Title : Formulation and evaluation of dasatinib loaded lipid nanocapsules for improved oral bioavailability
Abstract:
Dasatinib (DSB) is the second-generation potent tyrosine kinase inhibitor which is used in the treatment of chronic myeloid leukemia (CML). However low bioavailability, high toxicity, and rapid clearance rate limit the therapeutic efficiency of DSB. In this work, DSB loaded Lipid nanocapsules (LNCs) was formulated to improve the physicochemical stability, controlled drug release, enhanced cytotoxicity and oral bioavailability. The DSB-LNCs were formulated using modified Phase inversion temperature (PIT) method. The DSB-LNCs were evaluated by drug release kinetics, cell uptake and cytotoxicity in K562 cells, intestinal permeability and in vivo pharmacokinetics studies. The DSB-LNCs exhibited a sustained and controlled release with a significantly high percentage of total release (2.48 folds) than pure DSB. The release mechanism followed the Korsmeyer Peppas model, suggesting super case II transport method. The cellular uptake results showed a 3.9-fold increase in cellular internalization efficiency of DSB-LNCs in K562 cancer cells, whereas the cytotoxicity study suggested an enhanced anti-cancer efficacy of the LNCs. The ex-vivo studies on permeation showed a 3.23-folds increase in permeability flux rate and 2.45-folds increased apparent permeability coefficient compared to DSB. The pharmacokinetics studies showed a 2.82-fold increase in Cmax and a 2.15-fold increase in AUC, and an increased Tmax and half-life period. The DSB-LNCs showed remarkable improvements in the biopharmaceutical and pharmacokinetic behavior of DSB, proving high suitability as a promising oral nanocarrier system for improving the therapeutic efficiency of CML treatment.
Keywords: Dasatinib; Lipid nanocapsule; Chronic Myeloid Leukaemia; Bioavailability; Cytotoxicity.
