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.

Keywords: colon; colonic drug delivery; drug release profile; fluid dynamics; fluid–structure interactions; large intestine; mathematical modelling; smoothed particle hydrodynamics (SPH); spatiotemporal concentration profile; tablet disintegration.

Figure 7

Comparison of the drug release profile of the different models at low fluid viscosity conditions as well as the comparison of the shear stress/shear rate acting on the tablet.

Figure 8

Comparison of the drug release profile of the different models at medium fluid viscosity conditions as well as the comparison of the shear stress/shear rate acting on the tablet.

Figure 9

Comparison of the drug release profile of the different models at high fluid viscosity conditions as well as the comparison of the shear stress/shear rate acting on the tablet.

Figure 10

Comparison of the different models in respect to the distribution of the API along the colon at four different times at low fluid viscosity conditions.

Figure 11

Comparison of the different models in respect to the distribution of the API along the colon at four different times at medium fluid viscosity conditions.

Figure 12

Comparison of the different models in respect to the distribution of the API along the colon at four different times at high fluid viscosity conditions.

Figure 13

Comparison of the influence of different diffusion coefficients on the drug release profiles, where ‘high D’ represents the drug release profile of the high diffusion coefficient and ‘low D’ the drug release profile of the low diffusion coefficient simulation.

Figure A1

System parameter for the Dimensional Analysis.

Figure 1

(a) Section of the flexible membrane, showing the colon’s haustra and the intestinal fluid inside the colon. The membrane is built of particles which are connected by a network of springs to achieve a flexible behaviour. (b) 3D sketch of the tablet. The particles representing the tablet are connected by linear and diagonal springs to obtain a solid behaviour.

Figure 2

(a) 2D representation of the membrane particle anchored by a spring in equilibrium position and after the application of a radial force. (b) Illustration the particles representing the colon’s membrane including its characteristic haustra, before and after applying an individual radial force to each ring (‘circular muscle’).

Figure 3

The model is represented in two different forms: ‘Particle representation’ and a more realistic ‘Continuum representation’. This is an example of the dissolution process of a tablet in the colonic environment at three different time steps. Colonic contractions lead to the motion of the fluid and accordingly to the movement of the tablet which dissolves in the intestinal fluid. In the particle representation the shear stress acting on the tablet, and the API concentration in the surrounding of the tablet, i.e., in the fluid is shown.

Figure 4

Illustration of the different motility pattern, where (a) is the Baseline, (b) the Stimulant PEG, (c) the Stimulant Maltose, (d) the Comparison pattern and (e) the CPPW motility pattern. Here, the x-axis represents the time and duration of the actions taking place and the y-axis the colon section (haustra) addressed. The different actions are indicated by different hatches.

Figure 5

Representation of how the occlusion degree is defined.

Figure 6

Representation of the initial position of the tablet, which is in all models identical.