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

Background: 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. Methods: 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, in vitro release, and lung deposition were characterized. A rat model of acute lung injury was established and used for pharmacodynamic evaluations. Results: 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 mu m) and fine particle fraction (23.90%) were suitable for pulmonary delivery by inhalation. The in vivo 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. Conclusions: 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.