A 3-month Release Naltrexone for Addiction Treatment

Plumb Pharmaceuticals, Inc, Madison WI

Investigators

Abstract

Opioid misuse is a world-wide problem, and it is increasing. The epidemic has shifted from a problem largely confined to urban areas to one that is both urban and rural. Maintenance therapy helps alleviate situa- tional cravings and makes addiction therapy more effective, but methadone clinics are largely confined to larger cities, buprenorphine must be prescribed by physicians with a specific waiver, and it may be difficult to find ?waivered? physicians in rural areas. Naltrexone is an opioid antagonist that has broad usage in the treat- ment of opioid addiction. Naltrexone may be prescribed by any physician; no special authorization is neces- sary. Naltrexone is only an opioid antagonist, and is not subject to diversion, unlike methadone and buprenor- phine, making naltrexone therapy more acceptable to more conservative populations. Naltrexone is the only approved maintenance therapy available to certain sensitive professions, and the only maintenance therapy available in certain parts of the world (like Russia). The original naltrexone formulation is a daily oral pill. Daily oral naltrexone is effective, but is subject to sig- nificant medication compliance issues. A monthly formulation of extended-release naltrexone, VivitrolÒ, is available, and improves medication compliance compared to daily oral pills, but it suffers from variations in re- lease rates over its duration as well as significant side effects that reduce patient willingness to continue treat- ment. Medication compliance (and efficacy) would be improved if the interval between injections could be in- creased to greater than 1 month and if the release rates were more stable over time. Our company, Plumb Pharmaceuticals, is developing an extended-release formulation of naltrexone and has assembled the technical expertise and the business team necessary to develop, test and eventually com- mercialize this formulation for addiction maintenance. Our proprietary Advanced Quantload technology can potentially extend the release period of naltrexone from the current 1 month to 18 weeks (4.5 months) in opi- oid-maintenance patients with a very stable release rate. An 18-week release period would be of special bene- fit to patients in rural areas. We will develop this ultra-extended release naltrexone formulation by completing of the following Aims: (1) Determine optimal encapsulation procedure, and characterize the product. Milestone: Establish efficient (>75%) loading of naltrexone (a ratio of at least 1.3 mg naltrexone per mg phospholipid) and characterize liposomes for size and type using light-scattering analysis and/or single particle optical sizing, and cryoelectron microscopy. (2) Determine the in vitro release characteristics of the AQL-Nal formulation from Aim 1. Milestone: the lead formulation will release 80% of its naltrexone in vitro at a uniform rate commensurate with an 18 week in vivo release period. (3) Conduct preliminary pharmacokinetics on the lead formulation in rats (n=36). Milestone: The lead formulation will demonstrate ? 1 ng/mL blood serum concentrations for 16-18 weeks with minimal systemic side effects/localized tissue reactions. In Phase II, we will further refine the prod- uct, perform GLP experiments in animals and first-in-human trials.