Solid Dispersions of Gefitinib with D-α-Tocopherol Polyethylene Glycol-1000 Succinate and 2-Hydroxypropyl β-Cyclodextrin Complex Improved Their Solubility, Dissolution and Apoptosis against A549 Cells

Abstract

This study focuses on the development and characterization of solid dispersions (SDs) of Gefitinib (GEF) to improve its aqueous solubility and therapeutic activity against lung cancer. SDs were prepared by the co-precipitation method with tocopheryl-polyethylene-glycol succinate-1000 (TPGS) (F1), sodium lauryl sulfate (SLS) (F2) and complexation of F1 with hydroxypropyl β-cyclodextrin (HP-β-CD) (F3). Optimal formulations (F1 and F3) were used against A549 cells to determine the apoptosis, expressions of p53 and caspases. F3 has shown the highest solubility (1271.21 µg/mL), followed by F1 (1003.69 µg/mL), F2 (707.81 µg/mL) and GEF pure (303.85 µg/mL) in 0.1N HCl. Dissolution at 1.2 pH significantly enhanced the release from F3 (99.19%), followed by F1 (94.76%), F2 (85.70%) and GEF pure (37.26%) during 120 min. Complexation of GEF–TPGS with HP-β-CD significantly improved drug release with high dissolution efficiency (78.57%) in 24.9 min of mean dissolution time. Differential scanning calorimetry revealed crystalline to amorphous conversion of GEF in SDs, which was confirmed by scanning electron microscopy. Fourier transform infrared and proton nuclear magnetic resonance spectral analysis revealed no interaction between GEF and excipients. The IC50 values were 2.239, 3.135 and 4.471 µM for F3, F1 and GEF pure, respectively, against A549 cells. Increased expressions of p53 (5.9-, 4.6- and 3.04-fold), caspase-3 (5.38-, 3.78- and 3.01-fold) and caspase-9 (5.35-, 3.76- and 2.47-fold) in the case of F3, F1 and GEF pure, respectively, as compared to the untreated A549 cells indicated improved apoptotic potential of the SDs. TPGS SDs and their complexation with HP-β-CD improved the solubility, dissolution and efficacy of GEF against A549 cells. So, they can be a suitable alternative to the conventional GEF formulations against non-small-cell lung cancers.