Buccal and sublingual lyophilised naloxone for opioid overdose reversal: A Phase 1 open-label, random-sequence crossover pharmacokinetic study protocol in healthy volunteers (NalBuc)

BACKGROUND: Opioid overdose remains a major global public health emergency, with naloxone being an essential response. Benefit from existing naloxone formulations is limited by barriers to acceptability, fixed dosing, and poor real-world carriage. This study describes the protocol for a Phase 1 exploratory investigation of a novel ultra-portable lyophilised naloxone wafer designed to facilitate constant carriage and enable rapid mucosal absorption. METHODS: This open-label, randomised, random-sequence, five-way crossover pharmacokinetic (PK) exploratory study will recruit 12-15 healthy adults at a UK clinical research facility. Participants will receive five treatments, each separated by ≥36 hours: buccal naloxone wafer 2 mg, buccal wafer 4 mg, sublingual wafer 2 mg, intramuscular naloxone 0.4 mg, and intranasal naloxone 1.8 mg (Nyxoid®). Blood samples will be collected up to 240 minutes post-dose for PK analysis via validated LC-MS/MS methods. The primary endpoint is time to maximum plasma concentration (Tmax). Secondary endpoints include Maximum Plasma Concentration (Cmax), Time to 50% of maximum concentration (T50%), Area Under the Curve from time zero to 15 minutes (AUC0-15), Area Under the Curve from time zero to infinity (AUCinf), and safety/tolerability. Dose-proportionality and buccal-sublingual comparisons will be explored. Trial Registration:REC: 25/LO/0701; MHRA CTA (IRAS): 1011060. ISRCTN67173532. RESULTS & SIGNIFICANCE: This study will characterise the absorption profile, early exposure, and relative bioavailability of a novel naloxone wafer formulated for rapid buccal and sublingual administration. Findings will inform whether this technology could provide a practical, effective alternative to current injectable and intranasal products, with potential to substantially improve naloxone carriage and timely overdose response, and will guide the design of a subsequent, larger confirmatory study.