Co-amorphous mixture of erlotinib hydrochloride and gallic acid for enhanced antitumor effects

Abstract

Erlotinib hydrochloride (ERL) is a frontline drug approved by FDA for the treatment of several types of cancers, while its clinical application is seriously compromised by poor water solubility. In this study, gallic acid (GA) was utilized as a bioactive co-former, and the co-amorphous system of ERL and GA (ERL-GA CM) was constructed to improve the water solubility and bioavailability of ERL as well as produce synergistic antitumor effects. After being prepared by solvent evaporation method, ERL-GA CM was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, and molecular dynamics (MD) simulations demonstrated that the intermolecular hydrogen bonds were formed between ERL and GA in ERL-GA CM. The concentration of ERL in ERL-GA CM was 6.7 times (25 °C) and 5.1 times (37 °C) higher than that of ERL after shaking for 72 h at pH 2.0, and the dissolution rate of ERL in ERL-GA CM was also significantly increased. Pharmacokinetic assay demonstrated that ERL-GA CM obviously enhanced the oral bioavailability of ERL, and pharmacodynamic studies indicated that ERL-GA CM exerted synergistic antitumor effects characterized by Q value of 1.3. Besides, ERL-GA CM showed negligible toxicity to the healthy tissues. Taken together, co-amorphization of ERL using GA provides a promising strategy to improve the solubility and bioavailability of ERL for enhanced antitumor effects.