Research Project
2122797
The Phase I effort to develop narcotic antagonist controlled release vehicles demonstrated: i. that the cationic narcotic antagonist, Naltrexone, can be loaded to levels of more than 300 mg/cm3 into a protein-based polymer implant containing anionic carboxylate sites, ii. that sustained linear release profiles were achieved in which a period of greater than ten days was required for the released concentration to decrease by a factor of two. These results provide an experimental basis for a controlled release rationale whereby protein-based polymers can be designed with even more favorable, sustained release profiles. It is a dual approach: an injectable implant which disperses as it releases for periods up to weeks, and a trocar-emplaced implant capable of releasing competent doses for a month or more. The specific aims of this Phase II SBIR application are: 1. to design three different protein-based polymer constructs with optimized drug loading (0.25, 0.5, and 1 mmole per cc) and with sustained release profiles, 2. to carry out gene construction and expression of the designed protein-based polymers and to obtain genes with a series of values for n of the basic gene with lower values of n for the dispersible injectable implants and the larger values of n to prepare the cross-linked, biodegradable matrix rod implants, 3. to purify protein-based polymer gene products to endotoxin levels meeting the FDA standards, 4. to determine the optimal polymer constructs by means of in vitro release studies, 5. to package the drug-laden implants in sterile packets using a class 10,000 clean room for sample handling and packaging and 2.5 Mrads of gamma- irradiation for sterilization once in the sealed package, 6. to carry out in vivo release studies by following Naltrexone levels in the plasma resulting from subcutaneous implants in the dog and examine implant sites for dispersal and degradation, and 7. to determine the biocompatibility (toxicology) of the several chosen controlled release devices. PROPOSED COMMERCIAL APPLICATION: The worldwide drug addiction problem needs no elaboration. In the U.S. alone, it is estimated that between 3 and 30 million drug users would benefit from assistance. The safe and effective narcotic antagonist, Naltrexone, could provide that assistance, but suffers from patient motivation to continue use. The implantable narcotic antagonist delivery systems being developed are means whereby the crime-causing, life-destroying drug dependency could be removed without relying on the addict's compliance. The commercial value and the broader societal value of injectable implants and of biodegradable but removable rod implants are substantial.
