Development of a nalmefene formulation suitable for a community-use auto-injector

Time to onset of reversal is critical when treating opioid-induced respiratory depression and hypoxia. This study aimed to develop a formulation of the opioid antagonist nalmefene with an increased absorption rate and reduced time to onset of reversal following intramuscular administration.

Several absorption enhancers were screened in rats, followed by confirmatory studies in dogs. Subsequently, nalmefene formulations with a range of MgCl₂ concentrations were evaluated in a two-part translational clinical study in healthy participants. In Part 1 (N = 17), pharmacokinetic parameters were assessed following intramuscular injections of nalmefene formulated with MgCl₂ (0.47%-4.7%) or NaCl (0.9%). In Part 2 (N = 6), participants received intravenous fentanyl to produce opioid-induced respiratory depression. They were then dosed with intramuscular nalmefene formulated with 0.94% MgCl₂, intranasal naloxone or placebo (intramuscular saline) in a randomized six-period crossover sequence with each treatment administered on two separate occasions. Minute ventilation, oxygen saturation and carbon dioxide were monitored continuously, and pharmacokinetic and pharmacodynamic parameters were evaluated.

Pharmacokinetic profiles from animals indicated that MgCl₂ within a range of concentrations enhanced the nalmefene absorption rate. In the clinical studies, a nalmefene 1.5 mg formulation containing 0.94% MgCl₂ demonstrated more rapid absorption compared with a formulation containing 0.9% NaCl and also produced faster, more robust reversal of opioid-induced respiratory depression compared with intranasal naloxone.

These preclinical and clinical studies demonstrate that a nalmefene formulation containing magnesium chloride produced more rapid nalmefene absorption after intramuscular injection, which is advantageous for the treatment of opioid overdose in settings where life support is not immediately available.