Modelling and Simulation of the Drug Release from a Solid Dosage Form in the Human Ascending Colon: The Influence of Different Motility Patterns and Fluid Viscosities

Abstract

For colonic drug delivery, the ascending part of the colon is the most favourable site as it offers the most suitable environmental conditions for drug dissolution. Commonly, the performance of a drug formulation is assessed using standardised dissolution apparatus, which does not replicate the hydrodynamics and shear stress evoked by wall motion in the colon. In this work, computer simulations are used to analyse and understand the influence of different biorelevant motility patterns on the disintegration/drug release of a solid dosage form (tablet) under different fluid conditions (viscosities) to mimic the ascending colonic environment. Furthermore, the ability of the motility pattern to distribute the drug in the ascending colon luminal environment is analysed to provide data for a spatiotemporal concentration profile. The motility patterns used are derived from in vivo data representing different motility patterns in the human ascending colon. The applied motility patterns show considerable differences in the drug release rate from the tablet, as well as in the ability to distribute the drug along the colon. The drug dissolution/disintegration process from a solid dosage form is primarily influenced by the hydrodynamic and shear stress it experiences, i.e., a combination of motility pattern and fluid viscosity. Reduced fluid motion leads to a more pronounced influence of diffusion in the tablet dissolution process. The motility pattern that provoked frequent single shear stress peaks seemed to be more effective in achieving a higher drug release rate. The ability to simulate drug release profiles under biorelevant colonic environmental conditions provides valuable feedback to better understand the drug formulation and how this can be optimised to ensure that the drug is present in the desired concentration within the ascending colon.

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

“…The hydrodynamics of the proximal colon are crucial for the design and optimisation of colon-targeted formulations, particularly in terms of disintegration, dissolution, and distribution of the dosage form. To gain a better understanding of the hydrodynamics and mixing conditions in the intestinal environment, in vitro, as well as in silico, studies have been carried out, focusing on both the colon [3][4][5][6][7] and the small intestine [8,9]. In Vitro dissolution apparatuses have historically been used for biopredictive testing.…”

“…Pharmaceutics 2022, 13, x FOR PEER REVIEW 2 of 25 intestinal environment, in vitro, as well as in silico, studies have been carried out, focusing on both the colon [3][4][5][6][7] and the small intestine [8,9].…”

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

“…This additional sensitivity enables further understanding of the pathophysiology of colonic flow and the mode of action of treatments for functional colonic diseases, such as laxatives. In silico modelling of tablet dissolution in the proximal colon has shown that the ability of a motility pattern to distribute a dissolved API along the proximal colonic axis is highly dependent on the viscosity of the contents [6]. Viscosity has also been widely shown to influence dissolution in vitro [21,27,38].…”

“…The shear rates at the surface of these solid materials control the rate of erosion and hence drug release; therefore, understanding flow patterns is of high importance when designing medicines. For example, a recent simulation of drug release from a solid dosage form in the human ascending colon showed that motility patterns which provoked frequent single peaks in shear stress exerted on the surface of the dosage form, appeared to accelerate the release of the API [6]. Thus, any advances in knowledge of flows inside the DCM during the replication of motility patterns observed in healthy and diseased populations, enhances the value of this tool in the development of patient-centric formulations.…”

“…The combination of enhanced biorelevant in vitro and in silico dissolution testing could streamline the research and development process for new colon-targeted formulations [4,5]. In silico models that can simulate luminal flow inside the colon enable the investigation of colonic drug delivery systems to interpret how flow parameters can affect the breakdown of different formulations and API release [6,7]. Formulations can then be optimised by the use of quantitative simulations of how luminal flow affects mass transport phenomena of the API, including release and dissolution rates and distribution via convective transport inside the lumen.…”