Respiratory delivery of deslorelin, a peptide drug

Respiratory delivery is an attractive non-invasive alternative for the systemic delivery of macromolecules. However, proteolytic degradation and low permeability of macromolecules, limit their bioavailability and alveolar macrophage clearance of particles limits sustained macromolecule delivery. The long-term goal of this research is to devise strategies to overcome the above limitations, enhance systemic absorption and facilitate sustained systemic delivery of deslorelin, a nonapeptide, via the respiratory route.; In this study, we (a) assessed transport mechanisms of deslorelin in the respiratory epithelium, (b) elucidated the pathways and kinetics of deslorelin degradation and determined whether hydroxypropyl-beta-cyclodextrin inhibits deslorelin degradation, and (c) developed a delivery system comprising of large porous polymeric microparticles to avoid macrophage clearance and sustain deslorelin delivery. In vitro transport studies across respiratory epithelial (Calu-3) cell monolayers indicated that deslorelin is transported vectorially in the apical to basolateral direction via the LHRH receptor. Deslorelin degraded in the respiratory epithelium, with primary breakdown occurring between Trp3 and Ser4, followed by cleavage of the Ser4-Tyr5 and the Leu 7-Arg8 bonds. The aromatic amino acids of deslorelin complexed with the hydrophobic cavity of hydroxypropyl-beta-cyclodextrin, resulting in reduced degradation by a protease. Following intratracheal administration, deslorelin-HPbetaCD complexes provided 2 -, 3 -, and 3-fold higher plasma deslorelin levels at 3, 24, and 72 hours, respectively, compared to the solution formulation.; Using a novel supercritical fluid (SCF) process we prepared large porous deslorelin-poly(lactide-co-glycolide) (PLGA) microparticles (mean diameter-13.8 mum, bulk density-0.082 g/cc). These particles, compared to small conventionally prepared particles, exhibited reduced uptake by rat alveolar macrophages, human airway and alveolar epithelial cells, suggesting that they can be better retained in the lung. On day 7 following intratracheal dry powder administration in rats, large porous deslorelin-PLGA particles provided 120- and 2.5-fold higher plasma deslorelin concentrations compared to deslorelin powder and small non-porous particles, respectively.; In conclusion, deslorelin is transported across the respiratory epithelium via a LHRH-receptor mediated process. Protecting deslorelin against degradation using deslorelin-HPbetaCD complexes and avoiding macrophage clearance using large-porous particles are useful strategies to enhance and/or sustain deslorelin delivery.