Engineering Quick- and Long-acting Naloxone Delivery Systems for Treating Opioid Overdose.

Purpose: Opioids have been the main factor for drug overdose deaths in the United States. Current naloxone delivery systems are effective in mitigating the opioid effects only for hours. Naloxone-loaded poly(lactide-co-glycolide) (PLGA) microparticles were prepared as quick- and long-acting naloxone delivery systems to extend the naloxone effect as an opioid antidote.

Methods: The naloxone-PLGA microparticles were made using an emulsification solvent extraction approach with different formulation and processing parameters. Two PLGA polymers with the lactide:glycolide (L:G) ratios of 50:50 and 75:25 were used, and the drug loading was varied from 21% to 51%. Two different microparticles of different sizes with the average diameters of 23 μm and 50 μm were produced using two homogenization-sieving conditions. All the microparticles were critically characterized, and three of them were evaluated with β-arrestin recruitment assays.

Results: The naloxone encapsulation efficiency (EE) was in the range of 70-85%. The EE was enhanced when the theoretical naloxone loading was increased from 30% to 60%, the L:G ratio was changed from 50:50 to 75:25, and the average size of the particles was reduced from 50 μm to 23 μm. The in vitro naloxone release duration ranged from 4 to 35 days. Reducing the average size of the microparticles from 50 μm to 23 μm helped eliminate the lag phase and obtain the steady-state drug release profile. The cellular pharmacodynamics of three selected formulations were evaluated by applying DAMGO, a synthetic opioid peptide agonist to a μ-opioid receptor, to recruit β-arrestin 2.

Conclusions: Naloxone released from the three selected formulations could inhibit DAMGO-induced β-arrestin 2 recruitment. This indicates that the proposed naloxone delivery system is adequate for opioid reversal during the naloxone release duration.