Prolonged controlled-release of nafarelin, a luteinizing hormone-releasing hormone analogue, from biodegradable polymeric implants: influence of composition and molecular weight of polymer

Abstract

The release of the peptide hormone nafarelin, 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-3-(2-naphthyl)- D-alanyl-L-leucyl-L-arginyl-L-prolylglycinamide, a potent luteinizing hormone-releasing hormone (LHRH) agonist, from implants of the biodegradable copolymer poly(d,l-lactide-co-glycolide) (PLGA) has been studied both in vivo and in vitro. The release has a triphasic profile typical for bulk-eroding monolithic controlled-release systems, characterized by a secondary phase of lower release preceded and followed by phases of higher release. The primary factor controlling the peptide release profile is polymer erosion, which in turn may be controlled by modifying physical properties of the polymer such as the molecular weight or the ratio of the more hydrophobic lactic acid monomer to the less hydrophobic glycolic acid monomer. The duration of the secondary phase has been found to be directly proportional to the molecular weight of the copolymer, and the total duration as well as the duration of the secondary phase are both directly proportional to the monomer ratio. A system has been identified in which the secondary phase is sufficiently reduced to provide essentially continuous efficacy in the rat for greater then eight months, with partially effective levels of release of nafarelin continuing beyond 15 months.