title: In situ gelling hexagonal phases for sustained release of an anti-addiction drug.
abstract: In this study, fluid precursor formulations for subcutaneous injection and in situ formation of hexagonal phase gels upon water absorption were developed as a strategy to sustain the release of naltrexone, a drug used for treatment of drug addiction. Precursor formulations were obtained by combining BRIJ 97 with propylene glycol (PG, 5-70%, w/w). To study the phase behavior of these formulations, water was added at 10-90% (w/w), and the resulting systems were characterized by polarized light microscopy. Two precursor formulations containing BRIJ:PG at 95:5 (w/w, referred to as BRIJ-95) and at 80:20 (w/w, referred to as BRIJ-80) were chosen. Naltrexone was dissolved at 1% or suspended at 5% (w/w). Precursor formulations were transformed into hexagonal phases when water content exceeded 20%. Water uptake followed second-order kinetics, and after 2-4h all precursor formulations were transformed into hexagonal phases. Drug release was prolonged by the precursor formulations (compared to a drug solution in PBS), and followed pseudo-first order kinetics regardless of naltrexone concentration. The release from BRIJ-80 was significantly higher than that from BRIJ-95 after 48 h. The relative safety of the precursor formulations was assessed in cultured fibroblasts. Even though BRIJ-95 was more cytotoxic than BRIJ-80, both precursor formulations were significantly less cytotoxic than sodium lauryl sulfate (considered moderate-to-severe irritant) at the same concentration (up to 50 μg/mL). These results suggest the potential of BRIJ-based precursor formulations for sustained naltrexone release.
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Phelps
authors.forename: M Vitória L B
authors.initials: MV
authors.lastname: Bentley
authors.forename: Luciana B
authors.initials: LB
authors.lastname: Lopes
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000503:physiopathology; D001682:Biological Availability; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003692:Delayed-Action Preparations / Q000032:analysis / Q000138:chemical synthesis* / Q000494:pharmacology; D005782:Gels / Q000032:analysis / Q000138:chemical synthesis* / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007700:Kinetics; D051379:Mice; D008853:Microscopy; D009271:Naltrexone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D010938:Plant Oils / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D019946:Propylene Glycol / Q000737:chemistry; D041701:Swiss 3T3 Cells; D014867:Water
chemical_list: D003692:Delayed-Action Preparations; D005782:Gels; D009292:Narcotic Antagonists; D010938:Plant Oils; D014867:Water; D011092:Polyethylene Glycols; D009271:Naltrexone; D019946:Propylene Glycol; C033084:polyethylene glycol oleyl ether