Study On A Gastrointestinal Tract Biphasic Dissolution Model Of Poorly Water-Soluble Oral Solid Formulation

Oral solid drugs,especially poorly water-soluble oral solid drugs,whose bioavailability is affected by many factors,such as food,gastrointestinal tract p H,excipients,transport,metabolism,and their ingredients,etc.The commonly used single medium dissolution method is difficult to distinguish the different dosage forms of this class of drugs in vitro.And it is more difficult to establelish a good IVIVC,due to the lack of biological correlation.Among the many influencing factors of bioavailability,food and gastrointestinal tract p H are the two most important influence factors for the most poorly water-soluble oral solid drugs.In this paper,the following two biphasic dissolution models are constructed based on human gastrointestinal parameters:（1）Simulated fasted/fed biphasic dissolution model:In order to simulate the effect of the substance（bile salt）secreted by the human body after taking food,and to learn the effect of this substance on the gastrointestinal absorption of poorly water-soluble oral drugs.This article used non-ionic surfactant TPGS to replace the bile salt,then we selected contain 0.1%TPGS to simulate the state of fed,without TPGS to simulate the state of fasted.Next,we conducted biphasic dissolution studies and three pharmacokinetic studies on the the three formulations of poorly water-soluble drugs FEN and GRF.Finally,we compared the obtained in vitro results with the in vivo results.The experimental results:In the state of FEN fasted,the excellent linear correlationsbetween the percent drug dissolved in the organic phase and thein vivo C_max（R²=1）or the AUC（R²=0.99）,and in the fed state the good linear correlations between the percent drug dissolved in the organic phase and the in vivo C_max（R²=0.96）or the AUC（R²=0.97）.In the state of GRF fasted,the nice linear correlationsbetween the percent drug dissolved in the organic phase and thein vivo C_max（R²=0.95）or the AUC（R²=0.94）,and in the fed state the good linear correlations between the percent drug dissolved in the organic phase and the in vivo C_max（R²=0.99）or the AUC（R²=0.99）.And the drug released order of the formulation in vitro is consistent with the in vivo results.All in all,the results of this experiment prove the feasibility of the fasted/fed biphasic dissolution model.（2）Simulated gastrointestinal tract p H-gradient biphasic dissolution model:In order to simulate the effect of different p H of the gastrointestinal tract on the absorption of poorly water-soluble weakly basic drugs,an orthogonal test was designed to optimize the parameters of the biphasic model.By comparing the correlation between the orthogonal dissolution data and the published ketoconazole in vivo data,we selected a set of parameters as the optimal model parameters:paddle speed 30 rpm,organic phase volume100m L,and aqueous phase p H changes of 5.5,6.5,6.8（simulated duodenum,jejunum and ileum）.Under the optimal conditions,in vitro dissolution experiments of ketoconazole three formulations were carried out and fitted with rat pharmacokinetic parameters(C_max and AUC).In the two-phase model of p H change,the organic phase successfully distinguished three ketoconazole formulations,and it isrank was consistent with the bioavailability of the formulations obtained in therats.A well linear correlationsbetween the percent drug dissolved in the organic phase and thein vivo C_max（R²=0.96）or the AUC（R²=0.92）.The experimental results demonstrate that gastrointestinal tract p H-gradient biphasic dissolution model provides the potential to evaluate weakly basic drug formulations in early drug development.All in all,the two biphasicdissolution models constructed in this paper can distinguish the formulations of the poorlywater-solubledrug,predict the effect of food on drug absorption,and predict the the effect of p H on the absorption of weakly basic drugs in the gastrointestinal tract.