Oral drug delivery

Other efforts include making use Computational Fluid Dynamics (CFD) to create an intestinal model including motility aspects (peristalsis and segmentation) to understand its role on co-localisation of excipients (permeation enhancers) and drugs (macromolecules such as insulin) after oral intake (Naranjani et al., Int. J. Biol. Macromol., 2023) (work exemplified in figure 3). This workstream was developed jointly with our former Guest Professor James Brasseur who had a 20% appointment with SweDeliver 2020-2023.

The CFD work is carried out by PhD student Benyamin Naranjani, who is currently expanding his knowledge of CFD modelling with artificial intelligence during a twinning project with AstraZeneca. Benchtop research and development of effective and physiologically predictive in vitro model remains a vital part of drug delivery. The GI tract is a highly complex environment and many factors must be considered during the development of new drug formulations.

Complementary to the MD and CFD modelling efforts, we have developed in vitro models to understand drug dissolution, solubility and diffusion in colonic mucus with the overall aim to better understand the role of the mucus barrier on absorption from colon. Artificial mucus mimicking the colonic mucus in larger preclinical species used in absorption studies (dogs and pigs) have been developed by researcher Ilse Dubbelboer and PhD students Vicky Barmpatsalou and Marco Tjakra (Barmpatsalou et al., Eur. J. Pharm. Sci., 2023; Barmpatsalou et al., Eur. J. Pharm. Sci., 2024).

As life-style diseases such as ulcerative colitis and Crohn's disease are increasing globally, local treatment of the colon is of high interest. Tjakra therefore continues this work to develop artificial mucus mimicking the colonic mucus of the healthy and diseased colon. Jointly, Tjakra and PhD student colleague Mingjun Wu are currently developing an in vitro dissolution method for studies of the importance of the mucus barrier for drug release; the physical model used for these studies is currently explored for patentability. Further, Tjakra combines this work physiology-based pharmacokinetics (PBPK) and is out for secondment to MSD in the states to develop these skills in accordance with the plans included in the EU-ETN Colotan which is the main founder for this project.

Similar to Tjakra, PhD student Rebekkah Hammar of EU-ETN Colotan and SweDeliver has studied the influence of intra- and extracellular free drug concentrations in the human colon on local and systemic drug exposure (Hammar et al., Eur. J. Pharm. Sci., 2023). Hammar’s research has a focus on the optimisation of an organoid model of the colon, called colonoids. Hammar has managed to develop these to present the organoids in the ‘apical-out’ form in a robust manner, enabling rational studies of uptake in the colon in a small-scale format of more tissue-like cell systems than those currently in use (e.g. cell monolayers). During her secondment to AstraZeneca, Hammar has combined her skills in cell biology with studies of the microbiome to understand to what extent drugs are absorbed and affecting the microbiome naturally present in the large intestine.

Apart from the development of in vitro models, we are studying various formulations strategies – including lipid based nanoemulsions loaded with peptides. The digestion of lipids and their effect of the peptides stability and permeation have been developed by post doc Ann-Christin Jacobsen and is currently explored in a combined digestion-absorption assay by post doc Hannah Pohlit (Jacobsen et al., Drug Deliv. Transl. Res., 2022).

The generation of a generic, nano-sized drug delivery platform is being development by PhD Student Xiguo He and Associate Professor Madlen Hubert, currently focusing on engineering nanoparticles and loading liquid crystalline nanoparticles with antibiotics. Here, the effect of the antibiotics on the microbiome is also studied, with the intention to decrease adverse reactions in the gut by efficient encapsulation and increased uptake of nanoparticles by the enterocytes. The intestinal colloidal structures and their influence on self-assembly of lipid-based formulations are studied by PhD student Shahina Akter. using various screening techniques including SAXS combined with MD simulations.

The Work Package have established advanced in vivo models for studies of the molecular characteristics of macromolecular drugs and to support the selection of suitable permeation enhancers to improve oral absorption. This work has been carried out in the laboratories and state-of-the art animal facility at AstraZenec. These studies were spearheaded by PhD student Staffan Berg who has established a new rat instillation model and a pig intestinal absorption model at AstraZeneca as a result of his PhD studies carried out at SweDeliver (Berg et al., Mol. Pharm., 2021; Berg et al., J. Contr. Release, 2023).

Berg focused extensively on co-localisation studies of drug and permeation enhancers whereas PhD student Prosper Emeh, continuing the work, is currently expanding the knowledge on physicochemical properties and its role in selection of permeation enhancer. Emeh also has combined in vitro and in vivo work, identifying how to select a proper model for the question asked around macromolecular intestinal absorption (Emeh et al., Mol. Pharm., 2023).

Overall, SweDeliver Work package Oral Drug Delivery has successfully expanded the research and the team with other sources of funding, including internal Uppsala University funding (Uppsala Antiobiotic Center,. He), Swedish Neutron Education for Science and Society (SWEDNESS; Akter) and EU-ETN Colotan (Tjakra, Hammar). Still, note that all Work Packages are actively engaged in applications for funding from other sources to further support the work performed.

Work package Leaders