Colon-specific Release of Active Agents

Following oral administration, drugs are usually absorbed in the small intestine and are systemically distributedvia the circulation after their obligatory liver passage. Some indications however would greatly benefit from the release of the active agent in the colon.

In chronic inflammatory bowel diseases such as ulcerative colitis it is important that anti-inflammatory agents become effective at the site(s) of inflammation in the colon rather than already being absorbed at the level of the small intestine. Likewise, in Crohn's disease where large areas of the colon may be inflamed, or in colon or colorectal carcinoma, suitable drugs are ideally released in close proximity to the diseased tissue.

Via their local release, the concentration of active ingredients to be appliedenterically can be reduced considerably. Consequently, the risk for severe side-effects and/or toxicity by many of these active agents (e.g., glucocorticoids, cytotoxic drugs, immunosuppressants etc.) is thus strongly reduced as well.

It is assumed that some peptide agents (e.g., insulin) can be absorbed in the colon provided that they reach the large intestine in intact form after passing the stomach and small intestine. Vis-á-vis intravenous injection of these peptide drugs, their peroral intake would significantly improve the patients' compliance.

For these applications, it is desirable to achieve a controlled release of the drug in the colon from a solid dosage form. This approach is termed "colon targeting" or rather, "colon-specific drug delivery"; it may, for example, be achieved by developing coating materials or matrices for tablets, granules or capsules that will not be broken down by the digestive fluids of stomach and small intestine, but be tailored so as to be specifically dissolved by certain enzymes of the colonic bacterial flora where upon releasing the active agent.

The group of Professor Dr. Kurt H. Bauer had greatly progressed in this area by synthesizing suitable materials - mostly in the form of polysaccharide derivatives (PhD theses by Dr. Christian Wohlschlegel, Dr. Antonio W. Sarlikiotis, Dr. Jürgen Betzing, Dr. VerenaSiefke, Dr. Stefan Hirsch and Dr. Vera Binder) - so that these works will be continued at this Department.

We are evaluating combinations of proven coating materials with select active agents, and we are continuously improving existing in-vitro assays for measuring intra colonic drug release (PhD theses by Dr. Axel Fetzner, Dr. Dagmar König, Dr. Stefan Böhm, Dr. Ali Al-Raghban, Dr. Nadia Schwalm and Dr. Michael Drechsler).

At this Department, a colonic microflora assay for testing the enzymatic degradation of coating materials has been established for many years; this assay is continuously developed further. We are pursueing various strategies towards reducing the drug release in stomach and small intestine to zero, while trying to achieve a most rapid release of the active ingredient once the tablet reaches the colon. In collaboration with Dr. Grzegorz Garbacz of the University of Greifswald, Germany, we moreover investigate the influence of the diet as well as of physiological pressures in the gastrointestinal tract by employing a biorelevant drug release device. As to the polymers applied for film formation, their chain lengths, as well as their distribution, are being characterized in collaboration with BASF SE, Ludwigshafen, Germany. Here, the dedicated goal is to develop new coating dispersions that can be applied even more quickly and easily while still enabling a colon-specific drug release.

Funding
These works have been financially supported since 2004 by Dr. Falk Pharma GmbH, Freiburg, Germany