Development of molecularly imprinted hydrogels for drug release systems

In the past few decades, hydrogels have been a focal point of many researches in the biomedical and pharmaceutical fields. They offer great promise for applications in cell therapy, tissue engineering and as vehicles for controlled drug release. Recent studies in the area of molecularly imprinted hydrogels in controlled release of drugs highlighted these materials as a promising platform for controlled ocular drug delivery systems. The purpose of this study was to fabricate novel Doxycycline Hyclate (DOX)-imprinted ocular controlled release hydrogels by establishing a relationship between material structure and its performances . The material-property relationship was established and used to predict the releasing performances of the DOX-imprinted hydrogels. Initially, a systematic method was designed to investigate the parameters affecting the fabrication of MIPs by thermal and UV induced polymerization. Effectively optimization of the polymerization conditions including reaction type, initiator concentration, reaction period and reaction temperature resulted in high degree of monomer conversion. Design of experiments (DOE) as a systematic approach to engineering problem-solving was applied using MINITAB to ensure the generation of valid and defensible conclusions from the model parameters. The model parameters used in the pre-polymerization were comprised of crosslinker type, crosslinker ratio, monomer type, monomer ratio and drug ratio. Pre-polymerization interactions between template (DOX) and model parameters were investigated via UV measurements and binding studies. In the dissertation, statistical methods were also adopted to releasing pattern of DOX-imprinted hydrogels. Statistical analysis was performed with ANOVA (Analysis of Variance) with the data obtained from the drug release results. Four different releasing criterias were used to obtain regression models separately. The advantage of regression model lies in its flexibility regarding decision making process in controlled release hydrogel formulation prior to experimentation. Running the models obtained from statistical analysis played a key role in reduction of time and number of experiments. Furthermore, the obtained models facilitated optimization of the desired properties of the formulations for the subsequent synthesized materials. Response optimizer was used to decide the optimum formulation based on the desired properties. Based on the predicted optimum formulations new hydrogels were synthesized and the obtained results were compared with the predicted ones. The results showed that the predictive formulations obtained with the experimental design were consistent with the experimental results. Both imprinted and non-imprinted hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Morphological differences between non-imprinted and imprinted hydrogels were clarified by Scanning electron microscope (SEM) analysis. Structural analysis were conducted by NMR analysis. The effects of modelling parameters on release and loading performances of both imprinted and non-imprinted hydrogels were investigated experimentally. In this stage, interactions between the variables were explained via non-covalent chemistry. Then, based on the release performances, drug release kinetic profiles were evaluated. The structural and mass transfer properties of molecularly imprinted and non-imprinted hydrogels were explored for controlled drug delivery applications. Swelling behaviors of all hydrogel systems were studied in loading solution, releasing medium and distilled water. Then, the swelling behavior of the hydrogel systems were used to determine their structural properties. The determination was based on the calculation of volume fraction in swollen state (V2,s), the mesh size (ξ), and the average molecular weight between crosslinks (M̅c ) of the hydrogels. Thereafter, to obtain a more careful design of DOX-imprinted hydrogels along with network design, mathematical approaches were used to determine drug transport mechanisms of all hydrogels. The Mathematical models were used to fit the release data in order to gain insight into the release mechanism. For this purpose, Korsmeyer-Peppas and Higuchi Equations was used to understand the transport mechanism of drug molecules. Korsmeyer Peppas with the largest regression coefficient was determined as the best-fit model. The non-imprinted hydrogels had higher Korsmeyer release exponent (n) , indicating generally super case II transport. The DOX-imprinted hydrogels had relatively low n values and therefore, exhibited non-Fickian transport mechanism, in general. According to loading and release performances, DOX-imprinted hydrogel samples which included IA and TEGDMA, displayed great controlled drug release performance compared to the other hydrogels. According to this results, the hydrogels were synthesized in both high and low crosslinker ratios with IA-TEGDMA and their performances were compared with the non-imprinted counterparts. DOX-imprinted hydrogels with high crosslinker ratios provided highly effective controlled release performance than the others. This thesis study showed that experimental studies successfully used with statistical modelling methods. At the same time, the parameters affecting the properties of the imprinted hydrogels have been successfully defined and their interactions with each other has been examined. The results of the study showed that each imprinting system exhibited different characteristics due to diffirent affinities towards template molecule. Experimental and statistical studies could be used in a meaningful way and these studies contained informative information for studies with a low crosslinker ratio in the absence of solvent during polymerization. Finally, the thesis study will be followed by a mutli-disciplinary approach by biologists, physicians, chemical engineers and chemists in order to develop contact lens and perform in vivo studies for the treatment of neovascularization via TUBITAK supports (Project No:114M459).