| In-situ-forming gels refer to the polymer solutions can be administrated as liquid, which undergo a phase transition to a non-cross linked semisolid gel upon exposure to physiological environments. Most of the applications of the in-situ-forming gels are concerned with ophthalmic disease treatment for its convenient administration combined with the favorable ocular residence time.Objective: In this thesis,indometacin (IDM) was selected as the model drug,and a series of relative researches were carried out, including the drug of in-situ-forming eye gel with modulated phase transition temperature,drug release, the pharmacokinetics in tear and bioavailability after the in-situ-forming eye gel applied topically. The in-situ-forming gels substantially increased the bioavailability of the drug, and showed great potential in ophthalmic application.Methods : On the basis of scientific literatures, the formulation screening was performed by taking sol-gel transition temperature as indices in which poloxamer 407 was used as the main base material. The formulation was optimized using central composite design-response surface methodology (RSM plus CCD). The effects of two independent variables, poloxamer P407 and P188, were evaluated. Response variables selected in the research were the gelation temperatures before and after simulated tear fluid dilution.The release behavior of indometacin in-situ-forming eye gels (IDM-ISG) were studied, the release medium was artificial tears. With membraneless dissolution model at the temperature of 34.5±0.5℃,samples were obtained at set time,and then accumulated drug release were obtained.The chemical and physical stability of optimal formula was investigated under following circumstances: strong light and low temperature. The accelerated stability experiments of optimal formula were also investigated. The irritant effects of IDM-ISG on rabbit eyes were tested.Single dosing eye irritation and multiple dosing eye irritation were observed, recorded and evaluated. The IDM-ISG was topically administrated to the left eyes of 6 rabbits and a solution of 0.9%saline was administered to the right eyes.Pharmacokinetics study in vivo: Rabbits were selected as laboratory animals and divided into two groups at random.One group was given IDM-ED and the other was given IDM-ISG. The rabbit tears were obtained and quantified at different times after topically applying IDM-ISG and IDM-ED to the rabbit eye.Results were expressed using High Performance Liquid Chromatography(HPLC)with ultraviolet detector.Six-point standard curve were established for indometacin in rabbit tears, in order to calculate concentration of them.The pharmacokinetics parameters were calculated. Taking MRT and AUC as indexes, inspected the relative bioavailability of two preparations.Results: By taking sol-gel transition temperature as indices,the best formulation of in-situ-forming gels was 24.48%P407+1.46%P188. In this formulation, the sol-gel transition temperature was between 22.5～33℃.and the accumulative release profile of the drug in vitro could be distributed by Zero Order equation.Study of stability: IDM-ISG were investigated under different conditions of temperature and strong light.The results showed that the formulation was stable.But in the strong light, there is a light of decrease in content. That means the IDM-ISG should be reserved away from light.The irritant effects:Single dosing and multiple dosing had no markedly influences on tested rabbit eyes.Pharmacokinetics study:The pharmacokinetic parameter of two groups in tear were calculated. Comparison of the pharmacokinetic parameters were respectively as following:AUC gel/AUC drop=6.20,MRT gel/MRT drop=13.62.The results suggested that the experimental group is superior to the control group.Conclusion: The results in vitro and in vivo showed that the IDM in-situ-forming eye gels could prolong the residence time of drug in the ocular cavity.It was tolerated well and there were no obvious irritant effects to ocular tissues.The IDM-ISG, which upon exposure to physiological conditions will shift the gel phase,can significantly extend IDM release and increase the precomeal residence time of the drug,thus enhance ocular bioavailability compared with IDM-ED, and showed great potential in ophthalmic application.
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