The quest for targeted delivery in colon cancer: mucoadhesive valdecoxib microspheres

Naveen K Thakral¹, Alok R Ray^1,2, Daniel Bar-Shalom³, André Huss Eriksson⁴, Dipak K Majumdar^5
1Centre for Biomedical Engineering, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, India; ²Biomedical Engineering Unit, All India Institute of Medical Science, New Delhi, India; ³Department of Pharmaceutics and Analytical Chemistry, ⁴Bioneer:FARMA, Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark; ⁵Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, University of Delhi, Pushp Vihar, New Delhi, India

Abstract: The aim of the present study was to prepare valdecoxib, a cyclo-oxygenase-2 enzyme inhibitor, as a loaded multiparticulate system to achieve site-specific drug delivery to colorectal tumors. Film coating was done with the pH-sensitive polymer Eudragit S100 and sodium alginate was used as mucoadhesive polymer in the core. The microspheres were characterized by X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy and were evaluated for particle size, drug load, in vitro drug release, release kinetics, accelerated stability, and extent of mucoadhesion. The coated microspheres released the drug at pH 7.4, the putative parameter for colonic delivery. When applied to the mucosal surface of freshly excised goat colon, microspheres pretreated with phosphate buffer pH 7.4 for 30 minutes showed mucoadhesion. To ascertain the effect of valdecoxib on the viability of Caco-2 cells, the 3-(4,5-dimethylthiazol-2yl) 2,5-diphenyltetrazolium bromide) test was conducted using both valdecoxib and coated microspheres. In both cases, the percentage of dehydrogenase activity indicated a lack of toxicity against Caco-2 cells in the tested concentration range. Drug transport studies of the drug as well as the coated microspheres in buffers of pH 6 and 7.4 across Caco-2 cell monolayers were conducted. The microspheres were found to exhibit slower and delayed drug release and lower intracellular concentration of valdecoxib.

Keywords: Caco-2 cells, colon-delivery, COX-2 inhibitors, mucoadhesion, sodium alginate