Farmaci. Forskerne er opdelt efter fagområde. I farmaci skelnes der mellem teknologisk farmaci og lægemiddel-stof-transport. Teknologisk farmaci

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1 Farmaci Forskerne er opdelt efter fagområde. I farmaci skelnes der mellem teknologisk farmaci og lægemiddel-stof-transport. Teknologisk farmaci Annette Bauer-Brandl... 2 Martin Brandl... 3 Judith Kuntsche... 4 Lægemiddel-stof-transport Carsten Uhd Nielsen... 5 Bente Steffansen... 6

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3 Professor!!Martin!Brandl Drug!Transport!&! Drug!Delivery!Systems Updated: May 2015 Oral!Drug!Delivery!Systems We!aim!at!designing! smart!delivery!systems!for!oral!drug! delivery!by!elucidating!the!mechanism!behind!improved! dissolution!and!absorptionrbehaviour. In!vitro!testing:!passive!drug!absorption We!aim!at!developing!inrvitro!tools!for!the!prediction!of! drug!absorption!from!the!instestine. Amorphous solid dispersions Gastrointestinal pathways Dispersion in aqueous medium polyme r A: paracellular passive diffusion B: transcellular passive diffusion C + F: active transport G: transcytosis H: endocytosis (from Våbenø, thesis Univ. Tromsø 2004, with permission) Micro- / Nanopartic les (Super- )saturated Solution Micelles Drug / Polymer- Complex Enabling formulation disintegration disintegration Crystalline API crystallization release dissolution dissolution precipitation Solubilized API* (re-) distribution according to affinity of API to solubilizers Molecularly dissolved API Drop of concentration due to precipitation? M E M B R A N E Phospholipid!VesiclerBased!Permeation!Assay Amorphous API dissolution precipitation Truly supersaturated API (metastable) Parenteral!Drug!Delivery:!Nanoparticles We!aim!at!improving!parenteral!delivery!of!drugs!via! nanoparticles!!! Liposomal drug carrier Transfer of lipophilic drug from liposomal drug carrier to model acceptor analysed by flow field-flow fractionation Experimental!methods!portfolio 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 Impermeable top block From A. Holsæter thesis Univ. Tromsø with permission Channel flow Biological compartments: as potential sinks for lipophilic drugs Semipermeable membrane Frit Lipoprotein plasma protein membrane of red blood cell Cross-flow out web:! !mmb@sdu.dk

4 AssociateProfessorJudithKuntsche Topic:PharmaceuticalTechnology Lipidnanoparticlesandliposomes 220 nm Nanoemulsion 200 nm Solid lipid nanoparticles Cubic nanoparticles Can be prepared from physiological compounds (e.g. glycerides, cholesterol esters, phospholipids). Particle size in the nmsize range facilitates intravenous administration. Purposes: solubilization of poorly watersoluble drugs, drug targeting (e.g. tumor targeting), enhancement of drug absorption. Liposomes can encapsulate both lipophilic (membrane) and hydrophilic (aqueous core) drugs. Lipid nanoparticles have a lipid matrix. Flowfieldflowfractionation Separation of molecules and particles in dependence on size by applying a cross flow in a thin separation channel. Broad size range of about 5 kda 1 m and versatile separation conditions, no stationary phase. Connection with different detectors for comprehensive characterization (MALLS, dri, UV/Vis). Focus of research on size determinations (also stability in e.g. serum), quantification of coexisting colloidal structures (e.g. micelles, nanoparticles, vesicles), drug release and transfer studies. Analysisofamixtureofpolystyrenenanospheres 200 nm Liposomes Typesoflipidnanoparticles (stateofthelipidmatrix) Theoreticalmassratio: 83:13:2:2 Measuredmassratio: 82:14:2:2 100 nm Parenteraldrugdelivery Drug solubilization to facilitate intravenous administration (nanoemulsions in clinical use for, e.g. diazepam, propofol and etomidate) > rapid drug release and no distinct alteration of drugs pharmacokinetic profile. Drug targeting due to passive accumulation of nanoparticles in tissues with disturbed endothelia (e.g. solid tumors). Focus of research on comprehensive physicochemical characterization (colloidal structures, morphology, size and size distribution), interactions with physiological media (e.g. serum), understanding of mechanism of drug release and redistribution at the molecular level. Evaluationofefficiencyofnanoparticlepegylation Incubation ofsmecticlipid nanoparticles(nonpegylated) withdspempegmicelles pegylatednanoparticlesand excessmicelles (Trans)dermaldrugdelivery The skin presents an attractive administration route (painless and easy drug administration). The tight skin barrier presents the main challenge especially for transdermal drug delivery. Focus of research on lipidbased formulations (e.g. deformable vesicles and cubic nanoparticles) for (trans)dermal drug delivery, development and optimization of in vitro skin models (e.g. epidermal model based on rat keratinocytes, REK). REKorganotypicculture(ROC) Cultivation of ROC Morphology ofhuman(left)androc(right) epiderms Separation and quantification 10 μm 10 μm web: kuntsche@sdu.dk

5 Professor Carsten Uhd Nielsen Drug transporters in ADME In Vitro models and In Vivo impact ADME Drug Transporters The movement of drug substances in the body may be described by a number of different processes: Absorption (A), e.g. from the intestine Distribution (D), e.g. into the brain Metabolism (M), e.g. in the liver Excretion (E), e.g. via the kidney Toget her t hese processes define t he exposure of the body to a drug substance, often expressed as the plasma-concentration-time profile. Solut e Carriers (SLCs) and ATP-binding cassette (ABC) transporters affect the ADME properties of many drug substances: Figure 2: ATP-dependent efflux via P-gp and proton-coupled influx of substrates via PAT1 in an epithelial cell. Figure 1: Vigabatrin plasma concentration in rats after oral administration (Nøhr et al. EJPS, 2015) In vitro models in vivo impact The research aims to explain the role of transporters in defining ADME properties of different compound classes and to develop st rategies t o modulate t ransporter function or activity, e.g. in the intestine by formulation design. Therefore we need: - Expression systems for transporters - Assay development - Specific inhibitors - Epithelial cell cultures to investigate transporters - Modified cell cultures 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 distribution, metabolism or elimination. Project s Currently, Master Thesis projects could relate to: - Transport of GABA-mimeticsacross renal or intestinal cell models - Charact erizat ion of renal models t o predict renal clearance - Modulation of efflux transporter activity in Caco- 2 cell monolayers using polymers - Absorptive versus secretory transport of FDArecommended markers of efflux transporters in intestinal or renal cell lines - In vivo studies in animal models (rat, pig) - In vivo studies in KO-animals It is possible to make projects in collaboration with pharmaceutical companies in Denmark (e.g. with Dr. René Holm at H. Lundbeck, Valby) and research groups abroad. Such projects are not necessarily related to transporter-related research.

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