Jesper Østergaard
Associate Professor
E-mail: joe(at)farma.ku.dk
Phone: +45 35 33 61 38
Room: 13/510a

Drug – biomacromolcule interactions.
Determination of equilibrium constants and association- and dissociation rate constants. The interaction of a drug substance with a receptor or a protein is usually characterized by a binding or equilibrium constant (K). The equilibrium constant is given by the ratio between the association and the dissociation rate constants (ka/kd). The magnitudes of the rate constants may be of importance to the fate of drug substances in the body. For instance, the dissociation rate constant of a drug – albumin complex may be a determining factor for liver uptake and metabolism of a strongly bound drug. The aim of the project is to develop and validate capillary electrophoresis (CE) and surface plasmon resonance (SPR) methods for the determination of equilibrium and rate constants.
Supervisor: Jesper Østergaard & Henrik Jensen.

Pharmaceutical profiling of drug substances using capillary electrophoresis and electrochemical techniques
The chemical structure of a drug substance determines its degree of interaction with pharmaceutical excipients, e.g. cyclodextrins, surfactants and polymers, propensity for ion pair formation, self association, and distribution in two-phase systems. The objective of the project is to develop new micro techniques based on electrochemistry and capillary electrophoresis for the investigation of distribution and complexation phenomena. The methodologies are characterized by being fast and requiring small amounts of sample only. Hence, they may be used in drug discovery/ early drug development potentially offering a more thorough physical chemical characterization at an earlier time point and a better starting point for subsequent drug development.
Supervisor: Jesper Østergaard & Henrik Jensen.

Adsorption of protein drug compounds to oil-water interfaces
An increasing number of drug compounds under development are based on proteins and other biological macromolecules. This type of drug compounds requires different strategies with respect to development, production and analysis as compared to more traditional drug compounds based on smaller molecules. For example, proteins may change their structure irreversible upon adsorption to interfaces (such as those between water and oil) and thereby loose the pharmacological effect. The purpose of this project is to investigate the adsorption of proteins and other macromolecules to oil-water interfaces using a surface sensitive electrochemical method. Adsorption to the oil-water interface can be compared to adsorption onto modified gold surfaces studied by SPR (Surface Plasmon Resonance) techniques. The adsorption measurements will be supported by studies on protein interactions in aqueous solution in order to investigate how potential excipients may influence the adsorption
 Supervisor: Jesper Østergaard & Henrik Jensen.

Liposome – drug interactions Liposomes consist of a lipid double layer.
The structural characteristics resemble to a large degree those of biological membranes and, consequently, liposomes constitute an attractive model of such membranes. Furthermore, drug delivery systems based on liposome technology has been investigated and utilized for a number of years. The objective of the project is to develop capillary electrophoresis (CE) and surface plasmon resonance (SPR) based micro-analytical methods for investigation of drug – liposome interactions. The methods will be used for characterization of drug – liposome distribution coefficients, membrane adsorption, and membrane permeability studies as well as for the characterization of liposome drug delivery vehicles, e.g. stability, drug incorporation efficiency and membrane leakage.
Supervisor: Jesper Østergaard.

Permeability assessment of poorly water-soluble compounds under solubilizing conditions: getting the correct permeability by correction for the micellar bound fraction
Bile salts, as a natural surfactant in the gastrointestinal tract, play an important role in the absorption processes for compounds with a low aqueous solubility; hence they are applied in a number of in vitro assays used for prediction of oral absorption in the drug discovery phase. One of the absorption screening models is based on the Caco-2 cell line, in which bile salts are added to solubilize the compounds. This, however, may lead to an inaccurate estimate of permeability as only the free drug is available for permeation. The objective of the project is to develop capillary electrophoresis (CE) and/or membrane (dialysis) based methods for the determination of the free fraction of drug in bile salt media in order to obtain improved permeability data for compounds with poor aqueous solubility.
Supervisor: Jesper Østergaard in collaboration with René Holm (H. Lundbeck A/S).

Nanomedicine: New challenges in characterization and development!
During the past few years a revolution has taken place in nanotechnology. By now nanotechnology has matured and can be used in the development of new drug therapies. However, significant challenges related to characterization and development remains. In the present project the focus is on the development of new methods to characterize nanoparticulate drug delivery systems. Traditional analytical chemical procedures are not well-suited for characterization and analysis of these new drugs. New micromethods based on capillary electrophoresis, electrochemistry, surface plasmon resonance and UV-Imaging will therefore be developed. It is of paramount importance that the new methods requires very limited amount of sample as the new nanoparticular drug delivery systems are usually only produced in small amounts. The new methods will allow us to address critical parameters such as incorporation efficiency, release, non-covalent interactions, aggregation and adsorption.
Supervisors: Henrik Jensen & Jesper Østergaard (possibly in collaboration with LEO Pharma).

Design of intra - articularly injectable oil depots providing local prolonged balanced analgesia
Intra-articular injection of oil depot formulations containing two analgesic drug compounds acting by different mechanisms (multimodal analgesia) might contribute to improved effectiveness of postoperative pain control after arthroscopic surgery. In order to create a scientific template for rational design of novel prolonged release drug delivery systems feasible for intra-articular administration the purpose of the project is to i) identify and possibly quantify physicochemical and enzymatic events in vitro which are likely to be operating for drugs/prodrugs injected into the synovial space in the form of oil solutions and to ii) investigate the time dependence of these interrelated events each of which influencing drug residence time in the joint.
Supervisor: Susan Weng Larsen, Claus Selch Larsen & Jesper Østergaard.

Lymphatic targeting and biodistribution of drug nanocarriers based on cubosomes and hexosomes
The major goal is to investigate the potential applicability of cubosomes and hexosomes as drug delivery systems in relation to drug targeting to the lymphatic system after subcutaneous (s.c.) injection. The nanoparticulate systems enveloping internally self-assembled nanostructures are attractive drug nanocarriers. They are aqueous dispersions of inverted types of bicontinuous cubic and hexagonal liquid crystalline phases that are composed of biodegradable lipids enabling tailored solubilization of drugs with different physicochemical properties. This project will tackle ultimate concerns, namely, how advantageous the utilization of these novel drug delivery systems is as opposed to conventional formulations such as liposomes and emulsions. We believe that the proposed research project will advance knowledge on the physicochemical properties of cubosomes and hexosomes, their interactions with the solubilized model drug molecules, and on the nanostructure-activity relationship.
Supervisor: Anan Yaghmur, Claus Selch Larsen, Susan Weng Larsen & Jesper Østergaard (in cooperation with Arto Urtti, CDR, University of Helsinki).

Self-assembled liquid crystalline nanostructures as sustained release injectable formulations
The use of lipidic non-lamellar liquid crystalline phases as drug delivery systems for intra-articular or subcutaneous administration appear attractive due to the sustained release capability and also the high solubilisation capacity of these systems. These unique systems are compatible, biodegradable and bioadhesive matrices that are able to co-exist under equilibrium conditions with excess water and thus they display nanostructures closely related to those observed in biological membranes. The purpose of this project is to design drug-loaded dispersed and non-dispersed liquid crystalline phases as sustained release injectable formulations. To achieve this goal, physicochemical investigations are combined with in vitro release studies and eventually animal experiments.
Supervisor: Anan Yaghmur, Susan Weng Larsen, Jesper Østergaard, Claus Selch Larsen

Development of in vitro release methods for characterization of drug formulation based on self-assembled liquid crystalline nanostructures
Development of in vitro release models for quality control as well as formulation design purposes is a critical activity in the characterization of parenteral depot formulationss. Injectable drug-loaded systems based on lipids which self-assemble in water to form various well-ordered inverted-type nanostructures (e.g. biocontinuous cubic and hexagonal phases) are considered attrative for enhancing the solubilisation of various drugs, targeting to tissues and controlling drug release. The overall purpose of this project is to establish and evaluate in vitro release methods for these lipid drug nanocarriers. This includes i) studying the drug release characteristics using different in vitro models, ii) investigating drug release properties of various nanostructures, and iii) investigating in vitro release of model drug compounds with different physicochemical properties. 
Supervisor: Susan Weng Larsen, Anan Yaghmur, Jesper Østergaard, Claus Selch Larsen

Osteoarthritis – Improved therapy through drug targeting to the articular cartilage
Osteoarthritis is the most common arthritic disorder characterized by irreversible breakdown of the extracellular matrix (ECM) of the articular cartilage. The latter joint tissue is composed of a complex water-filled polymeric network which might constitute a barrier for drug transport to pharmacological targets located within the ECM, i.e. chondrocytes and enzymes secreted by this cell type. Project objective is to investigate the influence of drug molecular size and physicochemical parameters on transport (diffusion) into the cartilage. Also drug affinity to macromolecular structures comprising the cartilage will be investigated in order to obtain an in depth understanding of basic drug properties that might facilitate transport of anti-arthritic drug candidates into the ECM. The experimental work will encompass development of an artificial joint cartilage model for the study of the ability of model drug compounds to enter into this artificial ECM.
Supervisor: Jesper Østergaard, Claus Selch Larsen, Henrik Jensen, Susan Weng Larsen & Anan Yaghmur.

Utility of in vitro drug release methods to characterize in vivo performance of depot formulations for the subcutaneous route of administration
For drug candidates which suffer from poor oral bioavailability (for example biopharmaceuticals) injection might constitute the only realistic route of administration. In case of chronic use administration in the form of a sustained release formulation (depot) is preferable in order to minimize injection frequency. In this project focus is on the design of long-acting suspensions and particularly the design of in situ suspension forming drug delivery systems. The latter formulation principle involves injection of a composite liquid which upon contact with the aqueous tissue fluid forms the suspension at the site of injection. The aim of the project is to develop an in vitro release model to achieve a more in depth understanding of how formulation design as well as physiological parameters influences (i) in situ suspension formation and subsequently drug dissolution rate and (ii) drug transport to the blood capillaries after subcutaneous injection. The experimental work will encompass development of a gel column-based continuous-flow release model allowing diffusion and convective contributions to drug transport to be varied.
Supervisor: Claus Selch Larsen, Eva Lin, Susan Weng Larsen, Jesper Østergaard,

Enhancement of solubility in topical formulations, effect of physicochemical properties of drug molecule and excipients.
Efficacy of dermal drug products is influenced by the formulation vehicle. Delivery of the drug molecule from the topical formulation into the skin tissue is a complex process involving dissolution of drug crystals, partitioning of drug molecules from the formulation into the skin, occlusion and hydration of the skin. Solubility in the vehicle is a key parameter governing the delivery of the drug molecules. The present project focuses on influence of physicochemical properties of drug molecule and excipients on the solubility and drug delivery characteristics of novel topical formulations e.g. nanoparticulate or amorphous systems.
Supervisor: Jesper Østergaard & Hanne Mørck Nielsen (In collaboration with LEO Pharma)