ZHANG Lixing, DU Liping, FENG Zhong, HAO Guizhou
Gefitinib (1) is a novel medicament for a targeted tumor therapy. It is used in the treatment for latestage non-small cell lung cancer. The marketed formulation of 1 is tablets with low absorption and oral bioavailability. However, the adverse reactions of 1 are exacerbated with the increasing of dosage. To improve the poor oral bioavailability of 1, its inclusion complexes had been environmental-friendly synthesized by mechanochemical technology with GMS 10-8 roll mill in this study. Arabinogalactan (AG) and hydroxypropyl-β-cyclodextrin (HP-β-CD) were separately used as inclusion carriers for 1. The synthesized complexes were characterized by nuclear magnetic resonance (NMR) relaxation technique (T2), scanning electron microscopy (SEM), differential scanning calorimetry(DSC), powder X-ray diffraction (P-XRD). Results of in vitro tests showed that the solubility of 1 was increased from 0.77 g/L to 2.16 g/L, and the dissolution at 120 min was increased from 60％ to 92％ of its mechanochemical treated complexes with HP-β-CD. Similarily, the solubility of 1 in its complex with AG was increased to 1.32 g/L, and the dissolution at 120 min was increased to 75％. Pharmacokinetic behaviors of these inclusion complexes were investigated with male SD rats as the animal models. The rats were divided into 4 groups: injection group with 1 (10 mg/kg), intragastric administration groups with 1, 1/AG inclusion complexes or 1/HP-β-CD inclusion complexes (50 mg/kg). Results showed that the absolute bioavailability of 1 in rats with intragastric administration were 56.94％, 81.63％ and 78.48％ for 1, 1/AG inclusion complexes and 1/HP-β-CD inclusion complexes, respectively. In conclusion, the two synthesized complexes of 1 were in formation of the inclusion, with increased solubility, dissolution in vitro and absorption in vivo. It indicated that the mechanochemical technology was a promising approach to develop 1 solid oral dosage forms with decreased dosage and improved oral bioavailability.