Periodic Reporting for period 2 - COLOTAN (Boosting advanced doctoral training in innovative colon targeting drugs)
Okres sprawozdawczy: 2023-01-01 do 2024-12-31
The issue that the current drug delivery systems used to reach a high drug concentration in the colon (large intestine) are frequently unreliable is addressed by COLOTAN.
The potential to optimize effectiveness and reduce adverse effects by administering the appropriate dosage at the appropriate location is the main benefit of directing medications to a particular location in the gastrointestinal (GI) tract. A significant amount of effort has been made over the last 20 years to develop delivery systems that target medications particularly to the colon to treat disorders like Crohn’s disease, ulcerative colitis or irritable bowel syndrome. Despite this, there are still no ideal systems that can consistently transport medication to the colon.
Understanding the colonic environment and the behavior of the drug and formulation is essential for the best possible distribution and activity of medications to and inside the colon. The absence of meaningful drug absorption data and the poor forecasts of colonic absorption have made it difficult to build colon-targeting formulations.
The events that take place in the colon and lower small intestine are not yet completely taken into consideration by the in vitro absorption models that are now available. Similarly, physiology-based pharmacokinetic (PBPK) models for absorption prediction have emerged as a crucial instrument in both industrial and academic drug development. However, the colonic models created thus far are inefficient. Because of this, we can only confidently forecast plasma concentrations for medications that are absorbed in the upper gastrointestinal tract. In order to forecast drug efficacy in the colon more precisely, Colotan will enhance in vitro and in silico methods.
In order to effectively treat large intestine illnesses, Colotan addresses a topic of increasing medical and public concern: achieving a high enough medication concentration in the colon. In recent years, colon-targeted medication delivery systems have drawn more attention due to the high prevalence of colon disorders in Europe, including ulcerative colitis and colorectal cancer. The FDA and EMA both urge research into precision medicine techniques, novel medication delivery methods, and new predictive tools.
Although COLOTAN will provide specialists for drug delivery and disposition in the large intestine, the general scientific knowledge and transferable abilities will be as useful in other drug development domains. They will have everything they need to lead and innovate the pharmaceutical sector in the future and significantly improve the health and economics of Europe.
The overall objective of COLOTAN is to give 13 PhD students advanced training to become specialists in gastrointestinal (patho)physiology, drug delivery, and drug disposition. This will help them target medications more effectively to the colon, improving the treatment of large intestine diseases, and equip them with the scientific and transferable skills they need. Due to a lack of knowledge about the activities that take place in the large intestine, current colon targeting formulations work inconsistently.
The potential to optimize effectiveness and reduce adverse effects by administering the appropriate dosage at the appropriate location is the main benefit of directing medications to a particular location in the gastrointestinal (GI) tract. A significant amount of effort has been made over the last 20 years to develop delivery systems that target medications particularly to the colon to treat disorders like Crohn’s disease, ulcerative colitis or irritable bowel syndrome. Despite this, there are still no ideal systems that can consistently transport medication to the colon.
Understanding the colonic environment and the behavior of the drug and formulation is essential for the best possible distribution and activity of medications to and inside the colon. The absence of meaningful drug absorption data and the poor forecasts of colonic absorption have made it difficult to build colon-targeting formulations.
The events that take place in the colon and lower small intestine are not yet completely taken into consideration by the in vitro absorption models that are now available. Similarly, physiology-based pharmacokinetic (PBPK) models for absorption prediction have emerged as a crucial instrument in both industrial and academic drug development. However, the colonic models created thus far are inefficient. Because of this, we can only confidently forecast plasma concentrations for medications that are absorbed in the upper gastrointestinal tract. In order to forecast drug efficacy in the colon more precisely, Colotan will enhance in vitro and in silico methods.
In order to effectively treat large intestine illnesses, Colotan addresses a topic of increasing medical and public concern: achieving a high enough medication concentration in the colon. In recent years, colon-targeted medication delivery systems have drawn more attention due to the high prevalence of colon disorders in Europe, including ulcerative colitis and colorectal cancer. The FDA and EMA both urge research into precision medicine techniques, novel medication delivery methods, and new predictive tools.
Although COLOTAN will provide specialists for drug delivery and disposition in the large intestine, the general scientific knowledge and transferable abilities will be as useful in other drug development domains. They will have everything they need to lead and innovate the pharmaceutical sector in the future and significantly improve the health and economics of Europe.
The overall objective of COLOTAN is to give 13 PhD students advanced training to become specialists in gastrointestinal (patho)physiology, drug delivery, and drug disposition. This will help them target medications more effectively to the colon, improving the treatment of large intestine diseases, and equip them with the scientific and transferable skills they need. Due to a lack of knowledge about the activities that take place in the large intestine, current colon targeting formulations work inconsistently.
Pullulan derivatives with a lower degree of substitution were biodegradable, but also still water-soluble, making their usage as polymers for colon targeted drug delivery unsuitable. We are currently exploring disulfide-based polymers.
Our results also highlight that predicting drug release profiles based on microbial effect can be challenging in terms of species differentiation between humans and animal models.
The effectiveness of activated charcoal in physically eliminating drugs from the lower intestine in clinical practice may be limited by patients’ compliance to receiving the required dose.
An optimized selection of stabilizing buffers and excipients for colon targeting of proteins was established.
Results from two clinical studies contribute to an advanced understanding of factors affecting drug behavior in the colon and therefore facilitate the development of better predictive in-vitro and in-silico tools for colonic drug absorption.
Experimental protocols for producing colonoids of high viability and with high yield has been established and the proteome has been mapped. Culture conditions to develop colonoids of different types have been identified.
We developed an artificial model mimicking the colonic mucus of pigs. Methods to study diffusion and dissolution in, and binding to, the mucus have been established. Models to include the generated data in PBPK modelling have been explored.
A chemoselective probe was synthesized and evaluated for molecular interaction studies. The updated design offers the possibility for integration with new instrumental technologies.
JAK inhibitors were not susceptible to microbial degradation, whereas a microbial depletion of free ozanimod was observed. By building a PPBPK model, we predicted systemic drug concentrations using in vitro dissolution profiles as input to drive luminal dissolution. The PBPK model also demonstrated utility in predicting drug concentrations at the colonic level, providing valuable insights for specific drug-microbiota interactions.
The EpiColon Microtissue was found to be a suitable preclinical tool to study drug disposition. Further, colonoid derived monolayers (CDM) demonstrated variability among donors. Colonoid monolayers demonstrated increased sensitivity in toxicity screening compared to Caco-2 cells.
Gaps in the colon models of GastroPlus® and GI-Sim specifically for low-permeability compounds were found.
We further revealed that certain proteins in human colonic fluids significantly impact the solubility and behavior of drugs in the colon. Additionally, solubilizers like bile salts and phospholipids or non-ionic surfactants also enhance drug permeation through mucus and colonic absorption.
Exposure of CDM to an inflammatory milieu altered cell morphology, compromised the epithelial barrier integrity, and increased chemotactic cytokine secretion, although to different extents in different patients.
Our results also highlight that predicting drug release profiles based on microbial effect can be challenging in terms of species differentiation between humans and animal models.
The effectiveness of activated charcoal in physically eliminating drugs from the lower intestine in clinical practice may be limited by patients’ compliance to receiving the required dose.
An optimized selection of stabilizing buffers and excipients for colon targeting of proteins was established.
Results from two clinical studies contribute to an advanced understanding of factors affecting drug behavior in the colon and therefore facilitate the development of better predictive in-vitro and in-silico tools for colonic drug absorption.
Experimental protocols for producing colonoids of high viability and with high yield has been established and the proteome has been mapped. Culture conditions to develop colonoids of different types have been identified.
We developed an artificial model mimicking the colonic mucus of pigs. Methods to study diffusion and dissolution in, and binding to, the mucus have been established. Models to include the generated data in PBPK modelling have been explored.
A chemoselective probe was synthesized and evaluated for molecular interaction studies. The updated design offers the possibility for integration with new instrumental technologies.
JAK inhibitors were not susceptible to microbial degradation, whereas a microbial depletion of free ozanimod was observed. By building a PPBPK model, we predicted systemic drug concentrations using in vitro dissolution profiles as input to drive luminal dissolution. The PBPK model also demonstrated utility in predicting drug concentrations at the colonic level, providing valuable insights for specific drug-microbiota interactions.
The EpiColon Microtissue was found to be a suitable preclinical tool to study drug disposition. Further, colonoid derived monolayers (CDM) demonstrated variability among donors. Colonoid monolayers demonstrated increased sensitivity in toxicity screening compared to Caco-2 cells.
Gaps in the colon models of GastroPlus® and GI-Sim specifically for low-permeability compounds were found.
We further revealed that certain proteins in human colonic fluids significantly impact the solubility and behavior of drugs in the colon. Additionally, solubilizers like bile salts and phospholipids or non-ionic surfactants also enhance drug permeation through mucus and colonic absorption.
Exposure of CDM to an inflammatory milieu altered cell morphology, compromised the epithelial barrier integrity, and increased chemotactic cytokine secretion, although to different extents in different patients.
The Colotan project realized significant progress beyond the state of the art in the following areas:
• Awareness, knowledge and treatment of colonic diseases
• Scientific knowledge about colon and microbiota (patho)physiology and drug disposition
• Colon-targeting formulations with improved efficiency and specificity
• In silico and in vitro models to assess formulations
• New/improved PBPK models of drug disposition in the colon, high quality drug disposition and colon (patho)physiology data underpinning PBPK models and communicated our progress through:
• Publications in high impact scientific journals.
• Presentations at prestigious international conferences (AAPS annual meeting, World Meeting of Pharmaceutics, Biopharmaceutics and Pharmaceutical technology.
• The organisation of four symposia (advertised via consortium members, personal network of PI’s, the COLOTAN website, social media profiles)
• Awareness, knowledge and treatment of colonic diseases
• Scientific knowledge about colon and microbiota (patho)physiology and drug disposition
• Colon-targeting formulations with improved efficiency and specificity
• In silico and in vitro models to assess formulations
• New/improved PBPK models of drug disposition in the colon, high quality drug disposition and colon (patho)physiology data underpinning PBPK models and communicated our progress through:
• Publications in high impact scientific journals.
• Presentations at prestigious international conferences (AAPS annual meeting, World Meeting of Pharmaceutics, Biopharmaceutics and Pharmaceutical technology.
• The organisation of four symposia (advertised via consortium members, personal network of PI’s, the COLOTAN website, social media profiles)