Highly Respirable Dry Powder Inhalable Formulation of Voriconazole with Enhanced Pulmonary Bioavailability

Objective: To develop and characterise a highly respirable dry powder inhalable formulation of voriconazole (VRZ)  
Methods: Powders were prepared by spray drying aqueous/alcohol solutions. Formulations were characterised in terms of particle size, morphology, thermal, moisture responses and aerosolisation performance. Optimised powder was deposited onto air-interface Calu-3 model to assess their uptake across Calu-3 lung epithelia. Optimised formulation was evaluated for stability (drug content and aerosol performance) for 3 months. Additionally, Calu-3 cell viability, lung bioavailability and tissue distribution of optimised formulation were evaluated. 
Results: Particle size and aerosol performance of dry powder containing 80% w/w VRZ and 20% w/w leucine was appropriate for inhalation therapy. Optimised formulation showed irregular morphology, crystalline nature, low moisture sensitivity and was stable for 3 months at room temperature. Leucine did not alter the transport kinetics of VRZ, as evaluated by air-interface Calu-3 model. Formulation was non-cytotoxic to pulmonary epithelial cells. Moreover, lung bioavailability and tissue distribution studies in murine model clearly showed that VRZ dry powder inhalable formulation has potential to enhance therapeutic efficacy at the pulmonary infection site whilst minimising systemic exposure and related toxicity.
Conclusion: This study support the potential of inhaled dry powder VRZ for the treatment of fungal infections.