Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention

Three Itraconazole (ITZ) dry powders for inhalation (DPI) were prepared by spray-drying a mannitol solution in which the ITZ was in suspension (F1) or was in solution without (F2) or with phospholipid (PL) (F3). These powders were endotracheally insufflated in vivo at a single dose of 0.5 mg/kg for pharmacokinetic profile (lung and plasma concentration) determination in ICR CD-1 mice. ITZ was crystalline in F1 and assumed to be amorphous in the F2 and F3 formulations. F2 and F3 formulations allowed the in vitro formation of an ITZ supersaturated solution with a maximum solubility of 450 124 ng/ml (F2) and 498 44 ng/ml (F3), in contrast to formulation F1 (< 10 ng/ml). As a result of these higher solubilities, absorption into the systemic compartment after endotracheal administration was faster for formulations F2 and F3 (shorter t(max)) and in larger quantities compared to the F1 formulation (plasmatic AUC(0-24h) of 182 ng h/ml, 491.5 ng h/ml and 376.8 ng h/ml, and t(max) of 60 min, 30 min and 5 min for F1, F2 and F3, respectively). PL increased the systemic bioavailability of ITZ (determined by the AUC(plasma) to AUC(lung), ratio) as a consequence of their wetting and absorption enhancement effect. ITZ lung concentrations after pulmonary administration remained higher than the targeted dose, based on the minimal inhibitory concentrations for Aspergillus fumigatus (2 24 h post-administration for both F1 and F2 formulations. However, this was not the case for formulation F3, which exhibited a faster elimination rate from the lung, with an elimination half-life of 4.1 h vs. 6.5 h and 14.7 h for F1 and F2, respectively. (C) 2013 Elsevier B.V. All rights reserved.