Construction Of Dynamic Gastrointestinal Biomimetic Dissolution Model And Evaluation Of Drug In Vivo And In Vitro Correlation

For poorly soluble drugs,in order to obtain good in vivo and in vitro correlation(IVIVC),the pH gradient biphasic dissolution model is the focus of current research,but most of them were still connected to different chambers of the small intestine through a peristaltic pump.In a sense,it belonged to static dissolution,which was inconsistent with the continuous dissolution and absorption process in vivo,and for the weakly alkaline drugs,there would be an overestimation of the absorption in vivo.Based on this,this article mainly optimized and improved the biphasic dissolution model of pH gradient to improve its biological relevance and predictability of drug absorption in vivo:(一)Construction of dynamic gastrointestinal biomimetic dissolution modelIn order to more realistically simulate the dissolution and absorption of drugs in the gastrointestinal tract,based on the concept of a pH gradient biphasic dissolution model,a new type of dissolution device that simulates different small intestinal chambers was constructed in this paper.The small intestinal solution could flow spontaneously through fluid dynamics to the next chamber,the different parts are separated from each other and form a unified whole.The highlight of this model was the static in vitro dissolution was transformed into dynamic,and the influence of physiological factors on the dissolution of the drug was also considered.Firstly,the experimental parameters(organic-aqueous phase volume ratio,flow rate,gastric emptying time)of fenofibrate(FEN)and ketoconazole(KTZ)were optimized through single factor experiments.Subsequently,the dissolution studies of these two drugs were analyzed under the optimal conditions and established IVIVC.The best parameters of FEN were organic-aqueous phase volume ratio of 1:5,flow rate of 1m L/min,and gastric emptying time of 20min.As far KTZ,the optimal conditions were organic-aqueous phase volume ratio of 1:5,flow rate of 4m L/min and the gastric emptying time was20min.The in vitro dissolution sequence was the same as in vivo,and the A-level fitting results obtained under the optimal conditions were:FEN Capsule A’s R~2was 0.98,Capsule B’s R~2was 0.95,and Capsule C’s R~2was 0.98,which were higher than the control group’s 0.96,0.93 and 0.97(biphasic dissolution model);the R~2of KTZ-lactose was 0.91,the R~2of KTZ-β-CD was 0.92,the R~2of KTZ-MCC was 0.93,which were higher than 0.88,0.92 and 0.85 of the blank control group(without HP-β-CD).It indicated that improving its biological relevance in the in vitro dissolution model is helpful for improving its predictability,and has certain application value for evaluating the in vitro absorption of poorly soluble drugs.(二)Optimization of pH gradient biphasic dissolution model based on HP-β-CDIn order to improve the in vitro dissolution of poorly soluble and weakly basic drugs,maintain supersaturation for a long time,slow down the precipitation rate of drugs,and avoid overestimating the in vivo situation,this paper selected HP-β-CD(2-hydroxypropyl-β-cyclodextrin)as an additive to screen out the optimal molar concentration.Under these conditions,three different formulations of KTZ were dissolved in vitro,and the results were compared with in vivo bioavailability and established IVIVC.The experimental results showed that the optimal molar concentration of HP-β-CD was 1mmol/L,the dissolution sequence of the three different dosage forms in vitro was consistent with the real situation in vivo,and the A-level fitting result obtained under this dissolution condition was that the R~2of KTZ-lactose,KTZ-β-CD and KTZ-MCC were 0.90,0.94 and 0.95,respectively,which was higher than 0.88,0.92 and 0.85 of the blank control group(without HP-β-CD),which demonstrated that the addition of HP-β-CD could improve the dissolution model to effectively simulate the dissolution of weakly basic drugs in vivo and improve its predictability.In summary,the improvement and optimization of the pH gradient biphasic dissolution model in this paper could effectively improve the prediction of the in vivo absorption of poorly soluble drugs,which was of great significance for the early development of oral solid pharmaceutical preparations.