Nor-LAAM loaded PLGA microparticles for treating opioid use disorder

• Published in: Journal of controlled release Vol. 373; pp. 93 - 104
• Main Authors: Ingabire, Diane, Qin, Chaolong, Meng, Tuo, Raynold, Aji Alex Moothendathu, Sudarjat, Hadi, Townsend, E. Andrew, Pangeni, Rudra, Poudel, Sagun, Arriaga, Michelle, Zhao, Long, Chow, Woon N., Banks, Matthew, Xu, Qingguo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2024
• Subjects: Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - therapeutic use; Animals; Delayed-Action Preparations; Drug abuse; Drug Carriers - chemistry; Drug Liberation; Fentanyl-vs-food choice; Hydrophobic ion pairing (HIP); Male; Opioid-Related Disorders - drug therapy; Particle Size; Pharmacokinetics; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry; Rats; Rats, Sprague-Dawley; Sustained delivery; Fentanyl-vs-food choice; Drug abuse; Sustained delivery; Hydrophobic ion pairing (HIP); Pharmacokinetics
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2024.06.071

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt%) and an average diameter (19 μm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD. [Display omitted]