Study On Gabexate Mesilate Thermosensitive In Situ Hydrogels

Acute pancreatitis is a kind of acute abdomen with a high clinical incidence,and it has the properties of rapid onset and more complications.Gabexate mesilate is a synthetic non-peptidic protease inhibitor,which can inhibit the activity of trypsin,plasmin protease,plasma kallikrein and thrombin.However,due to its short half-life,intravenous infusion with high dose is adopted clinically and has to be used frequently.In order to reduce the systemic side effects and the frequency of administration,in situ thermosensitive gel with sustained release of gabexate mesilate was prepared in this research.Some common thermosensitive matrices material were introduced and the research progress of their applications in drug delivery systems were reviewed in this paper.The properties of gabexate mesilate was investigated base on relative information as well as its stability and solubility.The results showed that the solubility of gabexate mesilate was dependent on pH,the solubility would increase as the decreasing of pH within the tested concentration range.Moreover,humidity had great influence on the stability of gabexate mesilate,while temperature and lighthad little impact.The gelling temperature and pH value were regarded as the main evaluation indexes of thermosensitive gel.The concentration influence of poloxamer 407,poloxamer 188 and gabexate mesilate on the gelling temperature was investigated.The gelling temperature reduced as the concentration of poloxamer 407 increased in a certain concentration range.The gelling temperature increased with the increasing concentration of poloxamer 188 when the concentration of poloxamer 407 was not changed.When the concentration of poloxamer 407 and poloxamer 188 was fixed,the gelling temperature did not change significantly as the concentration of gabexate mesilate increased while the pH value decreased.Formulation was optimized by response surface methodology,and the best prescription was validated and evaluated.The best prescription consisted 20.60%(w/w)poloxamer 407 and 5.79%(w/w)poloxamer 188.Its gelling temperature determined by tube inversion experiment was 31?,the results of phase transformation kinetics showed that the phase-transition temperature was consistent with the gelling temperature measured by the tube inversion experiment.Moreover,,it was suitable to prepare injection due to its good gel-forming ability in vitro,good syringeability and easy injectabilty.Its in vitro release was investigated through membraneless dissolution method and the results showed that it had the effect of sustained release.Furthermore,corrosion is the main release mechanism,which means that drug would release with dissolution of the gel.In addition,the release profile of gabexate mesilate thermosensitive in situ gel was not significantly influced by different oscillation frequencies.Preparation methods of gabexate mesilate thermosensitive in situ gel were studied.Experiment results demonstrated that isometric dilution could improve drug-loading rate.The effects of different sterilization methods on gelling temperature were also studied.In order to reduce the costs and easy the facilitate industrialization,filtration sterilization and moist heat sterilization were both selected for sterilization process.A quantitative HPLC method for determining the content of gabexate mesilate was established,several experiments were performed and the results confirmed that the specificity,sensificity,precision,accuracy and repeatability of the method met requirements,the linear relation was good within the concentration range of 10?350 ?g·mL-1.The stability of gabexate mesilate thermosensitive in situ gel was studied.The results confirmed that light and temperature has no influence on the gelling temperature of preparation,but had much on the content of gabexate mesilate.The lyophilized process of gabexate mesilate thermosensitive in situ gel was studied finally.Rehydration time could be shortened by adding 5%of mannitol as cryoprotectant,which has no effect on gelling temperature of preparation.In addition,the pre-freezing temperature and the liquid volume in flask of gabexate mesilate thermosensitive in situ gel were investigated,and the best value of them were-20 ? and 2ml respectively.In the process of freeze-drying,properties of the finally freeze-drying product could be affected by freezing method and its speed,drying method and its time,storage conditions and other factors.Freeze-drying process of gabexate mesilate thermosensitive in situ gel should be studied further.