Development of a nalmefene formulation suitable for a community‐use auto‐injector
- 1Knoa Pharma LLC Stamford Connecticut USA
- 2Elacon LLC Princeton New Jersey USA
- 3Ohio Clinical Trials LLC Columbus Ohio USA
Abstract
Aim: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
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BibTeX
@article{cipriano2026development,
title = {{Development of a nalmefene formulation suitable for a community‐use auto‐injector}},
author = {Alessandra Cipriano and Manjunath S. Shet and Hugh Huang and Ronnie Ortiz and Garth T. Whiteside and Glen Apseloff and Stephen C. Harris},
journal = {British Journal of Clinical Pharmacology},
year = {2026},
month = jul,
doi = {10.1002/bcp.70685},
url = {https://doi.org/10.1002/bcp.70685},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Development of a nalmefene formulation suitable for a community‐use auto‐injector
AU - Alessandra Cipriano
AU - Manjunath S. Shet
AU - Hugh Huang
AU - Ronnie Ortiz
AU - Garth T. Whiteside
AU - Glen Apseloff
AU - Stephen C. Harris
PY - 2026
DA - 2026/07/14
JO - British Journal of Clinical Pharmacology
DO - 10.1002/bcp.70685
UR - https://doi.org/10.1002/bcp.70685
AB - Aim: 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. Methods: 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. Results: 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. Conclusion: 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.
SN - 0306-5251
SN - 1365-2125
ER -