Spray-Dried Inhalable Favipiravir Dry Powder Formulation for Influenza Therapy: Preparation and In vivo Evaluation

Background: Influenza, a seasonal infectious disease, has consistently posed a formidable challenge to global health in recent years. Favipiravir, an RNA-dependent RNA polymerase inhibitor, serves as an anti-influenza medication, currently administered solely in oral form for clinical use. However, achieving an effective therapeutic outcome often necessitates high oral doses, which can be accompanied by adverse effects and suboptimal patient adherence. Objective: To enhance favipiravir delivery efficiency and potentially mitigate dosage-related side effects, this study aimed to formulate favipiravir as a dry powder for pulmonary inhalation, facilitating direct targeting of lung tissue. Methods: Employing L-leucine as a carrier, favipiravir was prepared as an inhalable dry powder through the spray-drying technique. A 3x3 full-factorial design approach was adopted to optimize the formulation. The optimized spray-dried powder underwent comprehensive characterization, including assessments of its morphology, crystallinity, flowability, and aerodynamic particle size distribution. The therapeutic efficacy of the powder was evaluated in a mouse model infected with the H1N1 influenza virus. Results: The formulated powder demonstrated good aerosol properties, rendering it suitable for inhalation delivery. Its therapeutic efficacy was demonstrated in the mouse model, where it exhibited marked protective effects against the virus in vivo after 5 days of treatment. Notably, the inhalation dose required (15 mg/kg/day) was significantly lower than the oral gavage dose (150 mg/kg/day), indicating that substantially reduced doses, when administered via inhalation, were sufficient to confer protection against mortality in mice. Conclusion: The findings underscore the potential of inhalation therapy using spray-dried favipiravir powder as an effective and efficient treatment option for influenza, offering the promise of reduced dosing requirements and associated adverse effects.