Attention has begun to focus on the pulmonary delivery of antifungal agents for invasive fungal infections as inhalation of the fungal spores is often the initial step in the pathogenesis of many of these infections, including invasive pulmonary aspergillosis (IPA). IPA in immunocompromised patients has high mortality rates despite current systemic (oral or intravenous) therapies. In this study, particulate voriconazole (VRC) formulations were designed with suitable properties for inhalation using thin film freezing (TFF), a particle engineering process capable of producing low-density porous aggregate particles. Nanostructured amorphous morphology of VRC was less favorable in vitro and in vivo than microstructured crystalline morphology, despite being a poorly water-soluble compound. Using a Handihaler dry powder inhaler (DPI), microstructured crystalline TFF-VRC and nanostructured amorphous TFF-VRC-PVP K25 (1:3) had fine particle fractions of 37.8% and 32.4% and mass median aerodynamic diameters of 4.2 and 5.2 μm, respectively. Single dose 24-h pharmacokinetic studies were conducted in ICR mice. AUC(0-24h) in the lung tissue and plasma was 452.6 μg h/g wet lung weight and 38.4 μg h/mL, respectively, following a 10mg/kg insufflated dose of TFF-VRC directly into the lungs of the mice, while AUC(0-24 h) in the lung tissue and plasma was 232.1 μg h/g wet lung weight and 18.6 μg h/mL, respectively, following a 10mg/kg insufflated dose of TFF-VRC-PVP K25 (1:3). High concentrations of VRC in lung tissue coupled with clinically relevant plasma concentrations suggest that pulmonary delivery of microstructured crystalline VRC could potentially be a beneficial strategy for administration of VRC to patients with invasive pulmonary fungal infections.
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