Inhalable microparticles containing terbinafine for management of pulmonary fungal infections: Spray drying process engineering using lactose vs. mannitol as excipients

Abstract

Terbinafine is a broad-spectrum antifungal agent with potential therapeutic value in management of pulmonary aspergillosis. To this end, dry powder inhalation formulations of terbinafine hydrochloride were prepared by nano spray drying, following a 23 factorial experimental design. The experimental design aimed to study and optimize influences of the excipient (lactose vs. mannitol), the spray solvent (hydroethanolic vs. aqueous), and the drying gas inlet temperature (90 vs. 75 °C) on characteristics and aerodynamic performance of spray-dried formulations. For the mannitol-based formulations, the hydroethanolic (50.5% w/w ethanol) spray solvent resulted in smaller, up to 3.5-fold more-respirable particles and greater yields than the aqueous solvent. Increasing the inlet temperature had a negative impact on the aerodynamic performance of the mannitol-based formulations. For the lactose-based formulations, the hydroethanolic spray solvent also resulted in smaller, more-respirable particles but with poorer drug loading and poorer solid-state stability than the aqueous solvent. Increasing the inlet temperature had a positive impact on the aerodynamic performance of the lactose-based formulations. The observed influences are thoroughly discussed. After dispersion in a surrogate for the bronchial/alveolar fluid, all the formulations exhibited partial (<40%) drug dissolution. Undissolved drug particles were smaller than 160 nm in diameter, suggesting they have potential to avoid clearance by alveolar macrophages and mucociliary escalation and to thus provide prolonged local action. Two formulations were selected for further development and testing.