SUSTAINED DELIVERY OF DETIRELIX AFTER PULMONARY ADMINISTRATION OF LIPOSOMAL FORMULATIONS

The LHRH antagonist detirelix was efficiently incorporated into negati vely charged liposomes (170 +/- 80 nm) that were composed of distearoy l-L-alpha-phosphatidylcholine, distearoyl-L-alpha-phosphatidylglycerol , and cholesterol (molar ratio of 52/8.4/39.6, respectively). The phar macokinetics of detirelix were examined in briefly anesthetized dogs f ollowing pulmonary administration of two liposomal formulations that d iffered in their degree of detirelix incorporation. Liposomes that wer e purified of extra-liposomal detirelix, designated as Formulation A, retained encapsulated detirelix and also surface-adsorbed detirelix. S ubsequent removal of the surface-adsorbed detirelix by gel filtration chromatography gave highly purified liposomes, designated as Formulati on B. Intratracheal (i.t.) instillation of Formulation A resulted in r elatively high plasma levels in the first 24 h as compared to Formulat ion B, possibly because of the facile absorption of the surface-adsorb ed detirelix. The mean residence times (MRT) of detirelix following i. t. instillation and aerosol inhalation (a.i.) of Formulation A were si milar (31.4 h and 28.2 h, respectively). However, following i.t. insti llation of Formulation B, plasma levels were sustained up to 4 days an d the MRT was increased to 57.4 h. The bioavailability of detirelix fr om Formulations A and B was 13.5% and 9.6%, respectively, compared to intravenous injection determined from a previous study. Electrostatic and hydrophobic interactions between detirelix and the phospholipids o f liposomes and the pulmonary surfactant may account for the high lipo somal entrapment efficiency of detirelix and its slow systemic uptake following pulmonary delivery. Our study demonstrates the potential to modulate the absorption of peptides delivered via the lung.