Fabrication and Characterization of pH-Sensitive Hydrogels of Oxaliplatin for Colon-Specific Drug Delivery

Abstract

Background and Objective A foremost step towards targeted administration of therapeutic agents is the formulation of novel drug delivery systems. Oral route is the most preferred and desired route of administration as a non-invasive mean of transporting drug to a target site. The aim of current research work was to design site-specific hydrogels for target delivery of oxaliplatin, an anticancer agent, used for the treatment of colorectal cancer. Six different types of hydrogel formulations were synthesized by different proportions of polymers and monomers. Another objective was to conduct an oral acute toxicity study of drug carrier polymeric systems on rabbits. Methodology A chemical cross-linking technique, free radical polymerization was chosen for preparation of polymeric networks. Six different combinations i.e. CS-co-poly(MAA), CS-co-poly(AA), PEGMA 4000-co-poly(MAA), PEGA 4000-co-poly(AA), PEGMA 8000-co-poly(MAA) and PEGA 8000-co-poly(AA) hydrogels were fabricated and their response to buffer solutions of different pH i.e. pH 1.2 and pH 7.4 was studied. Cross-linking structure of all formulations were evaluated by Fourier Transform Infrared Spectroscopy (FTIR), scanning electron microscopy (SEM) and X-ray diffraction (XRD). For thermal stability all combination of hydrogels were also subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis. In-vitro drug release studies of all formulations were carried out in simulated gastric fluids. Moreover, in-vivo analysis of the best formulations was also conducted after the development of HPLC method. The drug release profile was evaluated by the application of zero order kinetics, first order kinetics, Higuchi model and Korsmayer- Peppas model. Oral acute toxicity study was also conducted for four formulations (CSA, CSMA, PEGA 4000, PEGMA 4000) by oral administration of drug carrier polymeric systems to healthy rabbits. Results All results of characterization confirmed the formation of newly developed polymeric hydrogels. Moreover, hydrogels were selected on the basis of their in-vitro studies and subjected to in-vivo evaluation. High performance liquid chromatography (HPLC) method was developed and validated for in-vivo analysis. The study was performed on thirty six xxvii rabbits and liquid-liquid extraction procedure was adopted for isolation of oxaliplatin from plasma samples. The bioavailability and pharmacokinetic parameters were computed by using a software PK Solver Add Inn program. Toxicity study which was conducted on five groups of rabbits, showed no toxic effects on biological systems of newly fabricated polymeric drug delivery systems. Conclusion From findings of our study it could be concluded that among six different cross-linked polymeric networks, PEGA 8000-co-poly(AA) and CS-co-poly(AA) hydrogels could be considered as superior as it showed better in vitro/in vivo release profiles and thus proven suitable for target delivery of Oxaliplatin to a specific site to treat colorectal cancer. Moreover, toxicity studies revealed that developed formulations were non-toxic to the biological system