Quantitative Assessment Of In Vivo Dissolution And Absorption Kinetics To Bridge In Vitro Dissolution Methods Of Pharmaceutical Preparations

Background:In vitro and in vivo correlation（IVIVC）forms a bridge between the critical quality attribute and clinical performance of the pharmaceutical preparation.IVIVC becomes one of the meaningful ways to apply for biowaiver.However,the efficiency and success rate of establishing level A IVIVC has been low levels,which is mainly limited by many problems.The lack of analytical methods for the in vivo dissolution and absorption kinetics of pharmaceutical preparations results in insufficiently understanding of the in vivo process of drugs.The phenomenon that the in vitro dissolution is not correlated with the in vivo process is unable avoided,because of no theory for the investigation of in vitro dissolution methods,and the defects of the dissolution apparatuses.Thus,the in vitro and in vivo methods of IVIVC still need to be innovated and optimized in the present.Objective:The novel models and corresponding methods of in vivo dissolution and absorption kinetics of pharmaceutical preparations are established to clarify the true in vivo dissolution rate,absorption rate,and absorption site of the drugs in terms of the sight of biopharmaceuticals and pharmacokinetics.The two models are applied to bridge the in vitro dissolution methods of drugs,and then to establish the in vitro strategies consistent with in vivo performance.This study aims to improve the efficiency and success rate of IVIVC study.Methods:（1）A novel pharmacokinetic model including the continuous dynamic in vivo processes of dissolution,absorption,and elimination was established by incorporating the in vivo dissolution process into the traditional pharmacokinetic model of pharmaceutical preparation.The in vivo dissolution rate constant（k_d）was analyzed by the residual method.The accuracies of the new model and method were verified by deducing the model equations of the oral solution（as a special solid formulation with k_d→+∞）and comparing the error of the estimated k_d value and true k_d value in literature.（2）According to the characteristics of pharmacokinetic profiles of oral drugs,a novel absorption kinetics model was established by comprising the linear kinetic processes of drug plasma concentration rising and falling with time.An iterative program was used to analyze the absorption rate constant（k_a）.This model and method were verified by the setting parameters of compartment model and the clinical data,respectively.（3）The new model of in vivo dissolution kinetics was applied to estimate k_d of the drug without dissolution rate limitation（i.e.,isosorbide mononitrate tablets）.The new model of in vivo absorption kinetics was applied to determine k_a values of drugs with dissolution rate limitation（i.e.,lurasidone hydrochloride tablets and nifedipine sustained-release tablets）.The solubilities and permeabilities of model drugs were respectively detected by the shake-flask method and Permea Pad^?plate.In vitro dissolution methods were established by paddle method and flow-through cell system to bridge the in vivo dissolution/absorption processes.A modified dissolution apparatus with an open-loop system was developed by combining with the traditional dissolution apparatus and flow-through cells system.The in vivo absorption kinetics model and in vitro-in vivo bridging conception were applied to inspect the in vitro dissolution method of high-specification dissolution rate-limiting drugs such as mycophenolate mofetil tablets.Results:（1）The equation of drug plasma concentration-time of oral solution using the in vivo dissolution kinetics model was consistent with that using the traditional model.All the relative errors of k_d estimated by the new model were within±22%comparing the true value of k_d in the literature.（2）The codes of iterative method were successfully constructed in Python software.The optimal k_a value（i.e.,the estimated k_a）was output when the minimum value of the sum of the absolute residuals was acquired between the predicted and the measured plasma concentration-time profiles.The accuracy of k_a estimated by the new model was better than that of k_a estimated by the traditional methods such as Wagner-Nelson,Loo-Riegelman.Moreover,the calculation process and accuracy of the new model did not correlate with the compartment model parameters.This model was applied to estimate the k_a values of carbamazepine tablets and cyclosporine soft capsules,which had good correlations with the pharmacokinetic parameters(C_max,T_max,etc.)that reflected the absorption properties of drugs in vivo.（3）The k_d values of isosorbide mononitrate tablets with different formulations were estimated by the in vivo dissolution kinetics model.The in vitro dissolution method involving paddle method,50 rpm,500 m L pure water medium was selected to bridge the in vivo dissolution process of isosorbide mononitrate tablets.A level A IVIVC was established and verified between the in vitro and in vivo dissolutions.（4）According to the new model of in vivo absorption kinetics,in vitro-in vivo bridging conception including the dissolution medium and minimum flow rate（F）were determined for the flow-through cells apparatus with an open-loop system.The high,medium,and low absorption rates of lurasidone hydrochloride tablets and nifedipine sustained-release tablets were analyzed by the in vivo absorption kinetics model.The dissolution media were determined to simulate the in vivo process.The in vitro cumulative dissolution fraction obtained by the flow rate at 4F was consistent with the in vivo absorption fraction.Thus,level A IVIVCs of two model drugs were well established and verified.（5）The traditional dissolution apparatus with close-loop systems could not distinguish the dissolution rate of different formulations of mycophenolate mofetil tablets.The mycophenolate mofetil tablets were not fully dissolved by using flow-through cells apparatus,because of the serious accumulation of insoluble particles in the cells.The modified dissolution apparatus with open-loop system overcame the deficiency of these two apparatuses.The in vitro-in vivo bridging conception was developed to distinguish the dissolution capacities of mycophenolate mofetil tablets in the fed state.Finally,a level A IVIVC of the mycophenolate mofetil tablet was well established and verified.Conclusions:In this study,the novel models and methods of in vivo dissolution and absorption kinetics of pharmaceutical preparations were established and verified for good accuracies from different perspectives.The two models guided the innovation of the in vitro-in vivo bridging methods.As a consequence,IVIVC evaluation systems were established for the different types of pharmaceutical preparations.In sum,this study provided vital theories and methods for the developments of IVIVCs.