Rod-shaped nintedanib nanocrystals improved oral bioavailability through multiple intestinal absorption pathways

Nintedanib (BIBF) is a biopharmaceutical classification system II (BCS II) drug that has a good therapeutic effect for the treatment of nonsmall cell lung cancer; however, it shows poor oral bioavailability due to low dissolution and intestinal absorption. This study aims to fabricate rod-shaped nanocrystals to enhance oral bioavailability by improving the dissolution and absorption of BIBF in the intestine. By prescription screening, BIBF nanocrystals (BIBF-NCs) with a particle size of 325.30 ± 1.03 nm and zeta potential of 32.70 ± 1.24 mV were fabricated by an antisolvent precipitation-ultrasound approach with a stabilizer of sodium carboxyl methyl cellulose (CMC-Na). BIBF-NCs exhibited a rod-shaped morphology by transmission electron microscopy (TEM). The results of powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) showed that the crystal form of BIBF in BIBF-NCs was altered. The BIBF-NCs remarkably improved the saturation solubility and dissolution of BIBF compared with BIBF powder. According to the results of in situ single-pass intestinal perfusion (SPIP), BIBF-NCs showed improved absorption and membrane permeability, with Ka and Papp values in the jejunum of 0.21 ± 0.01 min-1 and (4.34 ± 0.11) × 10-4 cm/min, respectively. Further, the Ka and Papp values of BIBF-NCs were all reduced significantly after the addition of inhibitors colchicine, chlorpromazine and indomethacin, which demonstrated that BIBF-NCs could be absorbed by endocytosis mediated by caveolae and clathrin and micropinocytosis in the intestine. The cell evaluation results showed that BIBF-NCs could be taken up by macrophages and transported from Caco-2 monolayers. The in vivo pharmacokinetic results showed that the bioavailability of the BIBF-NCs was 2.51-fold higher than that of the BIBF solution (BIBF-Sol) after oral administration with a longer Tmax (4.50 ± 1.00 h vs. 2.60 ± 1.92 h). In summary, rod-shaped BIBF-NCs could significantly improve oral bioavailability through multiple intestinal absorption pathways.