Objectives: This study aims to formulate nanodispersion-based sildenafil metered-dose inhalers (MDIs) by using poloxamer 188 (P188) as a stabilizer; to evaluate their stability, aerosol characteristics, cytotoxicity, and inflammatory effects; and to investigate the effects of P188 on stability and aerosol characteristics of the MDIs. Methods: The stability and uniformity of the formulations were evaluated by high-performance liquid chromatography method. The aerosol characteristics were evaluated by the Next Generation Impactor. The cytotoxicity and inflammatory effects on respiratory epithelial cells and alveolar macrophages were evaluated by MTT assay and TNF-α, IL-1β, and NO assay, respectively. Results: The optimal formulation was stable and well-uniform after 6 months. The fine particle fraction and mass median aerodynamic diameter (MMAD) of the formulation were 61.9% ± 2.5% and 1.69 ± 0.06 µm, respectively. The formulation was found to be nontoxic to respiratory epithelial cells and did not induce the inflammatory responses of alveolar macrophages. A positive correlation between P188 concentration and MMAD of the MDIs was observed. P188 possesses an ability to prevent the growth of sildenafil citrate monohydrate crystals in the formulations. Conclusions: The findings provided a basis for the development of sildenafil MDI as a potential candidate for the treatment of pulmonary arterial hypertension.
Keywords: Sildenafil; aerosol particle size distribution; metered-dose inhaler; nanodispersion; poloxamer; pulmonary arterial hypertension.