Physiologically Relevant In Vitro-In Vivo Correlation (IVIVC) Approach for Sildenafil with Site-Dependent Dissolution

Tae Hwan Kim,Soyoung Shin,Beom Soo Shin,Jong Bong Lee,Seok Won Jeong

doi:10.3390/pharmaceutics11060251

Tae Hwan Kim, Soyoung Shin + Show 3 more

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https://doi.org/10.3390/pharmaceutics11060251

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Abstract

This study aimed to establish a physiologically relevant in vitro-in vivo correlation (IVIVC) model reflecting site-dependent dissolution kinetics for sildenafil based on population-pharmacokinetic (POP-PK) modeling. An immediate release (IR, 20 mg) and three sustained release (SR, 60 mg) sildenafil tablets were prepared by wet granulation method. In vitro dissolutions were determined by the paddle method at pH 1.2, 4.5, and 6.8 media. The in vivo pharmacokinetics were assessed after oral administration of the prepared IR and SR formulations to Beagle dogs (n = 12). The dissolution of sildenafil from SR formulations was incomplete at pH 6.8, which was not observed at pH 1.2 and pH 4.5. The relative bioavailability was reduced with the decrease of the dissolution rate. Moreover, secondary peaks were observed in the plasma concentration-time curves, which may result from site-dependent dissolution. Thus, a POP-PK model was developed to reflect the site-dependent dissolution by separately describing the dissolution and absorption processes, which allowed for estimation of the in vivo dissolution of sildenafil. Finally, an IVIVC was established and validated by correlating the in vitro and in vivo dissolution rates. The present approach may be applied to establish IVIVC for various drugs with complex dissolution kinetics for the development of new formulations.

Highlights

Sustained release (SR) oral dosage formulations are designed to make a drug available for absorption over an extended period after administration
While sildenafil release from immediate release (IR) tablets was completed within 0.4 h at pH 1.2 (Figure 2A), drug releases from SR tablets were significantly delayed as their Hydroxypropyl methylcellulose (HPMC) compositions increased (Figure 2B–D)
To represent the changes of the dissolution rate of sildenafil along the gastrointestinal tract, the dissolved fraction that can change over time (FDiss, total) was incorporated into the Michaelis–Menten equation (Equation (2))

Summary

Introduction

Sustained release (SR) oral dosage formulations are designed to make a drug available for absorption over an extended period after administration. The major difficulty in the successful development of SR formulations is that it often requires multiple non-clinical and clinical studies to demonstrate the desired pharmacokinetics of the SR formulation compared to its reference immediate release (IR) formulation It is difficult if the drug possesses complex pharmacokinetic characteristics due to the unusual absorption behaviors, such as pH-dependent or site-specific dissolution or absorption. Since drugs may have variable solubilities depending on pH, the dissolution rates of the drug may be varying in different regions of the gastrointestinal tract Such pH-dependent dissolution characteristics can result in unusual pharmacokinetic profiles, such as the second or shoulder peaks in the plasma concentration versus time profiles or reduced bioavailability with the decrease in release rates. This can lead to difficulties in demonstrating equivalence in maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) between the SR and the reference formulations, providing one of the main hurdles for the development of new SR formulations

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