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FARMACI Forskerne er opdelt efter fagområde. I farmaci skelnes der mellem Drug Transport & Delivery,
Lægemiddelformulering og Lægemiddelstoftransport i ADME. Der udbydes også projekter fra fysik og
kemi.
Drug Transport & Delivery
Annette Bauer-Brandl ………………………………………………………………………………… 3
Judith Kuntsche ………………………………………………………………………………………….. 4
Martin Brandl …………………………………………………………………………………………….. 5
Paul C. Stein ……………………………………………………………………………………………….. 6
Lægemiddelformulering
René Holm …………………………………………………………………………………………………. 7
Lægemiddelstoftransport i ADME
Bala Krishna Prabhala ……………………………………………………………………………….. 8
Carsten Uhd Nielsen …………………………………………………………………………………. 9
Vejledere fra andre fagområder
Du kan finde beskrivelse af personens forskning i det pågældende katalog.
Adam Cohen Simonsen ……………………………………………………………………………… Fysik
Beate Klösgen …………………………………………………………………………………………….. Fysik
Christine McKenzie ……………………………………………………………………………………. Kemi
Erik Donovan Hedegård ……………………………………………………………………………. Kemi
Himanshu Khandelia …………………………………………………………………………………. Kemi
Jacob Kongsted …………………………………………………………………………………………… Kemi
Poul Nielsen ……………………………………………………………………………………………….. Kemi
Stefan Vogel ………………………………………………………………………………………………… Kemi
Ulla Gro Nielsen …………………………………………………………………………………………. Kemi
email: [email protected]://www.sdu.dk/en/forskning/drug‐transport‐delivery
Example: Solid Phospholipid NanoparticlesFormulation of Nanoparticles for better uptake and better bioavailability of poorly available drug substances:Manufacture of Nanoparticles by Spray Drying In vitro characterization of their properties:• Solid state structure• Solubility• Dissolution Rate• PermeabilityIn vivo bioavailability; IVIVC
Oral Drug Transport & Delivery
Figure 2: SEM micrograph of the SPLN Nanoparticles Figure 3: Nano Spray Dryer
Enabling Formulations: Development;
Preparation; understanding of in vivo performance
Oral dosage form
drug in gastro-intestine
drug in blood circulation
site of action
poorpermeability
non-specific distributionblood brain barrier
poor solubility
solid dispersionscrystals; co-crystalsdrug loaded
ion exchangers(mini)-tablets
partitioningpassive transport
solid state structuressolubilitysolvation
Basic StudiesChallenges Applied Examples
permeability assay
biomimeticbarriers
Oral Drug Dosage Forms (e.g. tablets, and capsules) are the most used drug formulations. However, there are a number of challenges for the drug substance to reach the target site (e.g. receptor). We address these challenges through basic physico‐chemical experiments to characterize both the drug substances themselves and selected (model) drug formulations. Moreover, in order to confirm our understanding and to apply the knowledge, we use in vitro‐models to avoid animal tests.
ABB, 2015
Professor Annette Bauer‐Brandl
Research Group:‐ Drug Transport & Delivery ‐
Formulations and Biopharmaceutics
High Throughput Sceening
Based on our novel artificial barrier Permeapd ® that mimics different biological barriers we have developed a microtiterplate system fir for automated handling.
Advantages:cost‐effective; easy to use; reproducible results; functional stability in presence of “aggressive” excipients
Uses:• in vitro measurement of permeability• Automated High throughput Screening of drug
permeability; data mining
Figure 1: Principle of the PermeaPad™ assay and examples of results; Jacobsen et al., 2020
We want to save the lives of animals by studying drugs and formulations in detail using artificial experimental methods and data modelling.Our novel artificial barrier Permeapd ® mimics the permeability of different biological barriers. We develop models for biopharmaceutical property characterization of drugs and drug formulations to select the most promising ones without the use of animals.
Taken from SDU homepage at:: https://www.sdu.dk/en/om_sdu/fakulteterne/naturvidenskab/nyheder-2020/ny-medicin-uden-dyreforsoeg
In!vitro!testing:!passive!drug!absorption
Professor!!Martin!BrandlDrug!Transport!&!
Drug!Delivery!Systems
Oral!Drug!Delivery!Systems
Experimental!methods!portfolioParenteral!Drug!Delivery:!Nanoparticles
We!aim!at!designing!“smart”!delivery!systems!for!oral!drug!delivery!by!elucidating!the!mechanism!behind!improved!dissolution!and!absorptionrbehaviour.
We!aim!at!improving!parenteral!delivery!of!drugs!via!nanoparticles!!!
email:[email protected]:!http://www.sdu.dk/ansat/mmb
A: paracellular passive diffusion B: transcellular passive diffusion C + F: active transportG: transcytosisH: endocytosis
(from Våbenø, thesis Univ. Tromsø 2004, with permission)
Dispersion in aqueous medium
polymer
Micro- / Nanoparticles
(Super-)saturated Solution
Micelles Drug / Polymer-Complex
Impermeable top block
SemipermeablemembraneFrit
Channel flow
Cross-flow out
MEMBRANE
Solubilized API*
Truly supersaturated API(metastable)
Molecularly dissolved API
Amorphous API
Crystalline API
precipitation
dissolution
(re-) distribution according toaffinity of API to solubilizers
Drop of concentrationdue to precipitation
crys
talliz
atio
n
precipitation
dissolution
Enablingformulation
release
dissolutiondisinte-gration
disinte-gration
?
Amorphous solid dispersions
We!aim!at!developing!inrvitro!tools!for!the!prediction!of!drug!absorption!from!the!instestine.
Gastrointestinal pathways
From A. Holsæter thesis Univ. Tromsø with permission
Liposomal drug carrier
Transfer of lipophilic drug from liposomal drug carrier to model acceptoranalysed by flow field-flow fractionation
Biological compartments: as potential ”sinks” for lipophilic drugs
Lipoprotein plasma protein membrane of red blood cell
• Phospholipid!vesicle!based!permeation!assay• Siderbyrside!permeation!experiment• Drugrtransfer!and!drugrrelease!assays!by!flow!fieldrflow!
fractionation,!size!exclusion!fractionation• Liposome!preparation
• filter!extrusion• Vesicular!phospholipid!gels
• Particle size!analysis (micron!&!submicron)!• Aseptic!techniques• GMPrconform!manufacture!&!qualit assurance!of!
parenteral!drug!formulations
Phospholipid!VesiclerBased!Permeation!Assay
Updated: May 2015
Associate Professor Judith KuntscheTopic: Pharmaceutical Technology
E-mail: [email protected]: http://findresearcher.sdu.dk/portal/da/person/kuntsche
Lipid nanoparticles and liposomes
Parenteral drug delivery Cochleates
Flow field-flow fractionation
200 nm
Nanoemulsion
100 nm
Liposomes
220 nm
Solid lipid nanoparticles
Cubic nanoparticles
200 nm
Types of lipid nanoparticles(state of the lipid matrix)
• Can be prepared from physiologicalcompounds (e.g. glycerides, cholesterolesters, phospholipids).
• Particle size in the nm-size rangefacilitates intravenous administration.
• Purposes:¾ solubilization of poorly water-soluble
drugs,¾ drug targeting (e.g. tumor targeting),¾ enhancement of drug absorption.
• Liposomes can encapsulate bothlipophilic (membrane) and hydrophilic(aqueous core) drugs.
• Lipid nanoparticles have a lipid matrix.
• Separation of molecules and particles in dependence on sizeby applying a cross flow in a thin separation channel.
• Broad size range of about 5 kDa – 1 µm and versatileseparation conditions, no stationary phase.
• Connection with different detectors for comprehensivecharacterization (MALLS, dRI, UV/Vis).
• Focus of research on¾ size determinations (also stability in e.g. serum),¾ quantification of co-existing colloidal structures (e.g.
micelles, nanoparticles, vesicles),¾ drug release and transfer studies.
Analysis of a mixture of polystyrene nanospheres
Theoretical mass ratio:83:13:2:2
Measured mass ratio:82:14:2:2
• Drug solubilization to facilitate intravenous administration(nanoemulsions in clinical use for, e.g. diazepam, propofol andetomidate) -> rapid drug release and no distinct alteration ofdrugs pharmacokinetic profile.
• Drug targeting due to passive accumulation of nanoparticlesin tissues with disturbed endothelia (e.g. solid tumors).
• Focus of research on¾ comprehensive physicochemical characterization (colloidal
structures, morphology, size and size distribution),¾ stability in physiological media (e.g. serum),¾ understanding of the mechanism of drug release and
redistribution at the molecular level.
• Cochleates are cylindrical particles composed of tightly packedphospholipid membranes.
• They are formed by the addition of calcium ions to negativelycharges liposomes, e.g. phosphatidylserine vesicles.
• Due to the tightly packed lipid structure, cochleate cylinderspossess a considerably high physical stability which makesthem very interesting for drug delivery.
• Focus of research on¾ preparation of cochleates and similar lipid particles from
naturally derived lipids (e.g. lower purity),¾ optimization of composition and production parameters
including scaling up, lyophilization and sterilization and¾ drug incorporation and release.
Cochleate formation and morphology
Søren Kristensen (PhD project)
DOPS
PS from soybean lecithin
Redistribution of a hydrophobic model drug (pTHPP) from liposomes to serum
Michelle Toftrup Broholm (MSc project)
Fractionation of pTHPP-loadedliposomes and serum components
Redistribution of pTHPP from liposomesto serum components
Professor René Holm
Topics: Physical pharmacy and advantaged drug delivery
Long acting injectables
The world is our labBachelor and master could be linked up to ongoing research projects, where examples are provided above.
Master thesis can also be conducted in cooperation with another university, e.g. in Belgium, US, UK, Ireland, Switzerland, where you will be a part of the research conducted at that institution.
Industrial projects, can be set up in both Danish and international companies, e.g. ‐ Pharmaceutical engineering and modelling ‐ Formulation design‐ Biopharmaceutics‐ Pharmaceutical processes
Specific project to be defined in cooperation with the company
Preformulation
Lipid based formulations
Long acting injectables provide patients with amore effective treatment when compared to dailyoral administration. Depending on the molecule anumber of different formulation strategies can beapplied – we conduct active research in all ofthem, including formulation evaluation, in vitrodissolution method development andmanufacturing.
Lipid based formulations have been appliedcommercially in a number of products – using the lipidssolubilizing power and the body’s physiology to make arobust formulation. We conduct research in lipid basedformulations with focus on hard to formulatecompounds and combination of approaches, i.e. lipidsuspensions, lipid formulations with crystallizationenhancers, use of liquid crystals to enable oralabsorption of biomolecules.
email: [email protected]: https://portal.findresearcher.sdu.dk/da/persons/ren%C3%A9‐holm
Understanding the formulation system throughwell designed characterisation is the best way tomake a robust formulation.
We look into a number of important formulationfundaments, e.g. characterisation of cyclodextrincomplexation, stability of suspensions oremulsions as a function of stabiliser, solubilityenhancement, measurement of solid solubilities,biophysical investigations on biomolecules informulation relevant buffers etc. all linking towardsnovel and innovative formulations where wedevelop a deep scientific insight.
We change absorption – ADME:
We run research project:Currently, Bachelor or Master Thesis projects could relate to:
- Ibuprofen transport in PC-3 cancer cells– findingthe ibuprofen transporter
- Modulation of efflux transporter activity in cellcultures using pharmaceutical excipients
- Impact of mucus on drug transport andtransporters
- Transporters and SLCs function in hyperosmoticenvironment
- Nutrient transporters in prostate cancer – impactof pH and osmolarity
- Identifying transporters of acamprosate in renalcells
- Novel materials for formulation of drug deliverysystems (Ulla Gro Nielsen and Rasmus BlaaholmNielsen)
Want to see the world?: It is possible to make MasterThesis projects at pharmaceutical companies in Denmark or abroad or at universities abroad. Such projects are not necessarily transporter-related research.
We use or modulate drug transporters:
Solute Carriers (SLCs) and ATP-binding cassette (ABC) transporters affect the ADME properties of many drug substances:
Figure 2: ATP-dependent efflux via P-gp or proton-coupled influx of substrates via PAT1 in an epithelial cell.
Drug transporters may facilitate or limit drug absorption, may facilitate or limit drug distribution, metabolism or excretion, and may transport drug metabolites. Thus cause dose-dependent drug absorption and drug-drug interactions (DDIs) due to effects on ADME properties.
We use in vitro models:Our research use cell cultures cultured at the FKF cell culture facility by Maria Pedersen:
The movement of drug substances in the body may be described by a number of different processes:
Absorption (A), e.g. from the intestineDistribution (D), e.g. into the brainMetabolism (M), e.g. in the liverExcretion (E), e.g. via the kidneyTogether these processes define the exposure of the body to a drug substance, often expressed as the plasma-concentration-time profile:
Figure 1: Vigabatrin plasma concentration in rats after oral administration (Nøhr et al. EJPS, 2015)
Epithelial cell cultures Intestinal Caco-2 cells Renal MDCK cellsProstate cancers PC-3 cell
Modified cell culturesMDCK MRP2 cellsMDCK MDR1 cells
Expression systems for transporters
To quantify drug substance transport we need Assay development Specific inhibitors
To quantify transporters we usePCRWestern Blotting
To Knock-down transporters we use siRNA approaches
E-mail: [email protected]://www.sdu.dk/ansat/cun
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Drug transporters in ADME GroupProfessor Carsten Uhd Nielsen
Maria Pedersen, Ahmed Al-Ali, Rasmus Blaaholm Nielsen & Bala Krishna Prabhala
Solute carriers and efflux transportersaffect permeability, ADME and bioavailability
Transportomics in ADME Asst. Professor Bala [email protected]
Synthesis of novel peptide/peptide-peptoidhybrid (solid phase and in solution) substrates for the delivery of antibiotics in to cells. (In collaboration with Roskilde University and University of Copenhagen)
Generation of gene knockouts of pathogenic bacteria crossing intestinal and blood brain barriers for the identification of biomarkers using metabolomics (Collaboration with BMB, Center for biosustainability, DTU).
Formulation of lipophilic drugs in exosomes and cellular vesicles for topical delivery of drugs. (In collaboration with JAIST, Japan, University of Washington, USA and University fo Copenhagen).
Identification of novel substrates for bacterial SLC transporters (In collaboration with University of Copenhagen).
Database development of drugtransporters, (In collaboration withUniversity of Cambridge and TeknikInstitute Coventry University UK)
Understanding the metabolome andproteome of skin under normal andcarcinogenic conditions (In collaborationwith University of Washington, USA,Odense University Hospital and RoskildeUniversity
Soria et al. 2017
Manuscript under preparation
Kelly et al. 2013
Prabhala et al. 2017
Neo4J Zhao et al. 2014
