Pulmonary targeted delivery of ivacaftor liposomes for F508 del-CFTR mutation mediated cystic fibrosis therapy.

Cystic fibrosis (CF) is an autosomal recessive genetic disease elicited by mutations in the gene encoding the CF transmembrane conductance regulator protein (CFTR). Complications associated with CF include airway blockade leading to lung damage, respiratory tract infection, etc. Ivacaftor (IVA), also known as VX-770, works by potentiating the CFTR, leading to improved chloride transport and relieving lung pulmonary complications. The DSPE-PEG containing liposomal formulations of IVA were prepared and optimized using Box-Behnken (BBD) design of the experiment. Further, the optimized liposomes were further characterized for drug excipient compatibility by performing FT-IR spectroscopy, differential scanning calorimetry, and X-ray diffraction analysis. Nanoparticle characteristics were evaluated using dynamic light scattering, while liposome shape and morphology were confirmed by transmission electron microscopy. Liposome uptake and cell viability assay was carried out in human bronchial epithelial cells (L-132 cells). In-vivo, studies including pulmonary drug distribution, retention, and toxicity assessments were carried out in Balb/c mice. The optimized IVA-loaded Liposomes (IVA-Lip) were found to have a particle size of 170.48 ± 8.37 nm, polydispersity index of 0.18 ± 0.09, and a zeta potential of -21.6 ± 4.9 mV. Encapsulation efficiency was determined to be 82.37 ± 5.48 % while the in-vitro drug release study revealed that 71.98 ± 6.39 % IVA was released from liposomes over 24 h. The drug excipient compatibility studies indicated no interaction between IVA and the excipients, while the transition of IVA from crystalline to amorphous form was noted. The TEM images revealed spherical-shaped liposome bilayer particles with smooth surfaces. The cell viability assay confirmed that IVA and IVA-liposomes are not cytotoxic. The pulmonary toxicity study revealed no recognizable toxicity as seen in the histopathology images. The pulmonary drug distribution study exhibited uniform lung distribution, while the drug retention study for 24 h showed 2.89 ± 0.98 % and 38.19 ± 2.98 % IVA retention, followed by inhalation exposure of IVA and IVA-Lip, respectively.