title: Implantable technology for long-term delivery of nalmefene for treatment of alcoholism.
abstract: Pharmacotherapy treatment for alcoholism is limited by poor compliance, adverse effects, and fluctuating drug levels after bolus administration. A long-term delivery system would improve upon these limitations. The current study describes the characterization of a sustained release implant containing nalmefene, an opioid antagonist, for treatment of alcoholism. Nalmefene was blended with ethylene vinyl acetate (EVA), extruded into 2.8 mm x 27 mm rods, and coated with EVA to optimize release. In vitro release was determined by HPLC, and in vivo release characteristics after subcutaneous implantation into rats were determined by LC-MS/MS analyses. Extrusion produced rods containing 80.09 +/- 6.0 mg nalmefene. In vitro release was high from the uncoated rods, and they were depleted of drug fairly quickly; however EVA coatings maintained release over longer periods. The 25 wt.% coated rods provided in vitro release of 0.36 mg/day/rod, and in vivo release of 0.29 mg/day/rod over 6 months, and showed dose-dependent nalmefene plasma concentrations (one rod: 3.33 +/- 0.56 ng/ml, three rods: 10.19 +/- 2.31 ng/ml). After explantation, nalmefene plasma concentrations were undetectable by 6 h. A sustained release nalmefene rod provides 6 months of drug with no adverse effects.
authors.affiliation: Titan Pharmaceuticals Inc., 400 Oyster Point Blvd, Suite 505, South San Francisco, CA 94080, USA. lcostantini@titanpharm.com
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Costantini
authors.forename: Sofie R
authors.initials: SR
authors.lastname: Kleppner
authors.forename: Joseph
authors.initials: J
authors.lastname: McDonough
authors.forename: Marc R
authors.initials: MR
authors.lastname: Azar
authors.forename: Raj
authors.initials: R
authors.lastname: Patel
mesh_terms: D000437:Alcoholism / Q000188:drug therapy*; D000818:Animals; D019540:Area Under Curve; D003692:Delayed-Action Preparations; D004867:Equipment Design; D006801:Humans; D015918:Infusion Pumps, Implantable; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013678:Technology, Pharmaceutical
chemical_list: D003692:Delayed-Action Preparations; D009292:Narcotic Antagonists; D009271:Naltrexone; C038981:nalmefene