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Boosting advanced doctoral training in innovative colon targeting drugs

Periodic Reporting for period 1 - COLOTAN (Boosting advanced doctoral training in innovative colon targeting drugs)

Reporting period: 2021-01-01 to 2022-12-31

COLOTAN, the European Training Network for the design of novel colon specific drug delivery systems and the study of drug disposition in the colon and models to improve colon specific drug delivery, addresses the problem that the current drug delivery systems that are used to reach a high drug concentration in the colon (large intestine) are often not reliable. A significant amount of drug is already released before the colon is reached, or the release is too variable. Another point is that our understanding of how the drug behaves in the colon, e.g. with respect to absorption potential, role of physical barriers and so forth appears to be insufficient to realize optimal pharmacotherapy for the treatment of colon diseases.

The key advantage of targeting drugs to a specific site in the GI tract is the possibility to maximize efficiency and minimize side effects by getting the right dose at the right site. The treatment of colonic diseases such as Crohn's disease, ulcerative colitis (UC), or irritable bowel syndrome (IBS) would be more efficient if the drug would be delivered locally in the colon after oral administration. During the past twenty years, a considerable amount of work has been carried out in order to design delivery systems for targeting drugs specifically to the colon. In spite of this, optimal systems that deliver drugs reproducibly to the colon are still lacking.

For optimal delivery and activity of drugs to/in the colon, it is crucial to thoroughly understand the colonic environment and the drug and formulation behavior in it. High permeability and lack of degradation by the microbiome are pre-requisites for efficient drug absorption in the colon. However, development of colon-targeting formulations for poorly soluble compounds has shown to be challenging due to a lack of clinically useful drug absorption data and poor predictions of colonic absorption despite high in vitro permeability and stability.

The use of in vitro and in silico models to predict drug performance reduces the need for animal experimentation and has become an integral part of drug development. However, existing in vitro models rarely take into account the events occurring in the lower small intestine and the colon. Similarly, absorption prediction using physiology based pharmacokinetic (PBPK) models has become a key tool in academic research as well as industrial drug development. These mechanistic models are the only tools able to take all key factors into account in the prediction of the oral absorption of a drug. Several commercial packages are available that provide a user-friendly platform for building PBPK models, each with its own strengths and limitations. A common limitation is the focus on the small intestine and consequently the colonic models developed so far are rudimentary with hardly any relevant publications supporting them. As a result, we can only predict plasma concentrations for drugs absorbed in the upper GI tract with sufficient confidence. Colotan will improve in vitro and in silico tools to more accurately predict drug performance in the colon.

COLOTAN deals with a topic of growing medical and societal concern: obtaining a sufficiently high drug concentration in the colon (large intestine) to efficiently treat diseases of the large intestine. Disorders of the colon, such as ulcerative colitis and colorectal cancer, are highly prevalent in Europe and colon-targeted drug delivery systems have received increased attention in recent years. Both EMA and the FDA call for research into new predictive tools, innovative drug delivery systems and precision medicine approaches. Issues related to pharmacokinetics and bioavailability remain the 3rd most prominent cause of oral, small-molecule drug candidate attrition in phase I clinical development, a major concern for the pharmaceutical industry.

In addition, the EC has highlighted new drugs as a focus area in their smart specialization strategy for public investments. It is thus clear that there is and will continue to be a large demand for highly skilled researchers in the pharmaceutical and biotechnological sector.
COLOTAN will deliver experts in drug delivery and disposition in the large intestine, but the general scientific and transferable skills will be equally applicable to other areas of drug development. They will be fully equipped to become future leaders and innovators in the pharmaceutical industry and create significant benefit for Europe’s economy and health care.

The overarching goal of COLOTAN is to provide high-level training to 13 PhD students (“early stage researchers” (ESRs)) to become experts in drug delivery, drug disposition and gastrointestinal (patho)physiology to improve targeting of drugs to the colon in order to treat diseases of the large intestine more efficiently and to provide them with the necessary transferable and scientific skills. Current colon targeting formulations suffer from an inconsistent and inefficient performance, due to incomplete understanding of processes occurring in the large intestine. Moreover, the currently available evaluation tools to predict drug performance focus mainly on the upper gastrointestinal tract, resulting in a lack of validated tools and models of the colon with high physiological relevance and predictive capability.
ESRs of WP1 worked on the development of new formulations capable of delivering molecules to the colon with a higher efficiency and specificity, and on innovative therapeutic modified release dosage forms for removing potentially harmful agent(s) from the colonic lumen: hence, biodegradable polymers, combinations of biodegradable polysaccharides and ethylcellulose, and systems relying on the pH gradient in the GI to deliver proteins in the large intestine. WP2 ESRs have been working on applications for ethical permits, method development and training. Methods and new technologies have been obtained to support characterization of luminal samples and tissues from healthy and diseased colon, culturing of organoids based on human colonic tissue, proteomics and metabolomics of intestinal tissue and luminal content, identification of new metabolites produced by the microbiome, diffusion in and binding to the colonic mucus, and effects of drugs on the microbiome and vice versa. A high risk for incorrect predictions of low permeable compounds using currently available PBBM models was observed. ESRs of WP3 investigated in this first period how to improve models to study colonic absorption.
Currently the progress and impact is still rather on the internal level (i.e. within the project),
although some research and review papers have been published/submitted. Also posters have already been presented on several occasions.
A special note can be made on the organization of three symposia (by KU Leuven, NKUA and University of Parma). During the symposia we focused on topics related to colon drug delivery and colon pathology. COLOTAN will contribute to stimulate the interest of children and young adults in engaging with pharmaceutical sciences, informing them about the important role of pharmaceutical sciences in everyday life as well as in academic and industrial research and production, raise the level of education and make it more meaningful on various levels, and increase diversity of students and employees.

Project video:
Project flow (the 3 scientific work packages)