Utilizing hydroxypropyl methylcellulose acetate succinate-based amorphous solid dispersions to enhance oral bioavailability and antifibrotic activity of nintedanib.

Nintedanib is a first-line therapeutic agent for idiopathic pulmonary fibrosis and interstitial lung disease. However, its weakly basic nature leads to low dissolution in the intestines, resulting in poor oral bioavailability and limited antifibrotic efficacy. This study aimed to develop amorphous solid dispersion (ASD) systems of nintedanib to enhance its oral bioavailability and antifibrotic efficacy. Two types of ASDs of nintedanib were prepared utilizing Soluplus® and hydroxypropyl-methylcellulose acetate succinate (HPMCAS) as polymer matrices through hot-melt extrusion. Subsequently, the ASDs were characterized using polarized light microscopy (PLM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). Compared to pure nintedanib crystal, the dissolution of ASD-Soluplus and ASD-HPMCAS in simulated intestinal fluid was enhanced by 10.1-fold and 16.4-fold, respectively. Furthermore, pharmacokinetic studies in rats demonstrated that ASD-Soluplus and ASD-HPMCAS exhibited 2.5-fold and 7.9-fold increases in oral bioavailability, respectively, after a single dosage compared to nintedanib. The antifibrotic efficacy of ASDs was remarkably improved compared to the pure drug. No significant adverse effects on the liver and limited weight reduction were observed following oral administration of ASDs in rats. Overall, this study indicates that ASD is an effective approach to enhance the oral bioavailability and antifibrotic efficacy of nintedanib.