Bioresponsive nanostructured systems for sustained naltrexone release and treatment of alcohol use disorder: Development and biological evaluation

• Published in: International journal of pharmaceutics Vol. 585; p. 119474
• Main Authors: Santos, Rogério A., Rae, Mariana, Dartora, Vanessa F.M.C., Matos, Jenyffer K.R., Camarini, Rosana, Lopes, Luciana B.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30-07-2020
• Subjects: Alcohol Deterrents - administration & dosage; Alcohol Deterrents - blood; Alcohol Deterrents - chemical synthesis; Alcohol use disorder; Alcoholism - blood; Alcoholism - drug therapy; Animals; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - chemical synthesis; Delayed-Action Preparations - metabolism; Drug Development - methods; Drug Evaluation, Preclinical - methods; Ethanol - administration & dosage; Hexagonal phase; In vivo swelling; Injections, Subcutaneous; Male; Mice; Mice, Inbred C57BL; Microemulsion; Naltrexone; Naltrexone - administration & dosage; Naltrexone - blood; Naltrexone - chemical synthesis; Nanostructures - administration & dosage; Nanostructures - chemistry; Sustained release; Sustained release; Alcohol use disorder; Hexagonal phase; Microemulsion; In vivo swelling; Naltrexone
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2020.119474

[Display omitted]
In this study, microemulsions capable of transforming into nanostructured hexagonal phase gels in vivo upon uptake of biological fluids for naltrexone prolonged release were investigated as a strategy for management of alcohol use disorder (AUD). Microemulsions were prepared using monoolein, tricaprylin, water and propylene glycol; after preliminary characterization, one formulation was selected, which contained 55% of monoolein-tricaprylin (M−55). This microemulsion displayed size below 200 nm and Newtonian rheological behavior. Liquid crystalline gels formed in vitro upon 8 h of contact with water following a second order kinetics. After 120 h, <50% of naltrexone was released in vitro independently on drug loading (5 or 10%). In vivo, gels formed within 24 h of M−55 subcutaneous administration, and persisted locally for over 30 days providing slow release of the fluorescent marker Alexa fluor compared to a solution. Using the conditioned place preference paradigm, a test used to measure drug’s rewarding effects, a single dose of M−55 containing 5% naltrexone reduced the time spent in the ethanol-paired compartment by 1.8-fold compared to saline; this effect was similar to that obtained with daily naltrexone injections, demonstrating the formulation efficacy and its ability to reduce dosing frequency. A more robust effect was observed following administration of M−55 containing 10% of naltrexone, which was compatible with aversion. These results support M−55 as a platform for sustained release of drugs that can be further explored for management of AUD to reduce dosing frequency and aid treatment adherence.