Construct A Bionic Model Of Absorption And Metabolism Of Poorly Water-soluble Oral Solid Formulations In Vitro

At present,drug metabolism is rarely taken into account in dissolution models in vitro.Therefore,starting from obtaining ideal in vitro-in vivo correlation(IVIVC),drug metabolism is integrated into in vitro dissolution models to improve the biological correlation of the models.In order to obtain more useful information points to establish the ideal IVIVC.In this paper,two biomimetic dissolution models were constructed:(1)Construction of in vitro dissolution adsorption and metabolism model:In this study,drug metabolism was simulated on the basis of adsorption principle,and a new type of dissolution adsorption metabolism model was established by screening suitable adsorbents on the basis of single-phase model and biphasic model.Taking carbamazepine as the model drug,the model parameters were optimized by investigating the type,time and amount of adsorbents,and the dissolution behavior of three different crystal forms of carbamazepine was investigated under the optimal model conditions.In vivo and in vitro correlations were established with the reported data to verify the predictability of the model.The results showed that the model could only simulate drug metabolism by adding activated carbon in the single-phase model.The optimal conditions of the model were as follows:paddle speed 75 rpm,aqueous volume 500 m L,and activated carbon added 8 g at 66 min.Under these optimized conditions,the dissolution differences of the three crystal forms of carbamazepine were successfully distinguished,and the order of absorption in mice was consistent with that reported in the literature.The fitting results of the area under the in vitro dissolution adsorption curve and the area under the blood concentration curve were R~2=0.999(formⅢ),R~2=0.938(formⅠ)and R~2=0.940(dihydrate form)respectively,which obtained a relatively ideal correlation in vitro and in vivo.(2)Construction of biphasic dissolution oxidation and metabolism model:In this study,drug metabolism was simulated based on the principle of oxidation catalysis.Based on the biphasic dissolution model,the oxidative metabolism of metabolic enzymes in vivo was simulated by screening suitable oxidation systems,and a new type of dissolution oxidation metabolism model was established.Using the enzyme substrate carbamazepine as a model drug,the model parameters were optimized by investigating the type of oxidation system,addition method,addition time and addition amount,and the dissolution behavior of three crystal forms of carbamazepine was investigated under the optimal model conditions.In vivo and in vitro correlations were established with the reported data to verify the predictability of the model.The results showed that the oxidation system was potassium permanganate and triethyl benzyl ammonium chloride(TEBAC)system.The optimal conditions of the model were as follows:paddle speed75 rpm,water volume 100 m L,oil volume 20 m L,potassium permanganate was added at 56 min(TEBAC was added at 0.27 g at the beginning to achieve oil-water balance).Under these optimized conditions,the dissolution differences of the three crystal forms of carbamazepine were successfully separated,and the order of absorption in mice was consistent with that reported in the literature.The fitting results of the area under the dissolution oxidation metabolism curve in vitro and the blood drug concentration curve in vivo were R~2=0.997(formⅢ),R~2=0.994(formⅠ)and R~2=0.992(dihydrate form)respectively,which obtained a good correlation in vitro and in vivo.In conclusion,the two novel in vitro dissolution biomimetic models constructed based on the simulation of metabolism in this paper have good identification and in vivo absorption prediction for oral solid drug preparations of insoluble drugs,and are of great significance for the early research and development of BCS II drug formulations.