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

Area of Science:

• Pharmaceutical Sciences
• Nanotechnology
• Drug Delivery

Background:

• Nintedanib (BIBF), a BCS II drug, exhibits poor oral bioavailability due to low dissolution and intestinal absorption, limiting its efficacy in non-small cell lung cancer treatment.
• Enhancing the oral bioavailability of BIBF is crucial for improving therapeutic outcomes.

Purpose of the Study:

• To fabricate rod-shaped nintedanib nanocrystals (BIBF-NCs) to enhance oral bioavailability.
• To investigate the effects of nanocrystal formulation on BIBF dissolution, intestinal absorption, and pharmacokinetic profile.

Main Methods:

• Rod-shaped BIBF nanocrystals (BIBF-NCs) were prepared using an antisolvent precipitation-ultrasound method with sodium carboxyl methyl cellulose (CMC-Na) as a stabilizer.
• Characterization included particle size, zeta potential, morphology (TEM), crystal form (PXRD, DSC), saturation solubility, and dissolution studies.
• Intestinal absorption was evaluated using in situ single-pass intestinal perfusion (SPIP) and cell uptake studies (macrophages, Caco-2 monolayers).
• In vivo pharmacokinetic studies were conducted after oral administration in rats.

Main Results:

• BIBF-NCs with a particle size of 325.30 ± 1.03 nm and rod-shaped morphology were successfully fabricated.
• BIBF-NCs demonstrated significantly improved saturation solubility and dissolution compared to BIBF powder.
• In situ intestinal perfusion studies revealed enhanced absorption and membrane permeability of BIBF-NCs, with improved K_a and P_app values.
• Inhibition studies indicated that BIBF-NCs are absorbed via endocytosis (caveolae, clathrin-mediated) and micropinocytosis.
• In vivo studies showed a 2.51-fold increase in oral bioavailability and a prolonged T_max for BIBF-NCs compared to BIBF solution.

Conclusions:

• Fabrication of rod-shaped BIBF-NCs effectively enhances the dissolution and saturation solubility of nintedanib.
• BIBF-NCs exhibit improved intestinal absorption and membrane permeability, utilizing multiple endocytic pathways.
• The nanocrystal formulation significantly boosts the oral bioavailability of nintedanib, offering a promising strategy for non-small cell lung cancer treatment.