Porous and highly dispersible voriconazole dry powders produced by spray freeze drying for pulmonary delivery with efficient lung deposition.

Systemic administration of antifungal agents for the treatment of pulmonary aspergillosis is limited by the poor lung deposition and severe adverse effects. In contrast, pulmonary delivery allows a higher amount of drug to be delivered directly to the infection site and therefore a lower dose is required. This study aimed to develop porous and inhalable voriconazole dry powder with good lung deposition by spray freeze drying (SFD), using tert-butyl alcohol (TBA) as a co-solvent. A three-factor two-level full factorial design approach was used to investigate the effect of total solute concentration, drug content and co-solvent composition on the aerosol performance of the SFD powder. In general, the SFD voriconazole powder exhibited porous and spherical structure, and displayed crystalline characteristics. The analysis of factorial design indicated that voriconazole content was the most significant variable that could influence the aerosol performance of the SFD powders. The formulations that contained a high voriconazole content (40% w/w) and high TBA concentration in the feed solution (70% v/v) displayed the highest fine particle fraction of over 40% in the Next Generation Impactor study in which the powder was dispersed with a Breezhaler® at 100 L/min. In addition, the fine particle dose of the SFD powder showed a faster dissolution rate when compared to the unformulated voriconazole. Intratracheal administration of SFD voriconazole powder to mice resulted in a substantially higher drug concentration in the lungs when comparing to the group that received an equivalent dose of liquid voriconazole formulation intravenously, while a clinically relevant plasma drug concentration was maintained for at least two hours. Overall, an inhalable voriconazole dry powder formulation exhibiting good aerosol property and lung deposition was developed with clinical translation potential.