Dynamic Colon Model (DCM): A Cine-MRI Informed Biorelevant In Vitro Model of the Human Proximal Large Intestine Characterized by Positron Imaging Techniques.

Konstantinos Stamatopoulos,Mark Goldstein,Hannah K Batchelor,Connor O’Farrell,Caroline L Hoad,Sharad Karandikar,Mark J H Simmons,Luca Marciani,Sarah Sulaiman

doi:10.3390/pharmaceutics12070659

Abstract

This work used in vivo MRI images of human colon wall motion to inform a biorelevant Dynamic Colon Model (DCM) to understand the interplay of wall motion, volume, viscosity, fluid, and particle motion within the colon lumen. Hydrodynamics and particle motion within the DCM were characterized using Positron Emission Tomography (PET) and Positron Emission Particle Tracking (PEPT), respectively. In vitro PET images showed that fluid of higher viscosity follows the wall motion with poor mixing, whereas good mixing was observed for a low viscosity fluid. PEPT data showed particle displacements comparable to the in vivo data. Increasing fluid viscosity favors the net forward propulsion of the tracked particles. The use of a floating particle demonstrated shorter residence times and greater velocities on the liquid surface, suggesting a surface wave that was moving faster than the bulk liquid. The DCM can provide an understanding of flow motion and behavior of particles with different buoyancy, which in turn may improve the design of drug formulations, whereby fragments of the dosage form and/or drug particles are suspended in the proximal colon.

Highlights

Local drug delivery to the colon offers opportunities for effective therapy for a range of conditions, including Crohn’s disease (CD) and ulcerative colitis (UC)
Baseline conditions showed the lowest activity of the wall motion
A short (3.9 cm) antegrade propagating wave was detected (Figure 1a (1st–3rd curve); the entire cine-magnetic resonance imaging (MRI) for the baseline condition can be found in Video S1

Summary

Introduction

Local drug delivery to the colon offers opportunities for effective therapy for a range of conditions, including Crohn’s disease (CD) and ulcerative colitis (UC). CD and UC primarily occur in the terminal ileum and the colon All these findings, alongside the increasing numbers of people affected by IBD [3], have led to a considerable effort to effectively deliver active pharmaceutical ingredients (API) to the colon for local treatment [4]. Acceleration of the design, development, and evaluation of MR formulations is vital, and in vitro in vivo extrapolation (IVIVE), when available, can help reduce the number of costly in vivo studies required. This requires that in vitro tools can reproduce both the physicochemical characteristics of the gastrointestinal fluids and the hydrodynamics to predict reliably the in vivo performance [6,7,8]. Since hydrodynamics, controlled by the motion of the colon wall, will dictate the shear forces of fluid within the colon and subsequent disintegration, erosion, and dissolution of MR formulations, the development of a biorelevant in vitro colon model for dissolution must accurately replicate colon hydrodynamics

Methods

Results

Conclusion