New thesis paving the way for oral delivery of peptide drugs

Oral drug delivery comes with many advantages. Not least for the patients who can easily swallow their prescribed tablets and capsules. Unfortunately, the complex environment and barriers of the gastrointestinal tract limit the absorption of active substances, which means that most peptide drugs still have to be injected. One possible method to address this is to add permeability enhancers, and in a new thesis, Rosita Pettersson Kneiszl, PhD student at Uppsala University’s Department of Pharmacy, presents results that pave the way for more precise prediction of how peptides, permeability enhancers and cell membranes will interact.

“Peptide drugs offer high activity, specific action, and low toxicity. However, their large size and hydrophilic nature often hinder their ability to permeate the intestinal epithelium. In my PhD thesis, we have used computer-based, molecular dynamics simulations to study how different permeability enhancers influence the intestinal cell membrane and the colloidal aggregates formed by peptide drugs and intestinal bile. Our results reveal fundamental molecular-level insights into the mechanisms by which permeability enhancers enhance the membrane permeability of peptides,” says Rosita Pettersson Kneiszl.

The central conclusions of the thesis include that a 15–20% concentration of permeability enhancers is required to increase water permeability through the model membrane. Moreover, the effect of the permeability enhancer depends on the physicochemical properties of the peptide, and by inhibiting peptide aggregation, permeability enhancers can increase absorption. The results further reveal specific mechanisms for individual permeability enhancers. For example, decanoic acid, C10, provides a linear concentration-dependent permeability-enhancing effect, while salcaprozate sodium, SNAC, does not generate an increased effect at higher concentrations.

“Our results show that permeability enhancers provide a promising strategy for oral delivery of peptide drugs as well as relevant starting points for future studies. We operate in a research-intensive field that is currently making several important advances. For example, Novo Nordisk have by adding SNAC developed Rybelsus, a diabetes drug with the same weight-loss effect as Ozempic but that can be taken as tablets, and this winter they also initiated studies in which they combine C10 and SNAC.”

Rosita Pettersson Kneiszl has carried out her PhD studies within the framework of the international research center SweDeliver's Oral Drug Delivery Work Package. A position that has enabled supervision at both Uppsala University's research environment for Molecular Pharmaceutics and big pharma giant Ferring Pharmaceuticals, and she is now aiming for a career in industrial research & development where positions as a Scientific expert or a Postdoc are possible directions.

“As a junior researcher, SweDeliver and the Faculty of Pharmacy provide inspiring environments with a wide range of opportunities. Here I have been able to develop my soft skills in a diversity of programs. In parallel, I have gained both academic and industrial perspectives in my work, which has been enormously valuable. Next, I want to integrate my background as a pharmacist with my skills in drug delivery to contribute to new generations of permeability enhancers, and after my dissertation I have interesting options to decide on,” concludes Rosita Pettersson Kneiszl.

text: Magnus Alsne, photo: Mikael Wallerstedt, Magnus Alsne