Oral Drug Delivery Platforms

Influence of intestinal colloidal structures and self-assembly on lipid-based formulations for enhancing peptide drug bioavailability.

Shahina AktarResearch scientist: Shahina Aktar, MSc
Principal Investigator: Associate Professor Per Larsson, Department of Pharmacy, Uppsala University

Scientific and industrial context: Bioavailability of peptide therapeutics is poor to non-existent when taken orally, which is the preferred route of administration. In general, and small fatty acid-based compounds specifically permeability enhancer, may be used to transiently boost peptide permeability, but this technique is linked with substantial inter- and intra-individual variability, which is not acceptable for disease treatment that requires a long duration of action.

Aim: To develop a hybrid of the small-angle neutron scattering (SANS) and the simulation methods to analyse complex intestinal colloidal structures and lipid-rich water-based formulations.

Outcome: Through the use of this hybrid method, it will be possible to understand the many essential intestinal processes, allowing for a more complete understanding of the constraints and variability associated with the use of permeability enhancer for peptide therapeutics.

Effects of molecular characteristics of macromolecular drugs and selection of permeation enhancer on oral absorption

Prosper Emeh, PhD StudentResearch scientist: Prosper Emeh, MSc.
Principal investigator: Professor Christel Bergström, Department of Pharmacy, Uppsala University.

Scientific and industrial context: The oral delivery of macromolecular drugs, beyond Lipinski’s Rule of 5 chemical space, such as peptides, proteins, and oligonucleotides, even when co-administered with transient permeation enhancers (TPEs), still presents the problem of a low (single digit) and variable bioavailability.

Aim: The project aims to study the physicochemical characteristics of beyond-the-rule-of-5 (bRo5) drugs and TPEs, explaining their interaction and the interplay with gastrointestinal barriers to improving oral bioavailability.

Outcome: We expect to improve our mechanistic knowledge of the influence of specific molecular descriptors of bRo5 drugs on oral absorption. The generated data could provide more insight into the macromolecule/permeation enhancer axis, possibly enabling a rational selection of TPEs while considering the physical-chemical properties of the orally administered macromolecule.

Influence of intra- and extracellular free drug concentrations in the human colon on local and systemic drug exposure

Rebekkah Hammar, MScResearch scientist: Rebekkah Hammar, MSc
Principal Investigator: Professor Per Artursson, Department of Pharmacy, Uppsala University

Scientific and industrial context: Colonic disorders are on the rise globally, but treatment options are limited due to poor predictability of colonic drug behavior. For generating useful predictive parameters such as intracellular bioavailability, representative in vitro models are needed. Though gut microbiota models have long been in use, it was not until recently that representative epithelial models became available. With the rise of organoid technology, native-like human colonic epithelium can now be generated in vitro.

Aim:  Determine drug distribution in a) human colonoids and b) microbiota models to then create a PBPK model of the colonic environment.

Outcome: A PBPK model of the colonic environment will allow for better estimation of colonic drug efficacy and reduce the need for animal models.

Drug delivery platform for optimal intestinal absorption of oral antibiotics

Xiguo He, MScResearch scientist: Xiguo He, PhD Student, MSc
Principal investigator: Professor Christel Bergström, Department of Pharmacy, Uppsala University

Scientific and industrial context: Global antibiotic consumption has increased significantly over the last two decades due to improved access to health care. Antimicrobial resistance is a huge threat to global health, and is high priority for public health authorities. It is crucial to identify strategies to improve the oral bioavailability of antibiotics and minimize adverse reactions in the gut to reduce the side effect of most oral antibiotics.

Xiguo He research

Aim: To improve the oral bioavailability of antibiotics using nanoparticles that are stable in the gastrointestinal tract (GIT), efficient solubilizers of poorly soluble antibiotics and highly membrane-permeable, with the purpose to increase drug delivery to the systemic circulation.

Outcome: A nanotechnology-based drug delivery platform that enhances the intestinal absorption for poorly permeables, with focus on oral antibiotics.

Mechanistic modeling of peptide drug permeability 

Rosita KneszlResearch scientist: Rosita Kneiszl, MSc
Principal investigator: Associate Professor Per Larsson, Department of Pharmacy, Uppsala University

Scientific and industrial context: The most common administration route of approved peptide drugs is by parenteral injection, which is often both costly and painful to the patients. Oral administration of these drugs would therefore be beneficial, but is associated with a number of issues related to low permeability and bioavailability. 

Aim: To use computational modeling and simulation to investigate the influence of peptide drug formulation components (such as medium chain fatty acids) on intestinal membranes, as well as to quantify and characterize binding and transport of peptide drugs across lipid bilayers.

Outcome: An in silico protocol to calculate permeation rates for peptide drugs across intestinal membranes, to support the development and design of rational formulations for peptide drugs. 

Combined computational modeling at different scales to understand peptide drug and excipient co-localization

Benyamin NaranjaniResearch scientist: Benyamin Naranjani, MSc
Principal investigator: Associate Professor Per Larsson, Department of Pharmacy, Uppsala University

Scientific and industrial context: The use of transient permeability enhancers to increase small intestinal delivery of biological drugs has regained in interest with a number of fatty acid-based excipients currently being explored. However, bioavailability remains low and variable.

Aim: To create a multi-physics simulation code to simulate interactions intestinal fluids, permeation enhancers and peptide drugs in response to contractions of localised intestinal segments, with application to distortion, transport and differential diffusion of different molecules. 

Outcome: With knowledge of the mechanisms behind efficient co-presentation of permeability enhancers and peptide drugs, delivery systems for can be designed with high specificity. In the end, this will reduce variability and increase bioavailability of orally administered peptide drugs.

Investigation of oral absorption of macromolecules using in silico techniques

Shakhawath Hossain, ResearcherResearch scientist: Shakhawath Hossain, Researcher
Principal investigatorProfessor Christel Bergström, Department of Pharmacy, Uppsala University

Aim: The primary aim of this research project is to improve the understanding of oral absorption of macromolecule using in silico modelling techniques e.g. molecular dynamics (MD). Much of the research focus was to explore the interaction of permeability enhancers (PEs) with different components of intestinal fluids and cell membrane in order to understand different PEs ability to enhance the permeability of macromolecules across the cell membrane. The interaction of macromolecules is also important for the development of an effective formulation. Therefore, the aggregation behavior of different peptide molecules is also studied in this project using the MD simulations.. 

Diffusion, dissolution, and release mechanisms for dosage forms delivering drugs to the colon: Importance of colonic mucus as a barrier to drug absorption

Marco TjakraResearch Scientist: Marco Tjakra, MEng
Principal Investigator: Professor Christel Bergström, Department of Pharmacy, Uppsala University

Scientific and industrial context: The unique structure of the mucus enables it to act as a barrier of drug absorption, but it can also be utilized as a reservoir by making use of mucoadhesive drug carrier. However, there are still some problem regarding specificity and release, in combination with properties such as low drug solubility and microbial interference. Currently, characteristics of the mucus together with drug interaction is still less explored.

Aim: To improve the understanding of drug dissolution, diffusion, and absorption from the human colon with a focus on the role of the colonic mucus layer. The obtained results will be used to design drug delivery decision trees for colonic drug delivery as well as improved in silico models for drug absorption from the colon.

Outcome: This project will contribute to the understanding of mucus in the human colon and its role as barrier to drug delivery. It will result in the improvement of human biosimilar mucus and methods useful to study drug and particle diffusion, dissolution and release in this complex hydrogel.

Further, it will contribute to more efficient in silico models to predict dosage form design as well as performance in vivo for complex controlled and sustained release formulations. Other than the field of pharmaceutics, the information will also be of importance to the field of nutrition science and food science, since the mucus also serves as a barrier for nutrition uptake process (Project is performed within COLOTAN).

In vivo dissolution in colon of poorly soluble drug substances

Mingjun Wu, MScResearch scientist: Mingjun Wu, MSc
Principle investigator: Professor Christel Bergström, Department of Pharmacy, Uppsala University

Scientific and industrial context: Limited fluid available in colon, the presence of mucus, colonic peristalsis, and the role microbiome could influence the drug dissolution in colon, resulting in inefficient colonic absorption. To date, we are still missing in vitro models that can effectively predict drug colonic release in vivo.    

Aim: To improve the understanding of the colonic dissolution of poorly water-soluble compounds by investigating the effect of different factors such as hydrodynamic, low fluid volume and binding to/degradation by bacteria on dissolution in colon, as well as to develop physiologically relevant in silico and in vitro models of colonic dissolution.

Outcome: The project will contribute to the understanding of factors that could influence drug dissolution in colon. In vitro and in silico models will be developed to predict the absorption in colon of poorly water-soluble drugs. The generated knowledge is expected to guide the design of successful dosage forms for efficient colonic release and absorption.

Completed projects

Investigation of The Interplay Between Permeation Enhancers, Gi Physiology and Macromolecular Drugs to Facilitate Design of Oral Dosage Forms

Research scientist: Staffan Berg, MSc
Principal Investigator: Professor Christel Bergström, Department of Pharmacy, Uppsala University

Scientific and industrial context: Oral delivery of macromolecular drugs, primarily peptides, proteins and oligonucleotides, remains an outstanding challenge for pharmaceutical scientists; after more than 90 years of attempts, the bioavailability of such molecules remains low and variable.

Aim: The overall aim of the project is to generate new insights to the interplay between permeation enhancers, macromolecular drugs of different physicochemical properties and the intestinal physiology. In vitro and in vivo models will be used to investigate these interactions and to study the absorption of macromolecules.

Outcome: The generated data is expected to enable the design of novel delivery systems that increase oral absorption of macromolecules and reduce the variability of absorption.

Local intestinal generation of transient permeability enhancers by digestion of lipid formulations

Research scientist: Ann-Christin Jacobsen, PhD
Principal investigator: Associate Professor Alexandra Teleki, Department of Pharmacy, Uppsala University

Scientific and industrial context: Despite single digit bioavailability and high variability, permeation enhancer-based delivery systems for oral systemic delivery of macromolecules such as peptides and proteins have reached the clinics with two recent approvals (Mycapssa® and Rybelsus®).

Aim: To investigate if lipid-based formulations such as self-emulsifying drug delivery systems (SEDDS) that release permeation enhancing medium chain fatty acids upon digestion can improve the efficiency of permeation enhancer-based drug delivery systems. In vitro lipolysis will aid designing lipid-based formulations with defined permeation enhancer release. The formulations will be evaluated in in vitro and/or in vivo absorption and stability models.

Outcome: This project will reveal if intestinal digestion can be harnessed for increased permeation enhancer efficiency. Formulation design guided by lipolysis will generate information on medium chain lipid digestion kinetics and how macromolecular drugs in lipid-based formulations are affected by digestion.

Exploring the impact of the Gastrointestinal Mucus on drug absorption: Characterization and development of novel predictive tools

Vasiliki Barmpatsalou portait photoResearch scientist: Vasiliki Barmpatsalou, MSc
Principal Investigator: Professor Christel Bergström, Department of Pharmacy, Uppsala University

Scientific and industrial context: The formulation of poorly soluble drug candidates as modified release (MR) dosage forms is challenging, mainly due to our limited understanding regarding the barriers towards colonic absorption and the resulting shortage of in vitro models that are in vivo predictive for release in and absorption from the colon.

Vasiliki B Research

Aim: To provide novel insights regarding the nature of the gastrointestinal mucus of preclinical species, with an end goal to develop in vitro models that will enable the assessment of the permeation behavior of poorly soluble drugs through the colonic mucus.

Outcome: The acquired knowledge is expected to serve as the basis of the development of novel in vitro tools that can be later used to predict the diffusion profile of advanced drug delivery systems within the colonic mucus. These in vitro models will contribute to the reduction of animal usage in the early stages of drug development.

Last modified: 2023-10-31