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

Author(s)

Santos, Rogerio A. ^[1] ; Rae, Mariana ^[1] ; Dartora, Vanessa F. M. C. ^[1] ; Matos, Jenyffer K. R. ^[1] ; Camarini, Rosana ^[1] ; Lopes, Luciana B. ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Pharmacol, Inst Ciencias Biomed, Sao Paulo - Brazil

• Document type: Journal article
• Source: International Journal of Pharmaceutics; v. 585, JUL 30 2020.
• Web of Science Citations: 0

Abstract

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 monooleintricaprylin (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. (AU)

• FAPESP's process: 17/04174-4 - Development and evaluation of cationic bioadhesive nanocarriers as a platform to localize piplartine in the breast for tumor treatment
• Grantee: Vanessa Franco Carvalho Dartora
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/05038-0 - Effect of environmental enrichment on resilience to chronic unpredictable stress: epigenetic regulation of the BDNF gene and consequences on ethanol consumption
• Grantee: Rosana Camarini
• Support type: Regular Research Grants
• FAPESP's process: 18/13877-1 - Nanocarriers for localized treatment and chemoprevention of breast tumors
• Grantee: Luciana Biagini Lopes
• Support type: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 13/16617-7 - Nanostructured systems for topical delivery and co-localization of chemopreventive and chemoterapeutic agents in the skin and breast tissue
• Grantee: Luciana Biagini Lopes
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 18/18813-1 - Bioresponsive gels containing nanoparticles for exudate control and co-delivery of propranolol and adenosine for wound healing applications
• Grantee: Jenyffer Kelly Rocha de Matos
• Support type: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 15/02397-0 - Study of environmental enrichment inducing a protective phenotype of behaviors that assess addictive features in mice
• Grantee: Rosana Camarini
• Support type: Regular Research Grants