Formulation of inhaled antifungal agent as dry powder using spray freeze drying technology

Abstract

Respiratory infections caused by fungus such as Apsergillus sp. have become an emerging focus of infectious diseases in recent years. With the growing number of patients with respiratory diseases such as chronic obstructive pulmonary disease (COPD) and pneumonia, it is expected that the number of patients with pulmonary aspergillosis will also increase in the coming years. The mainstay treatment of pulmonary aspergillosis involves the use of triazoles and amphotericin B for systemic administration. However, these antifungal agents are associated with severe side effects, erratic absorption and poor lung distribution. On the other hand, pulmonary delivery allows deposition of high drug concentrations at the site of infection and minimizes systemic exposure, hence reducing the risk of adverse effects. The aim of this study was to explore the potential of spray freeze drying (SFD) technology to produce inhaled powder formulation of voriconazole with high efficiency. SFD involves the atomization of liquid into fine droplets which are instantaneously frozen in a cryogenic liquid, followed by the freeze drying of samples which are sublimed at low temperature and pressure to form porous particles. In this study, -cyclodextrin was used to enhance the aqueous solubility of voriconazole, and the tert-butyl-alcohol (TBA) was used as a co-solvent. The effects of solute concentrations (2 to 8% w/v), composition of co-solvent (water or water/TBA at different ratios) and liquid feed flow rates during atomization (0.4 to 4 ml/min) on the aerosol properties of the powder formulations were examined. The results from laser diffraction and scanning electron microscope showed that SFD could produce spherical powders of voriconazole with relatively narrow particle size distribution. When water was used as the sole solvent, the particles appeared to be smooth on surface. However, the aerosol performance, evaluated by the Next Generation Impactor (NGI), showed that these formulations exhibited a relatively low fine particle fraction (FPF, fraction of powders with aerodynamic diameter below 5.0 m) of around 10%. The addition of TBA as co-solvent increase the porosity of the powders as well as the FPF to around 25-30%. Increasing the solute concentration from 2% to 8% reduced the aerosol performance, while varying the liquid feed flow rate did not have a major impact on the aerosol properties of the powders. The current study has demonstrated that the aerosol properties of SFD powders of voriconazole could be controlled by carefully manipulating the solute concentration and the solvent composition.