Parenteral Drug Delivery Projects

Physiochemical Aspects of Subcutaneous Administration of Drugs

Research scientist: Marcus Wanselius, MSc
Principal investigator: Professor Per Hansson, Department of Medicinal Chemistry, Uppsala University

Scientific and industrial context. Subcutaneous administration of drug formulations is an attractive alternative for the growing amount of active pharmaceutical ingredients (APIs) with low oral bioavailability. Therefore, it is important to investigate and understand the interactions between different drug formulations and the subcutaneous adipose tissue (hypodermis).

Aim. The aim of the project is to provide a mechanistic understanding of how APIs (especially biologics) and excipients in drug formulations interact with the components of the extracellular matrix in the hypodermis.A Further aim is to develop new formulation principles resulting in sustained release and high bioavailability of the APIs.

Out-come. The investigation will provide a basis for the development of novel in vitro methods to model the behaviour of subcutaneously administrated pharmaceutical products.

Amphiphilic Properties of Drug Molecules and Their Self-Assembly in Presence of Phospholipids

Research scientist: Vahid Forooqi Motlaq, MSc
Principal Investigator: Associate Professor Magnus Bergström, Department of Medicinal Chemistry, Uppsala University

Scientific and industrial context. Molecular components such as phospholipids, surfactants, proteins and drug molecules consist of both hydrophilic and lipophilic parts and are involved in various drug delivery systems. As a result, these components are able to self-assemble and interact strongly with one another in ways that usually determine molecular release mechanisms in drug delivery systems.

Aim. The aim of the project is to study the interactions and self-assembly in mixtures of different amphiphilic drug molecules and phospholipid bilayers. The study includes locating the drug molecules near liposomes and other bilayer structures, as well as to investigate their impact on bilayer structure, by mainly using various small-angle scattering techniques.

Outcome. A better fundamental understanding of self-assembly structures and release mechanisms in drug delivery systems.

Novel In Vitro Models for Subcutaneous Administration of Drugs: Transport Properties

Research scientist: Julia Parlow. MSc
Principal investigator: Professor Per Hansson, Department of Medicinal Chemistry, Uppsala University

Scientific and industrial context. Injection into the tissue under the skin is an attractive administration route for many biomolecular drugs available as a result of recent biotechnological progress. The development of drug formulations for this route is challenged by the difficulty to predict the fate of drug formulations after injection due to the complexity of the subcutaneous (SC) environment, the large variability between patients and biomolecular drug properties.

 Aim. The aim is to develop methods to study the transport of drug molecules in biorelevant synthetic models of human SC extracellular matrix, and to use the methods to clarify the key factors governing the transport with respect to interaction with the constituents of the matrix and the interstitial fluid.

Outcome. An in vitro method that can be used to predict the rate of drug absorption in humans after subcutaneous administration.

Self-assembly of therapeutic peptides

Research scientist: Ellen Brunzell, MSc
Principal Investigator: Associate Professor Magnus Bergström, Department of Medicinal Chemistry, Uppsala University

Scientific and industrial context. Aggregation of peptides in pharmaceutical formulations is a problem that affects the product’s shelf life, safety, and efficacy. Aggregated peptides is, in many cases, linked to increased immunogenicity and altered effect. A deeper understanding of mechanisms, causes, and driving factors behind self-assembly of peptides is meaningful to be able to increase their stability in pharmaceutical formulations. Accumulation of peptide aggregates occurs in several neurodegenerative diseases, and an increased knowledge of aggregation could contribute to the research of these illnesses.

Aim. The aim of the project is to characterize the structure of self-assembled peptides by using small-angle scattering measurements, mainly X-ray and neutron scattering. By comparing our results with in vivo methods, the structure of peptide aggregates and its correlation with biological effects can be investigated.

Outcome. Increased understanding of mechanisms behind self-assembly as way to predict peptide aggregation behaviour, and the significance of aggregation on biological response.

Physiologically based biopharmaceutics modeling for subcutaneous drug administration

Research scientist: Ilse Dubbelboer, Researcher
Principal Investigator: Assoc. Prof. Erik Sjögren, Department of Pharmaceutical Biosciences, Uppsala University

Scientific and industrial context. The subcutaneous route of administration is important for  current and future biologics. In addition to being the only option for parenteral self-administration, this route also presents many advantages such as the achievement of prolonged release and the possibility for administration of a wide range of formulations. Still, from a drug development perspective, readily available tools for translation of in vitro and pre-clinical data to clinical performance is still lacking.

Aim. To develop a physiologically based biopharmaceutics model for subcutaneous administration based on the interrelationships between physiology, the pharmacologically active substance and the drug delivery system.

Outcome. A freely accessible physiologically based biopharmaceutics model for subcutaneous drug administration.

Improving FRAP data analysis

Research scientist: Jonas Gernandt, PhD
Principal investigator: Professor Per Hansson, Department of Medicinal Chemistry, Uppsala University

Scientific and industrial context. Fluorescence recovery after photobleaching (FRAP) is a well-established method for measuring self-diffusion in a complex environment. Despite the popularity of the technique, fast and user-friendly software employing the latest developments in FRAP data analysis methodology is not publicly available.

Aim. The project aims to make the latest and most powerful FRAP data analysis methods readily accessible to scientists at little or no cost in workload.

Outcome. Upon completion of the project, a free, open-source tool for high-throughput analysis of FRAP experiments by modern techniques will be made available to the public.

Amphiphilic Drugs in Microgels

Research scientist: Yassir Al-Tikriti, MSc
Principal Investigator: Professor Per Hansson, Department of Medicinal Chemistry, Uppsala University

Scientific and industrial context. Amphiphilic drug molecules is an important group of active substances which are commonly used in cancer therapy, as antidepressants and antihypertensive agents. These molecules have properties in common with regular micelle-forming surfactants but the relationships between their molecular structure and self-assembling properties are not well understood. Polyelectrolyte microgels are interesting as carriers of amphiphilic drugs. To realize their potential as drug delivery systems it is necessary to study the basic principles governing the drug loading and release properties.

Aim. To relate the microstructure and thermodynamic stability of drug self-assemblies in microgels to the molecular properties of drugs and microgel networks and to the mechanisms and kinetics of release under physiological conditions.

Outcome. Release models that contribute to the development of novel release systems for amphiphilic drugs.

Immunogenicity of synthetic long peptides and the role of formulation and structure for efficacy and toxicity

Research scientist: Martin Lord, PhD
Principal investigator: Assistant Professor Sara Mangsbo, Department of Pharmaceutical Biosciences

Scientific and industrial context. To combat bacterial and viral infections, and as of recent, certain forms of cancer, vaccination has become an instrumental tool for eliciting disease-specific adaptive immune responses. One approach is to implement synthetic long peptides (SLPs), which exclusively encompass the immunogenic epitopes derived from one of these proteins, but often also including T and B cell epitopes to evoke a stronger immune stimulation. Thus, making peptide vaccines both more selective and faster to produce than conventional vaccines for pharmaceutical companies and research institutes.

Aim. This project aims to characterize a set of SLPs derived from the SARS-CoV-2 virus, and other peptides by input from industry parties, with respect to to secondary structure, electrostatic charge, and hydrophobicity and how formulation impacts these parameters and their immunogenicity. Longer synthetic peptides can harbor multiple HLA-specific T cell epitopes and formulation and structure could impact efficacy and toxicity.

Outcome. This study will lead to an increased understanding of optimal vaccine formulations for SLPs that best preserve the functional properties but also enhances lymph node drainage by non-cellular transportation within the extracellular matrix. In addition to a potential vaccine, these peptides are also used in assays for predicting T cell responses to SARS-CoV-2 (outside SweDeliver) in a KAW/SciLifeLab funded project.

Novel in vitro methods to understand transport properties of biologics

Research scientist: Enamul Mojumdar, Researcher
Principal investigator: Professor Per Hansson, Department of Medicinal Chemistry, Uppsala University

Aim. To develop in vitro methods to understand transport properties of biologics, e.g., peptides, antibodies etc. on a synthetic hydrogel model of the extracellular matrix of subcutaneous tissue.

Novel In Vitro Models for Subcutaneous Administration of Drugs

Research scientist: Agnes Rodler, PhD
Principal Investigator: Professor Per Hansson, Department of Medicinal Chemistry, Uppsala University

Scientific and industrial context. In drug delivery, the subcutaneous route increasingly supersedes the oral and intravenous routes of drug administration. Contrary to the latter two ways of delivery, there is lack of standardised in vitro model for robust prediction of in vivo absorption and bioavailability of drugs administered subcutaneously.

Aim. By developing a physiologically relevant model of the extracellular matrix we have improved the mechanistic understanding of subcutaneous injection to facilitate the innovation and development of formulations with high bioavailability of the active pharmaceutical ingredient and small variability between patients.

This model targets to identify biophysical factors which affect molecular transport through the interstitial space and to elucidate to which extent drug-extracellular matrix interactions are size- or charge related.

Outcome. An in vitro model capable of predicting in vivo behaviour of subcutaneous injection.