical pain management due to the limited penetration of hydrophilic anesthetics across biological barriers. This study introduces flavonoids as chemical permeation enhancers to improve delivery of tetrodotoxin and similar agents across tissue barriers. Flavonoids are shown to be generalizable permeation enhancers by demonstrating efficacy in both tympanic membranes and sciatic nerves. These enhancers enabled nerve blocks lasting up to 2 d following a single injection and over 25 d with a liposomal delivery system. This work demonstrates the utility of flavonoids as natural permeation enhancers for free and encapsulated hydrophilic drugs, as seen in the extremely long durations of nerve block demonstrated here. Site 1 sodium channel blockers (S1SCBs), such as tetrodotoxin (TTX) and neosaxitoxin, are ultrapotent local anesthetics with low tissue toxicity. Their duration of action is relatively brief, but increasing the dose can lead to systemic toxicity. Here, we report that selected flavonoids?puerarin (PUE), naringenin, and kaempferol?prolong nerve block from S1SCBs 4- to 25-fold. Using both tympanic membrane (TM) permeation and sciatic nerve fluorescence distribution models, we demonstrate the flavonoids increase drug penetration across biological barriers (the TM and the barriers in and around nerve), suggesting that they act as chemical permeation enhancers (CPEs). Importantly, flavonoids exhibited minimal tissue toxicity compared to conventional CPEs. Coencapsulation of TTX and PUE into a liposomal delivery system further prolonged local anesthesia to over 25 d from a single injection. These findings establish flavonoid compounds as a safe class of CPEs and provide a platform of long-acting, nonopioid pain therapies. Flavonoids may be attractive alternatives to conventional CPEs in biomedical applications.

Keywords: Q1 2026