Synthesis, optimization, and evaluation of polyvinyl alcohol-based hydrogels as controlled combinatorial drug delivery system for colon cancer

The purpose of current research work was to synthesize and evaluate the cross-linked ternary hydrogels using polyvinyl alcohol (PVA) and two monomers itaconic acid and methacrylic acid. Controlled combinatorial drug delivery systems (CCDDS) were synthesized by free radical solution polymerization method using ethylene glycol dimethacrylate (EGDMA) as cross-linking agent. 5-Fluorouracil (5-FU) and leucovorin calcium (LC) were loaded in combination into synthesized gels for colonic delivery. Various characterizations such as Fourier transform infrared spectroscopy, differential scanning calorimetry, TGA, powder X-ray diffraction, and scanning electron microscopy were performed to confirm the cross-linking of functional groups, thermal stability, crystal structure, and surface morphology of developed formulations. Swelling and drug release was performed at higher and lower pH (1.2, 7.4) buffer solution. Increase in swelling was observed at higher pH 7.4. Cumulative percent release of 5-FU and LC was 29.8% and 27.2% at pH 1.2, and 86.9% and 87.01% at pH 7.4, respectively. Kinetic modeling was applied on optimized hydrogel formulation, and the results showed that release of 5-FU and LC best expressed by first-order kinetic model with regression coefficient (R-2) value 0.937 for 5-FU and 0.963 for LC. Acute oral toxicity was performed on healthy rabbits, and results showed that the synthesized CCDDS is nontoxic and compatible with biological system. In vivo studies on rabbits were conducted using HPLC, and plasma drug concentration and pharmacokinetic parameters were estimated. Newly synthesized CCDDS showed a good pH-responsive swelling and controlled drug delivery characteristics. CCDDS can be used as excellent carrier for various therapeutic agents, which are compatible with biological system.