QbD-optimized novel oral nanoemulsion for co-delivery of capecitabine and morin for colorectal cancer to overcome monotherapy limitations

Abstract Colorectal cancer (CRC) remains a leading global health concern. Capecitabine (CAP) demonstrates limited clinical effectiveness due to intestinal mucositis, cachexia, chemoresistance, and organ toxicities. Morin posses modulating properties for such effects; however, no Quality-by-Design (QbD) optimized nanoemulsion has co-delivered CAP and Morin for CRC. Morin was initially computationally assessed against cyclooxygenase-2 (COX-2), P-glycoprotein (P-gp), and CYP3A4 using molecular docking and molecular dynamics simulations. A QbD-based O/W nanoemulsion was optimized using Design Expert software ( p-value < 0.05). CAP and Morin were incorporated into the aqueous and oily phases, respectively, using olive oil selected through preformulation studies. The nanoemulsion was characterized using Fourier Transform Infrared (FTIR) Spectroscopy, Scanning Electron Microscopy-Energy Dispersive X-Ray (SEM-EDX) spectroscopy, particle size, Polydispersity Index (PDI), zeta potential, entrapment efficiency, stability, and ex vivo release studies, followed by an in vivo evaluation in a DMH-induced CRC rabbit model. Morin exhibited strong binding affinity toward COX-2 (-9.0 kcal/mol), P-gp (-7.9 kcal/mol), and CYP3A4 (-7.5 kcal/mol), with stable molecular dynamics profiles. The optimized nanoemulsion (F10) showed a particle size of 131.7 nm, PDI of 0.157, and zeta potential of -13.1 mV. Furthermore, SEM revealed spherical nanosized droplets. In addition, ex vivo NE release was pH-dependent, reaching 66.9% at pH 1.2 and 89.1% at pH 7.4 after 24 h, following Korsmeyer–Peppas kinetics (R² = 0.987). Furthermore, in vivo studies revealed attenuation of mucositis, cachexia, cardiotoxicity, hepatotoxicity, and nephrotoxicity compared with CAP alone. The QbD-optimized nanoemulsion demonstrated favorable formulation characteristics and showed potential as an oral nanotherapeutic co-delivery strategy for CRC management.