Repositioning pentoxifylline via inhalable novasomes for pulmonary fibrosis: from statistical optimization to in-vivo evaluation

Pulmonary fibrosis (PF) represents the final stage of lung injuries, triggered mainly by viral infections. Pentoxifylline (PTX) is a hemorheologic drug that has been recently repurposed for the prophylaxis of PF. Nevertheless, it exhibits low oral bioavailability. This study aims to develop inhalable PTX-loaded novasomes with enhanced pulmonary deposition and improved therapeutic efficiency. PTX-novasomal nanovesicles were prepared using ethanol injection technique and characterized for particle size, zeta potential, and entrapment efficiency, adopting a central composite statistical design for optimization. The optimized PTX-novasomes were subsequently evaluated for in-vitro drug release and aerodynamic size characterization using Andersen Cascade Impactor. Furthermore, the optimized PTX-novasomes were characterized using transmission electron microscopy, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. Finally, an in-vivo pharmacodynamic study was performed in a bleomycin-induced PF rat model to assess the effects of inhaled PTX-novasomes on the inflammatory and fibrotic biomarkers, and fibrosis scoring via Masson's trichrome stain. Results showed that the optimized Novasomes were successfully prepared as spheroidal nanosized vesicles (239.80 nm) with high PTX encapsulation (59.22%), and a biphasic release profile. Moreover, the optimized novasomes demonstrated significantly higher fine particle fraction (43.819%) and smaller mass median aerodynamic diameter (1.612 μm) than free PTX. Furthermore, the in-vivo studies revealed a marked reduction in the levels of inflammatory and fibrotic biomarkers following inhalation of PTX-novasomes, outperforming the conventional oral formulation. These findings signify the impact of integrating novasomal formulation with inhalational delivery in enhancing aerodynamic performance and pulmonary deposition of PTX, supporting the potential repositioning of PTX inhalable novasomes for PF prophylaxis.