Please use this identifier to cite or link to this item: http://prr.hec.gov.pk/jspui/handle/123456789/10928
Title: Development and Characterization of Hydrogels Loaded with Antidiabetic Drug
Authors: Ubaid, Muhammad
Keywords: Pharmacy
Issue Date: 2019
Publisher: COMSATS Institute of Information Technology, Islamabad
Abstract: In this study, preparation and optimization of hydrogel formulations of chitosan/sodium alginate, chitosan/eudragit-L100 and chitosan/gelatin hydrogel films, containing metformin through solvent evaporation technique were developed, using central composite factorial design. Genipin was used as a crosslinking agent in all formulations. At first, low and high molecular weight (MW) chitosan was used as the polymer in different concentrations with Na-alginate to formulate chitosan/Na-alginate hydrogel films. Effect of low and high molecular weight chitosan was investigated in formulation development and drug release. Drug release kinetics were evaluated in the simulated gastric and intestinal medium at pH 1.2 and 7.4, respectively. For low MW chitosan hydrogels, highest drug release was observed at pH 1.2 i.e., 9.82 % for 2 hours while at pH 7.4, 95.52 % drug release was observed after 12 hours. In the case of high MW chitosan hydrogel, 9.67 % drug release was observed at pH 1.2 for 2 hours and 90.63 % drug release at pH 7.4 after 12 hours. The highest T50% (the time for 50 % of drug release) of low MW and high MW chitosan hydrogel was observed as 22.72 and 33.34 hours, respectively, while the highest dynamic swelling was observed as 8.21 and 7.9, respectively. It was found that by changing the ratio of polymers as well as crosslinking agent, the release rate of metformin can be modified. Low MW chitosan hydrogel showed an increased release rate when compared with high MW chitosan hydrogel. Also, by increasing the concentration of the crosslinking agent, the release rate was found to be decreased and vice versa. Further high molecular weight chitosan was used in the preparation and optimization of chitosan/eudragit L-100 and chitosan/gelatin hydrogel films based on the results of chitosan/sodium alginate hydrogel. Chitosan/eudragit L-100 hydrogel films were subjected to evaluate drug release in the simulated gastric medium and intestinal medium at pH 1.2 and 7.4, respectively. Effect of variables on T50% and dynamic swelling were studied by using regression analysis and surface plots for optimum formulation selection. During the first 2 hours, initial burst release was observed from PECs in a gastric simulated environment and slow release during the other 10 hours in simulated intestinal fluid. Polymers used in this study showed significant influence on T50% and dynamic swelling of the hydrogel. The highest value of T50% and dynamic swelling was observed at 9.89 and 7.86 hours, respectively. Results showed that change in polymers ratio and cross-linker concentration can affect the drug release in hydrogel. Chitosan/gelatin hydrogel films were subjected to study the drug release in the simulated gastric medium for 3 hours at pH 1.2. Effect of variables was evaluated by regression analysis and surface plots to select the optimum formulation. In first 2 hours, hydrogel showed burst release and drug release reached 100 % within 3 hours’ time in the gastric simulated environment. By changing the polymer ratios and crosslinking concentration a significant influence on T50% and dynamic swelling of hydrogel was observed. The highest T50% and dynamic swelling was observed at 40.23 and 9.1 min, respectively. It was noted that the release rate of metformin cloud be modified by changing the polymer and cross-linker concentration. Surface morphology of the optimized hydrogels was studied using an electron microscope to investigate the uniform presence of drug crystals in the hydrogel matrix. Fourier transform infrared spectroscopy (FTIR) for confirmation of ionic and hydrogen bonding between crosslinking agent and polymers leaving the drug intact in the matrix system. Thermal analysis, DSC were performed on polymers and hydrogel films to investigate the amorphous and crystalline behavior, polymorph and eutectic transitions. Scanning electron microscopy (SEM) images confirmed the uniform drug distribution. Acute oral toxicity studies were performed on optimized formulations to evaluate any toxic effects due to crosslinking agent and polymers in the hydrogel formulation. The clinical findings revealed no significant changes in complete analysis of blood, biochemical analysis and metabolic biomarkers. Histopathological findings revealed no signs of hemorrhage, lesion and tissue structure changes within the organ. Pharmacokinetic and pharmacodynamics evaluation of metformin was performed in rabbit plasma. Samples were estimated for blood glucose levels done by glucose oxidase method and drug plasma concentration was evaluated using sensitive HPLC method with UV detection. Plasma samples were prepared by precipitation of proteins with acetonitrile. Reverse phase chromatography technique with a silica gel column (250 mm × 4.6 mm, 5 µm) at 30 ºC was used for separation purpose. A mixture of methanol and phosphate buffer with pH adjusted to 3.8 was used as mobile phase with a flow rate of 0.8 ml/min and UV detector wavelength was adjusted at 240 nm. The calibration curve was linear in a range of 0.1-1 µg/ml with R² = 0.9982. The precision (RSD, %) values were less than 2 %, whereas, the accuracy of the method was higher than 92.37 %. The percentage recovery values ranged between 90.14 % and 94.97 %. Limit of detection (LOD) and limit of quantification (LOQ) values were 25 ng/ml and 60 ng/ml, respectively. Cmax and AUC0-t values were found to be 1154.67 ± 243.37 ng/ml and 7281.83 ± 210.84 ng/ml.h, respectively. The in-vivo pharmacokinetic profile of optimized chitosan hydrogel formulations T1 (chitosan/gelatin hydrogel), T2 (chitosan/Na-alginate hydrogel) and T3 (chitosan/eudragit L-100 hydrogel) after oral administration showed significant differences in plasma levels of T1, T2 and T3. The plasma level of T1 reached its maximum concentration (867.28 ± 7.78 µg/ml) in 3 hours after oral administration while maximum concertation of T2 was observed 794.23 ± 7.53 in 4 hours of oral administration. T3 showed maximum concentration 680.61 ± 6.78 at 6 hours that was lower than that of T1 and T2 that showed incomplete absorption. For hydrogels T3, maximum concentration (680.61 ± 6.78 µg/ml) was observed at 6 hour and slow decrease in drug concentration was noticed even at 24 hours after administration. Non-significant differences were found in the fall of blood sugar levels with T1, T2 and T3 in comparison with the control and evaluated by Dunnett’s test. It was observed that different formulations, with different drug release rates, showed a different pattern in the hypoglycemic effect of the drug due to variable bioavailability with respect to the oral solution of drug.
Gov't Doc #: 18399
URI: http://prr.hec.gov.pk/jspui/handle/123456789/10928
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

Files in This Item:
File Description SizeFormat 
Muhammad Ubaid_Pharmacy_2019_Comsats_PRR.pdf8.95 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.