RESEARCH PROPOSED: Research is proposed to investigate the feasibility of design and fabrication of an oral transmucosal drug delivery system for systemic delivery of nicotine. The drug delivery system is intended to attain a dual drug-release profile so that dual pharmacological actions, i.e., an initial rapid onset of action followed by period of prolonged effect, can be achieved. PROBLEM/OPPORTUNITY: Many drug-abuse medications (e.g., nicotine) cannot be effectively administered orally. Alternate drug delivery systems are therefore needed for drug abuse studies and in treatment clinics. The dosage form should also be convenient for administration, cost-effective, and provide controlled pharmacological actions. We propose an oral transmucosal system that provides a rapid onset of drug action (to address period of acute craving) followed by a prolonged release of the drug to maintain a lower, constant drug plasma concentration. Such dual drug-release delivery system addresses the therapeutic gap problems of the fast-onset dosage forms (e.g., injections and nasal sprays) and sustained-release delivery systems such as transdermal patches and depot implants. Also, this simple single-dosage form offers convenience of dose administration (thus ensures compliance); is less expensive (vs. implants, transdermal, nasal and inhalation devices); and improves bioavailability of drugs with high first-pass metabolism or significant gastrointestinal degradation (vs. oral dosage forms). LONG-TERM GOAL: The long-term goal of the proposed research is to develop a convenient, cost- effective, and controlled multiple drug-action thin-film transmucosal delivery system for drugs that can be effectively administered through the oral mucosa. This innovation provides an alternate dosage form to deliver medications, with controlled therapeutic dosage and action, which otherwise may not be efficaciously administered using conventional dosage forms. PLAN OUTLINE: Phase I task objectives are a) design and fabrication of biphasic constructs with dual drug release (fast and slow) characteristics, to meet targeted fast onset of action and prolonged pharmacological effect of nicotine, b) development of in vitro drug release test method and testing of candidate formulations, and c) development of in vitro transmucosal permeation evaluation method using cultured buccal epithelium and testing of candidate formulations to determine the bio-absorption efficiency of the formulations. Plans for follow-on Phase II research include completing product development program, and demonstration of efficacy in animals and preliminary human studies. COMMERCIAL OPPORTUNITY: The proposed drug delivery system can be used in research clinics to study potential improvement in efficacy of existing mediations or research experimental therapeutic agents. Furthermore, applications of this technology can be extended to commercial pharmaceutical market as a more efficacious form of administering drug-abuse medications (e.g., smoking cessation therapy). ? ? Public Health Relevance: The proposed study """"""""Oral transmucosal drug delivery system for nicotine"""""""" aims at developing a novel and improved dosage form for smoking cessation therapy. The results may lead to greater cessation rates, and thus bring improved health to cigarette smokers. Also, the proposed technology could be extended and developed into improved dosage forms of drug-addiction treatment medications. ? ? ?