Naftopidil-fumaric acid interaction in a solid dispersion system: Improving the dissolution rate and oral absorption of naftopidil in rats

The aim of this study was to improve the dissolution rate and oral absorption of naftopidil (NAF) in rats via solid dispersion (SD) with a weak acid and copolymer. We hypothesized that the dissolution rate and oral bioavailability of NAF would increase through hydrogen bonding between NAF and weak acids/hydrophilic polymers. D-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS) and fumaric acid were selected as the hydrophilic polymer and weak acid based on their apparent solubility and pre-dissolution test results, respectively. The optimal formulation (SD5) comprised NAF: fumaric acid: TPGS: Aerosil (R) 200 at a ratio of 1:1:1:1. The dissolution rate of SD5 in distilled water and pH 1.2 media was significantly higher than that of a commercial product (Flivas (R)). The chemical interaction between NAF and fumaric acid was confirmed using attenuated total reflectance Fourier transform infrared spectroscopy. The SD5 formulation was stable for 12 months. The oral bioavailability and peak plasma concentration (C-max) of NAF present in the SD5 formulation improved compared with those of Flivas (R) after oral administration to rats (185% and 1.88-fold, respectively). In conclusion, fumaric acid is the major factor contributing to the TPGS-induced improvement of the dissolution rate of NAF in SD5 formulation, thereby increasing the oral absorption of NAF in rats.