The Pharmaceutical Journal
Vol 277 No 7483 p722
22/29 December 2007

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Employment and situations vacant: new opportunities for colonic bacteria

Emma McConnell, a PhD student at The School of Pharmacy, University of London, describes work on delivery systems that use colonic bacteria

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We each employ one hundred billion entities. They work for free, only asking for food and lodgings in return. These are our resident bacteria, the inhabitants of our gastrointestinal tract.

Playing an integral part in our digestive and immune health, these are the infamous “friendly bacteria”.

Most of these bacteria reside in the colon; over 400 species compete for its relative tranquility. Escaping the harsh acidity of the stomach and the disruptive motility of the small intestine, they are free to scavenge the melange of our undigested food. Extremely efficient, they produce enzymes (polysaccharidases and proteases), which ferment the remaining material, breaking it down to nutrients they can absorb.

In addition, from these nutrients, we as human hosts can gain up to 10 per cent of our energy, massively increasing our digestive efficiency. This, combined with immune system priming and prevention of potentially dangerous pathogenic colonisation, seems to be a fair exchange for room and board. Some of us, however, want just a little more.

Diseases of the colon are common in the Western world; colorectal cancer is the third most common cancer, and inflammatory bowel diseases affect 408 people per 100,000 per year. Systemic treatments for these diseases have unpleasant, even debilitating, side effects. Local treatment is preferable, but the application of enemas can be distressing and inconvenient, fueling the development of oral dosage forms to deliver drugs to the colon itself.

There are other reasons we want to target the colon. It is a good site for delivery of proteins and it has a unique immunological environment — it has a different antibody and T-cell population from the small instestine. So, whether it is drug or vaccine delivery, the multifarious intestinal bacteria can be employed to enable colon-specific targeting.

A traditional oral dosage form shows immediate release. A tablet, once taken, disintegrates after contact with fluid in the stomach. Here, water is the trigger. To target drug release to different areas of the gastrointestinal tract, different triggers need to be found. The sharp rise in bacterial numbers, and associated metabolic activity, between the sparsely inhabited small intestine, and the densely populated colon, provides such a trigger.

Some marketed products use this technique. Several treatments for inflammatory bowel disease are delivered as pro-drugs that require activation by colonic bacterial enzymes. However, this approach is highly drug specific and work is being carried out in the department of pharmaceutics at The School of Pharmacy, University of London, to develop more universal systems.

Bacterially initiated colon-specific drug delivery requires that the dosage form reach the colon intact, avoiding disintegration in aqueous conditions, and eschewing pancreatic digestion. Upon reaching the colon, bacterial enzymes must be capable of breaking down the dosage form to release the drug. Candidates to make such delivery systems were found among the polysaccharides.

Our research group showed that chitosan, a polysaccharide by-product of the seafood industry, can be digested by human colonic bacteria. Combining this with a non-toxic ionic crosslinker produced some resistance to pancreatic digestion. Addition of a crosslinker changes a polysaccharide chain into a dense network, which pancreatic enzymes find difficult to penetrate.

Similarly, heating ordered and easily digestible starch produces a tangled network of chains, which rapid cooling can set or “freeze in”. This “resistant starch” provides a tortuous path for enzyme ingress, effectively preventing pancreatic digestion.

The hardworking colonic enzymes, used to tackling difficult to digest materials, are much more efficient, and can break down these networks. Starch, in combination with a water-insoluble polymer to control swelling, has shown highly specific colonic release, with a variety of drugs, and is currently in phase III clinical trials.

These polysaccharides, in combination with their bacterial stimuli, may herald more efficacious and cost-effective treatments for diseases of the colon, and open pathways for new drug molecules.

There are one hundred billion bacterial cells in the gastrointestinal tract, outnumbering all our cells by a factor of 10. We are trying to employ them for drug delivery, but they are already an essential symbiosis, and much more than just “friendly bacteria”.

This article was adapted from an essay that was runner up in the 2007 Wellcome Trust and New Scientist essay competition

Gamma scintigraphic images of the transit and spread of a resistant starch based, coated pellet formulation (developed at the School of Pharmacy, University of London) in the gastrointestinal tract of a human