Studies On Tiopronin In Situ Gel For Ophthalmic Use

Tiopronin is a kind of glycine derivative with thiol group,its chemical name is N-(2-Mercaptopropionyl)glycine.Because of the sulfhydryl on side chain,tiopronnin has various pharmacologic actions,and was always clinically used to therapy hepatitis, hepatic injury and Cystinuria,in addition tiopronin also has curative effect on senium cataract through cleaning excess free radicals and inhibiting crystallin agglomeration.Traditional eye drops has the problems of being diminished rapidly by tear fluid and poor bioavailability.Compared with them,in situ gel can be administrated as liquid,which undergo a phase transition to a non-crosslinked semisolid gel upon exposure to physiological environments,thus in situ gel combines convenient administration and the favorable ocular residence time.In this dissertation,tiopronin was selected as a model drug,and a series of relative researches were carried out, including the drug permeability across isolated cornea,development of in situ gels with modulated phase transition temperature,drug release,characters of preparations, delaying of selenite-induced cataract and pharmacokinetics in aqueous humor.Adjusting pH value to acidity(pH5.8)and adding 0.05%NaHSO₃ and 0.05%EDTA can enhance stability of tiopronin in water.The diffusion behaviors of tiopronin across isolated rabbit cornea possessed zero-order kinetic characteristic. Between the pH value of 5～8,change of pH has no obvious affect on permeability of tiopronin.0.075%Azone improved the apparent permeability of tiopronin as much as 2.03 folds,but further increase the concentration of Azone,irritancy observed.According to the in vivo characteristic of ocular administration,a membraneless model was used to study the gel dissolution and drug release simultaneously. Correlation analysis demonstrated that drug release,which followed zero-order kinetics,from poloxamer vehicle was completely controlled by gel dissolution. Incorporating HA-Na,drug release pre-proceeded than gel dissolution.Release area, shaking frequency and the content of HA-Na influenced the rate of gel dissolution and drug release.Through making 22%poloxamer 407 and 6%poloxamer 188 as gel matrix,and adding 0.2%HA-Na achieved in situ gel of tiopronin has proper gelation temperature and certain sustained releasing ability,Papp and retention time of gel and solution was 15.43 cm·s^-1and 17.39cm·s^-1,130min and 7min respectively.Both preparations have good stability and without irritancy,accord with standardization of ophthalmic preparation.The pharmacodynamics of tiopronin in situ gel and solution were studied and compared with the model of selenite-induced cataract rats.As a result tiopronin in situ gel and solution of high dose group relayed the development of initial cataract 6d and 4d respectively,and in situ gel roled better than solution both in middle dose groups and high ones.Using continuous sampling,pharmacokinetics in aqueous humor was studied. The area under the aqueous humor concentration vs.time curve for in situ gel increased 1.59 folds,and with higher C_maxand postponed T_max,in contrast with that of solution,substantially increased the bioavailability of tiopronin.