Trimetazidinin Kontrollü Salımı için Kriyojel Membranların Sentezi ve Karakterizasyonu

Abstract

In this thesis, tablet synthesis of trimetazidine dihydrochloride imprinted poly(2-hydroxyethyl methacrylate/acrylamide) [poly(HEMA/AAm)] cryogel membranes was performed at low temperatures and the release of the active substance was evaluated. The release of the active substance from the trimetazidine dihydrochloride -imprinted poly(HEMA/AAm) cryogel membranes was monitored by varying the crosslinking ratio in the polymer. In this context, monomer mixtures containing 7.4%, 11.1% and 14.8% moles ratios of N,N-methylenebis(acrylamide) [(MBAAm)] in the polymerization solution were prepared and expected to transform into cryogel form at low temperatures. For characterization studies, non-imprinted poly(2-hydroxyethyl methacrylate) [poly(HEMA)] and poly(HEMA/AAm) were synthesized under the same conditions. The physical properties of the synthesized cryogel membranes were followed and their formation was observed. The resulting cryogel membranes were characterized by Fourier Transform Infrared Spectroscopy (FTIR). In infrared spectroscopy of poly(HEMA/AAm) cryogel, hydrogen bonding of amine groups originating from acrylamide with hydroxy group originating from 2-hydroxyethyl methacrylate was evaluated. When the infrared spectroscopy of the trimetazidine dihydrochloride imprinted poly(HEMA/AAm) cryogel was examined, hydrogen bonding effect caused by trimetazidine dihydrochloride was also observed. The synthesized cryogel membranes were also characterized by the thermogravimetric analysis method. According to the thermogravimetric results, it was observed that the poly(HEMA/AAm) cryogel was the most thermally stable structure. Trimetazidine dihydrochloride, on the other hand, degraded the fastest thermally, and suppression of trimetazidine dihydrochloride to the cryogel membranes decreased the thermal stability of the cryogel membranes. For surface characterization, images of trimetazidine dihydrochloride imprinted poly(HEMA/AAm) cryogel were taken with Scanning Electron Microscopy (SEM), in addition, trimetazidine dihydrochloride unimprinted poly(HEMA) and trimetazidine dihydrochloride imprinted poly(HEMA/AAm) containing different crosslinking ratios as well as trimetazidine dihydrochloride released poly(HEMA/AAm) containing different crosslinking ratios were analyzed for surface characterization with Brauner Emmett and Teller (BET) surface porosity analysis and macroporosity analysis obtained from swelling test results of the same cryogel membranes. While the macroporosity of trimetazidine dihydrochloride unimprinted poly(HEMA/AAm) was 48.4%, this value was found to be 58.8% in the imprinted cryogel and 54.3% in the trimetazidine dihydrochloride-removed cryogel. It was observed that the crosslinking ratio did not cause a significant change in the surface area of the trimetazidine dihydrochloride imprinted cryogels. Biocompatibility tests were performed for the synthesized poly(HEMA), poly(HEMA/AAm) and trimetazidine dihydrochloride imprinted poly(HEMA/AAm) cryogel membranes by following blood compatibility. In this context, prothrombin time, activated partial prothrombin time and in-vitro coagulation times were determined. According to the results obtained, it was observed that poly(HEMA), poly(HEMA/AAm) and trimetazidine dihydrochloride imprinted poly(HEMA/AAm) cryogel membranes were biocompatible. For the release of trimetazidine dihydrochloride from the cryogel membranes, a pH value at which maximum loading was first determined. It was observed that the adsorption capacity of the poly(HEMA) cryogel membrane did not change at all pH values, and the poly(HEMA/AAm) and trimetazidine dihydrochloride imprinted poly(HEMA/AAm) cryogel membranes reached the maximum adsorption capacity at pH 7.0. Maximum adsorption capacities at pH 7.0 are 22.5 mg/g, 18.5 mg/g and 16.3mg/g for poly(HEMA/AAm), trimetazidine dihydrochloride-imprinted poly(HEMA/AAm) cryogel membranes containing 7.4%, 11.1% and 14.8% crosslinking, respectively. A pH scan was also performed to determine the maximum desorption capacity for trimetazidine dihydrochloride-imprinted cryogel membranes, for trimetazidine dihydrochloride-imprinted poly(HEMA/AAm) cryogel membranes containing 7.4%, 11.1% and 14.8% crosslinking in aqueous NaCl solution that the values were found as 21.3 mg/g, 17.8 mg/g and 15.8 mg/g at pH 8.0, respectively. It has been evaluated that the desorption capacity is not affected by the pH value for all cryogel membranes and the variation of the desorption capacity against time at pH 8.0, a low increase, was investigated. Trimetazidine dihydrochloride-imprinted poly(HEMA/AAm) cryogel membranes with the lowest crosslinking ratio had the equilibrium desorption time, 110 minutes, and the same was 80 minutes in the one with the highest crosslinking rate. Diffusion analysis of the swelling-controlled release of trimetazidine dihydrochloride was also performed, and it was determined that the diffusion type in all three cryogel membranes containing varying amounts of crosslinkers conformed to the Pseudo-Fickian Diffusion. Kinetic studies were performed for trimetazidine dihydrochloride-imprinted cryogel membranes containing varying proportions of crosslinking, and it was observed that trimetazidine dihydrochloride release from all three cryogels was suitable for pseudo-second-order kinetic modeling. With the increase in temperature, the desorption capacity of trimetazidine dihydrochloride released from the trimetazidine dihydrochloride-imprinted cryogel membranes increases, and this value was observed as 22.5 mg/g at 37˚C, which is body temperature.