Nasal Delivery of Naltrexone for Treatment of Alcoholism

DESCRIPTION (provided by applicant): Alcohol abuse, dependence, and related societal effects exert a tremendous toll on world-wide and American health and economics. Given this devastating impact, the significant lack of pharmaceutical intervention, even for those patients seeking treatment, is troubling. This phase 1 Small Business Technology Transfer Research (STTR) project will apply novel nasal drug delivery platform technologies to develop a nasally delivered pharmaceutical to acutely and rapidly attenuate drinking behavior and to curb alcohol craving. The general goal of this project is to create and develop a novel nasal delivery dosage form of naltrexone (NTX) hydrochloride useful in the pharmacologic treatment of alcoholism. The specific goals are to: 1) create a nasal spray producing improved biopharmaceutics over the oral tablet, and 2) offer an adjunct, novel therapeutic option of a rapid-acting, interventional medication intended to acutely extinguish alcohol craving symptoms. The hypothesis of the proposed project is that nasally delivered NTX will have substantially improved biopharmaceutics over the FDA-approved oral tablet as demonstrated by attaining: 1) at least twice the mean systemic bioavailability (F= 50%), 2) less than half the pharmacokinetic parameter variability (S.D. = 30% of the mean), and, 3) one-third to one-quarter the absorption time (tmax = 20 minutes). The project hypothesis will be tested by the following specific aims: 1) develop two pilot prototype formulations of NTX HCl meeting appropriate standards for potency and stability, 2) demonstrate systemic exposure and assess bioavailability in an in vivo rat model for the two prototype formulations, 3) manufacture a nasal spray batch of NTX HCl for human clinical testing, and 4) conduct a pilot bioavailability study of the nasal spray system in human volunteers. Objectives 1 and 2 of this phase 1 STTR project will create a pharmaceutically appropriate NTX nasal spray that produces consistent absorption resulting in rapid systemic blood levels in animals. Objectives 3 and 4 will permit verification that an improved NTX delivery system is feasible for human use. Future STTR phase 2 clinical studies will address a hypothesis that a more completely, consistently and rapidly absorbed anti-relapse drug can be a tool to acutely reduce alcohol craving in actively consuming and abstinent alcoholics and improve chronic treatment success rates by improved biopharmaceutics and decreased untoward effects. The long-term goal of this work is to develop and commercialize nasal delivered NTX for the treatment of alcoholism.