Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose.

ABSTRACT: The opioid crisis, driven by synthetic opioids like fentanyl, demands innovative solutions. The opioid antidote naloxone has a short action ( ~ 1 hour), requiring repeated doses. To address this, we present a new and simple naloxone prodrug delivery system repurposing a hydrophilic derivative of acoramidis, a potent transthyretin ligand. When the fully soluble prodrug solution is administered subcutaneously, the prodrug forms a zwitterionic depot at physiological pH, enabling extended naloxone release. This non-polymeric depot-forming approach is rare and employs carboxylesterase 2 for selective bioactivation, ensuring controlled drug release. In male rats and cynomolgus monkeys, a single subcutaneous dose provides steady naloxone release over several days, reducing blood-brain barrier dif

SUBMITTER: Aldawod H 

PROVIDER: S-EPMC11758388 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature