Simulating the Hydrodynamic Conditions of the Human Ascending Colon: A Digital Twin of the Dynamic Colon Model

Abstract

The performance of solid oral dosage forms targeting the colon is typically evaluated using standardised pharmacopeial dissolution apparatuses. However, these fail to replicate colonic hydrodynamics. This study develops a digital twin of the Dynamic Colon Model; a physiologically representative in vitro model of the human proximal colon. Magnetic resonance imaging of the Dynamic Colon Model verified that the digital twin robustly replicated flow patterns under different physiological conditions (media viscosity, volume, and peristaltic wave speed). During local contractile activity, antegrade flows of 0.06–0.78 cm s−1 and backflows of −2.16–−0.21 cm s−1 were measured. Mean wall shear rates were strongly time and viscosity dependent although peaks were measured between 3.05–10.12 s−1 and 5.11–20.34 s−1 in the Dynamic Colon Model and its digital twin respectively, comparable to previous estimates of the USPII with paddle speeds of 25 and 50 rpm. It is recommended that viscosity and shear rates are considered when designing future dissolution test methodologies for colon-targeted formulations. In the USPII, paddle speeds >50 rpm may not recreate physiologically relevant shear rates. These findings demonstrate how the combination of biorelevant in vitro and in silico models can provide new insights for dissolution testing beyond established pharmacopeial methods.

The Effect of Biorelevant Hydrodynamic Conditions on Drug Dissolution from Extended-Release Tablets in the Dynamic Colon Model

“…However, the stimulated colon may generate hydrodynamic conditions that lie somewhere between 25 and 50 rpm. This data builds upon previous conclusions that the use of > 50 rpm in the USPII is not recommended for colon-targeted dosage forms [ 10 ].…”

“…Higher release was achieved in the USPII at 25, 50 and 100 rpm. Although conclusions cannot be drawn on the shear rates likely to have occurred from this comparison, since a constant shear is applied in the USPII and shear in the DCM has a high spatiotemporal dependence [ 10 ]. Previous MRI studies of the DCM found velocities to vary from −2.16–0.78 cm s −1 and shear rate fluctuating between 0–8 s −1 when slower CPPWs were applied (0.4 and 0.8 cm s −1 ) at the same volume and viscosity as in this study.…”

“…In addition, a low amplitude cyclic antegrade propagating wave (CPPW) travelling the 28 cm length of the DCM (mimicking from caecum to hepatic flexure) has been used in previous studies [ 10 , 11 , 12 ]. Its motility was based on observations from a high resolution manometry study on healthy volunteers by Dinning et al [ 13 ].…”

Digital twin in healthcare: Recent updates and challenges

“… 22 The Blue Brain Project, for example, began in 2005 as a collaboration between EPFL (Ecole Polytechnique Fédérale de Lausanne) and International Business Machines and aims to model the neocortical column. 23 Schütt et al 24 developed a DT of the Dynamic Colon Model that considered media viscosity, and peristaltic wave speed. It provided new insights for dissolution testing beyond established pharmacopoeial methods.…”

Correction: Schütt et al. Simulating the Hydrodynamic Conditions of the Human Ascending Colon: A Digital Twin of the Dynamic Colon Model. Pharmaceutics 2022, 14, 184

“…In the original publication [ 1 ], there was a mistake in Figure 6 when published. The experimental data points in the upper diagram were missing.…”