Enhanced Aerosolization of High Potency Nanoaggregates of Voriconazole by Dry Powder Inhalation

Invasive pulmonary aspergillosis is a deadly fungal infection with a high mortality rate, particularly in patients having undergone transplant surgery. Voriconazole, a triazole antifungal pharmaceutical product, is considered as a first-line therapy for invasive pulmonary aspergillosis, and exhibits efficacy even for patients who have failed other antifungal drug therapies. The objective of this study is to develop high potency nanoaggregates of crystalline voriconazole composition for dry powder inhalation using the particle engineering process, thin film freezing. In this study, mannitol at low concentrations acted as a surface texture-modifying agent, and we evaluated the physicochemical and aerodynamic properties of the voriconazole formulations containing different amounts of mannitol. In vitro aerosol performance data demonstrated that powder formulations consisting of 90 to 97% (w/w) voriconazole were the optimum for inhalation with a fine particle fraction (% of delivered dose) as high as 73.6 ± 3.2% and mass median aerodynamic diameter of 3.03 ± 0.17 μm when delivered by a commercially available device. The thin film freezing process enabled phase-separated submicron crystalline mannitol to be oriented such as to modify the surface texture of the crystalline voriconazole nanoaggregates, thus enhancing their aerosolization. Addition of as low as 3% (w/w) mannitol significantly increased the fine particle fraction (% of metered dose) of voriconazole nanoaggregates when compared to compositions without mannitol (40.8% vs 24.6%, respectively). The aerosol performance of the voriconazole nanoaggregates with 5% (w/w) mannitol was maintained for 13 months at 25 °C/60% RH. Therefore, voriconazole nanoaggregates having low amounts of surface texture-modifying mannitol made by thin film freezing are a feasible local treatment option for invasive pulmonary aspergillosis with high aerosolization efficiency and drug loading for dry powder inhalation.