Question

Sustained delivery of detirelix after pulmonary administration of liposomal formulations

Answer 1

The LHRH antagonist detirelix was efficiently incorporated into negatively charged liposomes (170 ± 80 nm) that were composed of distearoyl-L-α-phosphatidylcholine, distearoyl-L-α-phosphatidylglycerol, and cholesterol (molar ratio of 52/8.4/39.6, respectively). The pharmacokinetics of detirelix were examined in briefly anesthetized dogs following pulmonary administration of two liposomal formulations that differed in their degree of detirelix incorporation. Liposomes that were purified of extra-liposomal detirelix, designated as Formulation A, retained encapsulated detirelix and also surface-adsorbed detirelix. Subsequent removal of the surface-adsorbed detirelix by gel filtration chromatography gave highly purified liposomes, designated as Formulation B. Intratracheal (i.t.) instillation of Formulation A resulted in relatively high plasma levels in the first 24 h as compared to Formulation B, possibly because of the facile absorption of the surface-adsorbed detirelix. The mean residence times (MRT) of detirelix following i.t. instillation and aerosol inhalation (a.i.) of Formulation A were similar (31.4 h and 28.2 h, respectively). However, following i.t. instillation of Formulation B, plasma levels were sustained up to 4 days and the MRT was increased to 57.4 h. The bioavailability of detirelix from 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 of liposomes and the pulmonary surfactant may account for the high liposomal 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.




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