Pulmonary delivery of ivacaftor via proliposomal dry powder inhalers for cystic fibrosis therapy

Ivacaftor, a CFTR potentiator, is clinically effective in treating cystic fibrosis (CF), but it has poor lung targeting, variable oral bioavailability, and poor aqueous solubility. The objective of the study was to develop and optimize an inhalable proliposomal dry powder inhaler (DPI) of ivacaftor for pulmonary delivery. The optimized ivacaftor-loaded proliposomes were optimized using a face-centered central composite design (α = 1) by varying soy phosphatidylcholine (SPC) concentration and drug: cholesterol ratio, with particle size, zeta potential, and entrapment efficiency. The optimized formulation was spray dried with mannitol and leucine to obtain inhalable microparticles. The optimized proliposomal formulation had nanosized vesicles (∼198 nm), high entrapment efficiency (∼73%), and good colloidal stability. The solid-state characterization confirmed amorphization and molecular dispersion of ivacaftor without chemical incompatibility. The spray-dried formulation exhibited high emitted dose (96.45%), fine particle fraction (52.38%), and MMAD (1.66 µm), and sustained drug release, good cytocompatibility, and satisfactory accelerated stability supported its suitability. Conclusively, proliposomal inhalation delivery is a promising approach to enhance pulmonary targeting of ivacaftor in cystic fibrosis.