In vitro models to evaluate ingestible devices: Present status and current trends

O’Farrell, Connor; Stamatopoulos, Kostas; Simmons, Mark; Batchelor, Hannah

doi:10.1016/j.addr.2021.113924

Cited by 13 publications

(10 citation statements)

References 385 publications

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“…The DCM is able to mimic the motor patterns of the colon, which mostly occur as propagating pressure waves (PPWs): one of the identified motor patterns in the colon [13]. The DCM is the most physiologically relevant in vitro colon model to date as it is the only model that replicates peristaltic motility in a lumen with the segmented architecture of the human colon [14]. A recent study has shown that when a PPW is applied to the DCM, the motion of the walls causes the contents of the lumen to flow in a way that closely reproduces the flow in the human proximal colon [12,15], verifying the hydrodynamics of the model.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…This research aims to use MR tagging to visualise, assess and discriminate between different motility patterns applied to an in vitro model of the human AC, the dynamic colon model (DCM). The DCM (Figure 1) replicates the anatomy, physical pressures and motility patterns of the human AC [21][22][23]. Precise replication of well controlled, repeatable motility patterns and therefore hydrodynamic conditions permits an intensive analysis which is not possible in vivo as colonic motility is inherently erratic.…”

Section: Introductionmentioning

confidence: 67%

“…Figure 7 presents a selection of morphological images with the associated spatially registered through-plane velocity maps superimposed over the lumen media, acquired using PC cine-MRI at the midpoint of segment 7, the cross section at Tag 11, and at different temporal locations. As highlighted in a recent review of in vitro models of the GI tract, the DCM is currently the only in vitro model to replicate peristaltic motility in a lumen with the segmented architecture of the human colon [23]. Therefore, understanding the streamwise velocity profile through a segment of the DCM at different stages of biorelevant motility adds insights to how intestinal wall motion influences the hydrodynamics that drive dissolution and mixing.…”

Section: Pc Cine-mri Velocimetry Of the Dcm Lumen Contentsmentioning

confidence: 99%

Luminal Fluid Motion Inside an In Vitro Dissolution Model of the Human Ascending Colon Assessed Using Magnetic Resonance Imaging

et al. 2021

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Knowledge of luminal flow inside the human colon remains elusive, despite its importance for the design of new colon-targeted drug delivery systems and physiologically relevant in silico models of dissolution mechanics within the colon. This study uses magnetic resonance imaging (MRI) techniques to visualise, measure and differentiate between different motility patterns within an anatomically representative in vitro dissolution model of the human ascending colon: the dynamic colon model (DCM). The segmented architecture and peristalsis-like contractile activity of the DCM generated flow profiles that were distinct from compendial dissolution apparatuses. MRI enabled different motility patterns to be classified by the degree of mixing-related motion using a new tagging method. Different media viscosities could also be differentiated, which is important for an understanding of colonic pathophysiology, the conditions that a colon-targeted dosage form may be subjected to and the effectiveness of treatments. The tagged MRI data showed that the DCM effectively mimicked wall motion, luminal flow patterns and the velocities of the contents of the human ascending colon. Accurate reproduction of in vivo hydrodynamics is an essential capability for a biorelevant mechanical model of the colon to make it suitable for in vitro data generation for in vitro in vivo evaluation (IVIVE) or in vitro in vivo correlation (IVIVC). This work illustrates how the DCM provides new insight into how motion of the colonic walls may control luminal hydrodynamics, driving erosion of a dosage form and subsequent drug release, compared to traditional pharmacopeial methods.

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“…Besides from the DCM, the architecture of most advanced in vitro models of the colon takes the form of a single tube [ 5 ]. The most advanced physiologically based pharmacokinetic (PBPK) models use oversimplified first order transit rate models that consider the colon to be a single homogeneously mixed compartment.…”

Section: Resultsmentioning

confidence: 99%

“…The dynamic colon model (DCM), shown in Figure 1 , is an advanced in vitro model of the human proximal colon that replicates segmental peristaltic motility [ 5 ]. It is the only model known to the authors to reproduce peristaltic motility of the colon in a segmented luminal architecture.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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The in vitro release of theophylline from an extended-release dosage form was studied under different hydrodynamic conditions in a United States Pharmacopoeial (USP) dissolution system II and a bespoke in vitro tubular model of the human colon, the Dynamic Colon Model (DCM). Five biorelevant motility patterns extracted from in vivo data were applied to the DCM, mimicking the human proximal colon under baseline conditions and following stimulation using polyethylene glycol or maltose; these represent the lower and upper bounds of motility normally expected in vivo. In the USPII, tablet dissolution was affected by changing hydrodynamic conditions at different agitation speeds of 25, 50 and 100 rpm. Applying different motility patterns in the DCM affected the dissolution profiles produced, with theophylline release at 24 h ranging from 56.74 ± 2.00% (baseline) to 96.74 ± 9.63% (maltose-stimulated). The concentration profiles of theophylline were markedly localized when measured at different segments of the DCM tube, highlighting the importance of a segmented lumen in intestine models and in generating spatial information to support simple temporal dissolution profiles. The results suggested that the shear stresses invoked by the unstimulated, healthy adult human colon may be lower than those in the USPII at 25 rpm and thus insufficient to achieve total release of a therapeutic compound from a hydroxyethyl cellulose matrix. When operated under stimulated conditions, drug release in the DCM was between that achieved at 25 and 50 rpm in the USPII.

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In vitro models to evaluate ingestible devices: Present status and current trends

Cited by 13 publications

References 385 publications

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

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

Luminal Fluid Motion Inside an In Vitro Dissolution Model of the Human Ascending Colon Assessed Using Magnetic Resonance Imaging

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

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