Bioavailability enhancement of vitamin E TPGS liposomes of nintedanib esylate: formulation optimization, cytotoxicity and pharmacokinetic studies

Abstract

Nintedanib esylate is a kinase inhibitor designated for the cure of non-small cell lung cancer suffered from first-pass metabolism which resulted in low oral bioavailability (~ 4.7%). The exploration intended to increase the oral bioavailability of drug by means of D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) liposomes. The nintedanib esylate-loaded TPGS liposomes were prepared by thin-film hydration method by optimizing process parameters like phospholipids:cholesterol ratio, drug loading and sonication time through the design of experiments. The drug's behaviour was studied using a variety of techniques, including physicochemical characterization and in vitro and in vivo studies. TPGS liposomes had a particle size of 125 ± 6.7 nm, entrapment efficiency of 88.6 ± 4.1% and zeta potential of + 46 ± 2.8 mV. X-ray diffraction analysis revealed the drug was converted to partially amorphous state, while transmission electron microscope images showed the spherical shape with TPGS on the surface of liposomes. The formulation showed Higuchi kinetics with sustained drug release of 92% in 36 h. Cellular uptake of C-6-labelled liposomes was observed in A-549 cells and cytotoxicity testing revealed that liposomes were more effective than marketed formulation. The preparation was found stable in stability chamber and simulated fluids. Liposomal oral bioavailability was ~ 6.23 times greater in Sprague-Dawley male rats compared to marketed formulation, according to in vivo pharmacokinetic data. Liposomes performed better than marketed capsules upon oral administration because of the prolonged drug release and increased oral bioavailability; as a result, the developed formulation can become a successful strategy in cancer chemotherapy.

Keywords: Bioavailability; First-pass metabolism; Liposomes; Nintedanib esylate; Pharmacokinetics.