title: Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention.
abstract: 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 0.5mg/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±124ng/ml (F2) and 498±44ng/ml (F3), in contrast to formulation F1 (<10ng/ml). As a result of these higher solubilities, absorption into the systemic compartment after endotracheal administration was faster for formulations F2 and F3 (shorter tmax) and in larger quantities compared to the F1 formulation (plasmatic AUC0-24h of 182ngh/ml, 491.5ngh/ml and 376.8ngh/ml, and tmax of 60min, 30min and 5min for F1, F2 and F3, respectively). PL increased the systemic bioavailability of ITZ (determined by the AUCplasma to AUClung 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 (2μg/glung), 24h 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 4.1h vs. 6.5h and 14.7h for F1 and F2, respectively.
authors.affiliation: Laboratoire de Pharmacie Galénique et de Biopharmacie, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: cduret@ulb.ac.be.
authors.forename: Christophe
authors.initials: C
authors.lastname: Duret
authors.affiliation: Laboratoire de Pharmacie Galénique et de Biopharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Romain
authors.initials: R
authors.lastname: Merlos
authors.affiliation: Laboratoire de Pharmacie Galénique et de Biopharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wauthoz
authors.affiliation: SMB S.A., Brussels, Belgium.
authors.forename: Thami
authors.initials: T
authors.lastname: Sebti
authors.affiliation: SMB S.A., Brussels, Belgium.
authors.forename: Francis
authors.initials: F
authors.lastname: Vanderbist
authors.affiliation: Laboratoire de Pharmacie Galénique et de Biopharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Karim
authors.initials: K
authors.lastname: Amighi
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001232:Aspergillus fumigatus / Q000187:drug effects; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004339:Drug Compounding; D058995:Dry Powder Inhalers; D006207:Half-Life; D017964:Itraconazole / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D010316:Particle Size; D011208:Powders; D012995:Solubility; D013499:Surface Properties; D014018:Tissue Distribution
chemical_list: D000935:Antifungal Agents; D011208:Powders; D017964:Itraconazole
keywords: Amorphous; Antifungal; Aspergillosis; Dry powder; Inhalation; Insufflation; Pharmacokinetic; Poorly water-soluble; Solid dispersion