Comparison of bioavailability of amorphous versus crystalline itraconazole nanoparticles via pulmonary administration in rats.

The effect of supersaturation on bioavailability of inhaled nebulized aerosols is compared for amorphous versus crystalline nanoparticulate dispersions. The nanocrystalline formulations of itraconazole (ITZ) were made by wet milling (i.e. Wet-milled ITZ), whereas amorphous nanostructured aggregates (ITZ/mannitol/lecithin=1:0.5:0.2, weight ratio) were made by an ultra-rapid freezing process (i.e. URF-ITZ). Dissolution tests revealed the extent of supersaturation was 4.7-times higher for URF-ITZ versus Wet-milled ITZ, though their dissolution rates were similar. The aerodynamic performances of both aqueous colloidal dispersions were comparable and suitable for deep lung delivery. Single-dose 24-h pharmacokinetic studies were conducted in Sprague-Dawley rats following inhalation of the nebulized colloidal dispersions (equivalent to 20mgITZ/mL dispersion in 5mL) in a nose-only dosing apparatus. Lung depositions following inhalation were similar for both compositions. In systemic circulation, Wet-milled ITZ and URF-ITZ achieved C(max) of 50 and 180ng/mL at 2.7 and 4.0h, and AUC(0-24) of 662 and 2543ngh/mL, respectively, based on a one-compartmental analysis. Pulmonary delivery of the nanoparticulate amorphous ITZ composition resulted in significantly higher systemic bioavailability than for the nanocrystalline ITZ composition, as a result of the higher supersaturation that increased the permeation.