Formulation of inhalable voriconazole dry powders using spray freeze-drying technique

Abstract

Systemic administration of antifungal agents intended for the treatment of pulmonary aspergillosis is limited by the poor lung distribution and severe adverse effects. Pulmonary delivery is desirable as it allows deposition of drug at high concentrations directly in the site of infection. Voriconazole is the primary treatment of pulmonary aspergillosis with potent and wide-spectrum activity. This study aimed to develop inhalable voriconazole dry powder formulation with excellent aerodynamic performance by constructing porous particles using spray freeze-drying technique. Mannitol was included in the formulation as a bulking agent. Since voriconazole has a poor aqueous solubility, tert-butyl alcohol (TBA) was used as a co-solvent. A two-level full factorial design was employed to systematically investigate the effect of three factors and their interactions on the aerosol performance of the formulations. These factors were (i) solute concentration of the feed solution; (ii) the voriconazole concentration; and (iii) the co-solvent composition. The cascade impactor study revealed that spray freeze-dried powder containing high level of voriconazole concentration could reach the highest fine particle fraction (FPF, <5 μm) of 47.4%. After analysing the factorial design using Minitab® 18 statistical software, the voriconazole concentration was found to be the most significant factor that can positively affect the fine particle fraction and negatively affect the emitted fraction. This result suggests that, with current production method, increasing the voriconazole concentration in the feed solution could not only improve the delivery efficiency as higher percentage of voriconazole was included in same amount of powder, but also enhance the aerosol performance of powder formulation as higher FPF was achieved.