SBIR-STTR Award

This proposed SBIR Phase I project will demonstrate the feasibility of developing a novel oral transmucosal drug delivery method and dosage form for alcohol dependence treatment. The proposed system is a small, thin, and flexible film, containing the treatment drug, naltrexone. It is applied intra-orally to affect a rapid onset of action, followed by moderate release of drug for extended pharmacological action. The Phase I project will consist of design, fabrication and in vitro evaluation of thin-film dosage forms. The dosage form is applied "as needed" when alcohol craving occurs. The method/dosage form is cost- effective, convenient (can be administered without water), and could fill the gaps of current patient and market needs. PROBLEM/OPPORTUNITY: There are two naltrexone products marketed for treatment of alcohol dependence: oral tablets and injectable depot formulation. The former suffers from low bioavailability, poor patient compliance, and significant side effects. The later overcomes bioavailability and patient compliance problems but is expensive, inconvenient and has injection site reaction. Proposed drug delivery system is expected to overcome the poor oral bioavailability of the oral naltrexone tablets, and high cost and inconvenience of the injectable naltrexone depot formulations. Results from this study are anticipated to lead to better efficacy, more convenient, and better patient compliance of alcohol-dependence medical treatment, and thus improve the health of alcoholism patients. This market sector is presently under-served and has substantial potential. The proposed technology could be extended and developed into improved dosage forms for other substance- addiction treatment medications. PLAN OUTLINE: Specific aims of the Phase I study are a) design and fabrication of film constructs with desired film properties (flexibility and integrity) and dose of naltrexone, b) development of in vitro drug release test method, and testing of the formulations, c) development of in vitro transmucosal permeation method using cultured mucosa tissues, and evaluation of candidate formulations to determine their bio-absorption efficiency, and d) stability study to determine shelf-storage stability of the prototype drug product. Plans for Phase II follow-on research include completing product development program, GMP manufacturing of PK (pharmaco-kinectic) and clinical batches, conducting in vivo PK study, and demonstration of efficacy in human clinical study.

Public Health Relevance:
The proposed drug delivery system is expected to result in improved efficacy and better compliance in the pharmacological therapies for alcohol dependence. This will reduce the public health burden of heavy drinking to our society and significantly reduce related healthcare costs. In addition, the proposed technology is a platform that could be extended and developed into improved dosage forms for other substance abuse medications.

Public Health Relevance Statement:
PUBLIC HEALTH RELEVANCE STATEMENT The proposed drug delivery system is expected to result in improved efficacy and better compliance in the pharmacological therapies for alcohol dependence. This will reduce the public health burden of heavy drinking to our society and significantly reduce related healthcare costs. In addition, the proposed technology is a platform that could be extended and developed into improved dosage forms for other substance abuse medications.

NIH Spending Category:
Alcoholism; Bioengineering; Biotechnology; Brain Disorders; Neurosciences; Substance Abuse

Project Terms:
API; Absorption; Acute; Address; Adverse effects; Affect; Alcohol dependence; Alcoholism; Assay; Bioassay; Bioavailability; Biologic Assays; Biologic Availability; Biological Assay; Biological Availability; Blood Circulation; Bloodstream; Body Tissues; Bristol-Myers Squibb Brand of Naltrexone Hydrochloride; Buccal Mucosa; Circulation; Clinical; Clinical Research; Clinical Study; Clinical Trials, Phase I; Compliance behavior; Dependence, Substance; Development; Devices; Dosage Forms; Dose; Drug Delivery; Drug Delivery Systems; Drug Formulations; Drug Targeting; Drug Targetings; Drugs; Du Pont Brand of Naltrexone Hydrochloride; Early-Stage Clinical Trials; Ethanol dependence; Evaluation; Excipients; Film; Formulation; Formulations, Drug; Goals; Health; Health Care Costs; Health Costs; Healthcare Costs; Heavy Drinking; Hour; Human; Human, General; Hydrogen Oxide; In Vitro; Injectable; Injection Site Reaction; Lamepro Brand of Naltrexone Hydrochloride; Lead; MAPI; Man (Taxonomy); Man, Modern; Marketing; Medical; Medication; Methods; Morphinan-6-one, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-, (5alpha)-; Mouth Mucosa; Mucosa; Mucosal Tissue; Mucous Membrane; Nalorex; Naltrexone; Naltrexone HCl; Naltrexone hydrochloride; Nemexin; Oral; Oral Mucosa; Oral mucous membrane structure; Orphan Brand of Naltrexone Hydrochloride; Outcome; PBO; Palate; Patient Compliance; Patient Cooperation; Patients; Pb element; Permeability; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Physiologic Availability; Placebos; Preparation; Process of absorption; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Public Health; ReVia; Research; SBIR; SBIRS (R43/44); Schering-Plough Brand of Naltrexone Hydrochloride; Sham Treatment; Small Business Innovation Research; Small Business Innovation Research Grant; Societies; Solid; Substance Addiction; Substance abuse problem; System; System, LOINC Axis 4; Tablets; Technology; Temperature; Testing; Therapeutic Effect; Time; Tissues; Tongue; Treatment Compliance; Treatment Side Effects; United Drug Brand of Naltrexone Hydrochloride; Water; absorption; abuse of substances; alcohol addiction; alcohol addiction therapy; alcohol craving; alcohol dependence therapy; alcohol dependency; alcohol-dependent; alcoholism therapy; alkaline protease inhibitor; bioavailability of drug; compliance cooperation; cost; cost effective; design; designing; drink heavily; drug/agent; ethanol addiction; ethanol craving; ethanol dependency; ethanol-dependent; excess alcohol consumption; excess alcohol ingestion; excess ethanol ingestion; excessive alcohol consumption; excessive alcohol ingestion; excessive alcohol intake; excessive drinking; excessive ethanol ingestion; extreme drinking; flexibility; heavy alcohol use; heavy metal Pb; heavy metal lead; improved; in vitro Assay; in vivo; microbial alkaline proteinase inhibitor; novel; oral mucosae; oral mucosal; patient adherence; phase 1 study; phase 1 trial; phase I trial; product development; programs; protocol, phase I; prototype; public health medicine (field); public health relevance; sham therapy; side effect; substance abuse; tablet (pharmacologic); therapy adverse effect; therapy compliance; therapy cooperation; treatment adverse effect

The proposed SBIR Phase II project aims at developing a new drug product, the naltrexone orally dissolving film (ODF), for treatment of alcohol dependence. The naltrexone ODF is a small, thin, and flexible film, containing naltrexone hydrochloride and other excipients. It is applied intra-orally and adheres to the oral mucosa to affect a rapid onset of action due to oral mucosal absorption, followed by an extended pharmacological action. The naltrexone ODF is administered 30 to 60 minutes prior to a drinking episode or as-needed when alcohol craving occurs. The naltrexone ODF is novel, cost- effective, convenient to use, dissolves in the mouth without the need for water and fills the gaps of current treatment regimens and market needs. Phase I of this project was highly successful wherein the specific aims were met in demonstrating the feasibility of developing a prototype naltrexone ODF formulation which met the targeted milestone having optimal functional properties. The Phase II program will extend to product development/ early-commercialization phase by validating the prototype formulation with IND-enabling safety studies, technology transfer and scale-up and manufacturing of clinical supplies. PROBLEM/OPPORTUNITY: Naltrexone is an approved drug for treatment of alcohol and opioid dependence. There are two naltrexone drug products marketed for treatment of alcohol dependence: oral tablets and injectable depot formulation. The former suffers from low bioavailability, poor patient compliance, and significant side effects. The later overcomes bioavailability and patient compliance issues but is expensive, inconvenient and has injection site reaction. The proposed naltrexone ODF drug product is expected to overcome the poor oral bioavailability of the oral naltrexone tablets, and the high cost and inconvenience of the injectable naltrexone depot formulations. The alcohol dependence medication market sector is under-served and has substantial potential. The proposed ODF technology could be extended and developed into improved dosage forms for other drugs targeted at treatment of substance-addiction. PLAN OUTLINE: The aims of this proposed SBIR Phase II program on the naltrexone ODF are to: 1) manufacture preclinical supplies, 2) conduct preclinical studies, 3) technology transfer, scale-up and manufacture Phase 1 clinical supplies, and 4) prepare regulatory (CMC) documentation for a pre-IND (Investigational New Drug) meeting. Upon successful completion of this program, a SBIR Phase III follow-up program is proposed that will include filing of IND and conducting the Phase I clinical safety/proof-of-concept study.

Public Health Relevance:
The proposed new product, naltrexone orally dissolving film (ODF), is expected to result in improved efficacy and better compliance in the pharmacological therapies for alcohol dependence. This will reduce the public health burden of heavy drinking to our society and significantly reduce related healthcare costs. In addition, the proposed technology is a platform that could be extended and developed into improved dosage forms for other substance abuse medications.