The goal of this program was the development of biocompatible sustained-release systems that would release naltrexone at a rate of 20 to 25 microgram/hr for 30 days, and that would biodegrade within 90 days. The focus was on the use of macrocapsules prepared from synthetic polypeptides, specifically copolymers of glutamic acid and ethyl glutamate (i.e., Glu/EGlu copolymers). Tubular capsules prepared from 18/82 Glu/EGlu were the most promising systems developed. Capsules 1 cm in length, 0.19 cm in outside diameter, and 0.005 cm in wall thickness released naltrexone in mice at rates in the range of 20 to 40 microgram/hr for 18 days. The rates then decreased during the next 12 days as the capsules became exhausted of drug. These capsules were biocompatible and they appeared to biodegrade within 90 days. In general, the Glu/EGlu copolymers exhibit permeation and degradation rates that increase as the glutamic acid content is increased. Radiotracing studies revealed that the ultimate degradation product was carbon dioxide, which appeared in the expired air. This result is consistent with a polypeptide degradation process that involves hydrolysis of the ethyl esters followed by hydrolysis of the peptide bonds to produce glutamic acid, which enters the metabolic pool.