Engineering Quick- and Long-acting Naloxone Delivery Systems for Treating Opioid Overdose.
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ABSTRACT: 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.
SUBMITTER: Sharifi F
PROVIDER: S-EPMC8192039 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Importance:The US opioid crisis was deemed a public health emergency in 2017. More than 130 individuals in the US die daily as a result of unintentional opioid overdose deaths. Objective:To measure use of take-home naloxone for overdose reversals performed by study participants with opioid use disorder receiving treatment at an opioid treatment program. Design, Setting, and Participants:In a year-long cohort study, between April 4, 2016, and May 16, 2017, 395 study participants enrolled at the University of New Mexico Addiction and Substance Abuse Opioid Treatment Program, an outpatient clinic treating substance use disorders. Inclusion criteria included all patients enrolled at University of New Mexico Addiction and Substance Abuse Opioid Treatment Program during the study enrollment period; positive history of opioid use disorder treated with methadone, buprenorphine, or naltrexone; and age 18 years or older. Exclusion criteria included allergy to naloxone and age younger than 18 years. The study closed 1 year after enrollment, on May 17, 2018. Data analysis was performed from May 2018 to July 2019. Exposure:Two doses of take-home naloxone combined with opioid overdose education were provided to study participants. Main Outcomes and Measures:The primary outcome was to measure the association of take-home naloxone with overdose reversals performed by patients with opioid use disorder enrolled in an opioid treatment program. Results:We enrolled 395 study participants (270 female [68.4%]; mean [SD] age, 35.4 [12.6] years; 260 [65.8%] with Hispanic white race/ethnicity) in the 1-year prospective trial. Sixty-eight female participants (25.2% of all female participants) were pregnant at the time of enrollment. Seventy-three of the 395 study participants (18.0%) performed 114 overdose reversals in the community. All community reversals were heroin related. Most study participants (86.8%) stated that the person on whom they performed an overdose reversal was a friend, relative, acquaintance, or significant other. In the year before enrollment, only 18 study participants (4.5%) had been prescribed naloxone. Conclusions and Relevance:Take-home naloxone as part of overdose education and naloxone distribution provided to patients in an opioid treatment program may be associated with a strategic targeted harm reduction response for reversing opioid overdose-related deaths. Policy makers may consider regulations to mandate overdose education and naloxone distribution in opioid treatment programs.
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