Summary

Dry powder inhalers (DPI) are increasingly investigated in the treatment of respiratory diseases. Spray freeze drying (SFD) is a particle engineering technique suitable for preparing inhalable powder formulation. In this study, inhaled powder formulation of voriconazole, a hydrophobic antifungal agent, was developed using the SFD technique with a two-fluid nozzle employed for atomisation. Mannitol was included in the formulation as bulking agent and tert-butyl alcohol (TBA) was used as co-solvent. A two-level full factorial design was adopted to systematically investigate the effect of three factors namely (i) atomisation gas flow rate; (ii) voriconazole concentration; and (iii) primary drying temperature of the freeze-drying process. The in vitro aerosol performance was evaluated by Next Generation Impactor (NGI) coupled with Breezhaler^® operated at 90 L/min and 60 L/min. The factorial analysis of NGI results demonstrated that both the voriconazole concentration and the primary drying temperature could positively affect the aerosolisation performance of the SFD powders. The formulation that contained high voriconazole content (80% w/v) with a high primary temperature in the freeze-drying step (-10°C) was identified to be the optimal formulation as it exhibited good aerosol performance with fine particle fraction (FPF) > 40%. Furthermore, the aerosol formulation of this formulation was not impaired when the NGI was operated at a lower flow rate.

Key Message

Using factorial design approach, this study identified that the primary drying temperature in the freeze-drying step and the voriconazole concentration are the two most important factors that affect the aerosol performance of the spray freeze-dried voriconazole powder.