Naringenin-Loaded Dipalmitoylphosphatidylcholine Phytosome Dry Powders for Inhaled Treatment of Acute Lung Injury.

Acute lung injury is a severe respiratory disorder characterized by overwhelming lung inflammation. Dipalmitoylphosphatidylcholine (DPPC) is the major lipid component of pulmonary surfactant, which here acts as a carrier delivery system for drugs, while also preserving surface tension in the lung. The clinical development of naringenin (NG) is limited by its low solubility and bioavailability. Novel NG-loaded DPPC phytosomes for dry powder inhalation (NPDPIs) were prepared by solvent evaporation and a freeze-drying method. The particle size, electric potential, release, and lung deposition were characterized. A rat model of acute lung injury was established and used for pharmacodynamic evaluations. A mixture of NG/DPPC 1:2 (w/w) formed stable phytosomes with the addition of appropriate ethanol. The phytosomes had high complexation efficiency (92.1% ± 1.87%) with NG, a small mean size (150.8 ± 6.9 nm), and a high zeta potential (20.97 ± 0.55 mV). NPDPIs composed of mannitol/DPPC/NG (4:2:1, w/w/w) presented a satisfactory appearance, good fluidity, quick reconstitution to naringenin phytosomes (NGPs), and small (167.2 nm) reconstituted NGPs. The aerodynamic diameter (12.48 μm) and fine particle fraction (23.90%) were suitable for pulmonary delivery by inhalation. The NPDPIs demonstrated efficacy in a rat model of acute lung injury. NPDPIs significantly inhibited the phosphorylation of P38 in the mitogen-activated protein kinase pathway and suppressed oxidative stress. Surprisingly, the DPPC vehicle exhibited potential effects against acute lung injury by protecting respiratory function. NPDPIs were developed for sustained drug release, promoting pulmonary bioavailability of drug and protecting against acid-induced acute lung injury in rats by pulmonary delivery. NPDPIs are a promising dry powder inhaler for clinical application in acute lung injury.