Development of an inhaled controlled release voriconazole dry powder formulation for the treatment of respiratory fungal infection

The present research aimed to develop and characterize a sustained release dry powder inhalable formulation of voriconazole (VRZ) for invasive pulmonary aspergillosis. The developed formulations were studied for their in vitro release profile, aerosol, and physicochemical properties as well as interactions with lung epithelia in terms of toxicity and transport/uptake. VRZ and VRZ loaded poly lactide microparticles (VLM) were prepared by aqueous/organic cosolvent and organic spray drying, respectively. Powders were characterized using laser diffraction, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS), and electron microscopy. Aerosol performance was evaluated using an RS01 dry powder inhaler and in vitro cascade impaction. Uptake across Calu-3 lung epithelia was studied, using aerosol deposition of the powder onto cells cultured in an air interface configuration, and compared to dissolution using a conventional dialysis membrane. Additionally, toxicity of VRZ and VLM and the potential impact of transmembrane proteins on uptake were investigated. The particle size and the aerosol performance of spray-dried VRZ and VLM were suitable for inhalation purposes. VRZ exhibited a median volume diameter of 4.52 ± 0.07 μm while VLM exhibited 2.40 ± 0.05 μm. Spray-dried VRZ was crystalline and VLM amorphous as evaluated by DSC and XRPD, and both powders exhibited low moisture sorption between 0 and 90% RH (<1.2% w/w) by DVS. The fine particle fraction (FPF) (% aerosol <5 μm) for the VRZ was 20.86 ± 1.98% while the VLM showed significantly improved performance (p < 0.01) with an FPF of 43.56 ± 0.13%. Both VRZ and VLM were not cytotoxic over a VRZ concentration range of 1.2 nM to 30 μM, and the VLM particles exhibited a sustained release over 48 h after being deposited on the Calu-3 cell line or via conventional dialysis-based dissolution measurements. Lastly, VRZ exhibited polarized transport across epithelia with basal to apical transport being slower than apical to basal. Influx and efflux transports may also play a role as transport was altered in the presence of a number of inhibitors. This study has established an inhalable and sustained release powder of VRZ for targeting invasive pulmonary aspergillosis.