Sidman K R, Schwope A D, Steber W D, Rudolph S E
NIDA Res Monogr. 1981;28:214-31.
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.
该项目的目标是开发生物相容性缓释系统，该系统能以每小时20至25微克的速率释放纳曲酮，持续30天，并在90天内生物降解。重点是使用由合成多肽制备的大胶囊，特别是谷氨酸和谷氨酸乙酯的共聚物（即Glu/EGlu共聚物）。由18/82 Glu/EGlu制备的管状胶囊是所开发的最有前景的系统。长度为1厘米、外径为0.19厘米、壁厚为0.005厘米的胶囊在小鼠体内以每小时20至40微克的速率释放纳曲酮，持续18天。在接下来的12天里，随着胶囊内药物耗尽，释放速率下降。这些胶囊具有生物相容性，并且似乎在90天内生物降解。一般来说，Glu/EGlu共聚物的渗透和降解速率随着谷氨酸含量的增加而增加。放射性示踪研究表明，最终降解产物是二氧化碳，它出现在呼出的气体中。这一结果与多肽降解过程一致，该过程包括乙酯的水解，随后是肽键的水解以产生谷氨酸，谷氨酸进入代谢池。
