Building an artificial colon to mimic how drugs work inside the large intestine
The colon, also known as the large intestine, plays a vital role in the way the human body rids itself of waste. Food, excess water and nutrients are squeezed along by muscles lining the colon’s wall.
The colon is susceptible to a range of illnesses, many of them debilitating, from ulcerative colitis to bowel cancer, and treating them can be difficult. One reason for this is the way drugs are delivered to the large intestine, which resembles a long tube made up of linked chambers. If you introduce a drug at the beginning of the colon, the question is how much has reached the walls by the time it reaches the end?
Dynamic Colon Model (DCM)
To give scientists a better idea of what exactly goes on inside the large intestine, the University’s chemical engineers and pharmacologists have joined forces to build a novel biorelevant Dynamic Colon Model (DCM), the first-ever physiologically relevant working prototype of an artificial human colon. It provides a realistic environment in terms of the architecture of the smooth muscle, the physical pressures and the motility patterns that occur in the proximal human colon.
The idea behind the DCM was to create a model more physically representative than the current test used for drug delivery to the colon.
The project forms the basis of a recently completed PhD by chemical engineering student Konstantinos (Kostas) Stamatopoulos and has resulted in a trio of published papers. The third, published in the European Journal of Pharmaceutics and Biopharmaceutics, entitled ‘Dissolution profile of theophylline modified release tablets, using a biorelevant Dynamic Colon Model (DCM),’ has won the College’s Paper of the Month Award.
To have one published paper to your name before you’ve been awarded your PhD is impressive enough; to have three is ‘pretty good going,’ acknowledges Kostas’s supervisor, Head of the School of Chemical Engineering Professor Mark Simmons, who together with Birmingham pharmacologist Dr Hannah Batchelor co-authored the winning paper.
Using the colon for treatment delivery
‘The human proximal colon has been considered a favourable site to deliver drugs for local and systemic treatments,’ they explain in the paper. ‘However, modified dosage forms face a complex and dynamically changing colonic environment. Therefore, it has been realised that in addition to the use of biorelevant media, the hydrodynamics also need to be reproduced to create a powerful in vitro dissolution model to enable in vivo performance of the dosage forms to be predicted.’
At present, the most commonly used in vitro dissolution model is not much more sophisticated than the equivalent of placing a soluble drug in a vessel and stirring it to see how well it dissolves.
‘What we want to do is to assess how drug delivery systems behave in the body,’ says Kostas. ‘The current way it’s done over-simplifies what’s going on in the digestive system, so our aim is to see more clearly what’s happening inside there, how fluids are mixing and so on.’
It is not, of course, possible to do this ‘for real’, so the DCM provides the next-best thing. ‘This is the first model that reproduces the physiology of the colon and the smooth muscle wall.’
Constructing the DCM
Constructed of ten segments stuck together to form a tube, Kostas and his team can control the wall of each section, using a computer, by inflating and deflating each one in turn to mimic the undulations of a real colon. ‘Then we used sophisticated medical scanning techniques to see what was going on in our model.’
Next, the researchers used common, over-the-counter tablets and tested how the drug was released into a simple fluid. ‘The dissolution profile and the distribution of the highly soluble drug, theophylline, were assessed by collecting samples at different locations along the DCM tube. Differences in the release rates of the drug were observed.’
The next step, says Kostas, is to improve the wall motion so that it is as close as possible to the natural organ. ‘Then we want to develop a membrane in order to reproduce how the cells located in the colon wall absorbs the drugs or other nutrients. So there are two things: to analyse the mixing, but also the absorption.
‘This project isn’t about looking at how new drugs behave; it’s about how the drug distributes through the colon. And that means that if you want to use a drug delivery system, you will know how the colon is going to behave. With the current stirred method, that’s not possible.’
What is the future for the research?
Kostas and Mark are now applying for an EPSRC grant to take the research further. ‘There has also been a lot of interest from industry, so we are hopeful this should lead to further work if the grant is awarded.’
They are also hopeful that eventually the work will lead to new drug delivery systems and even new drugs.
‘This could also be used in future as an educational tool. It could help to monitor how healthy someone’s colon is, develop a better management strategy for patients, and improve techniques for treatment.’