Jette Jacobsen
Lektor 
E-mail: jeja(at)farma.ku.dk
Telefon: 35 33 62 99
Rum: 13/305a

Oromucosal drug delivery – in vitro in vivo evaluation of oromucosal bioadhesive properties of polymers
There are several advantages when using the oral cavity for local or systemic drug delivery. Biooadhesive drug delivery systems have gained considerable interest as a means to prolong the residence time of an active pharmaceutical ingredient (API) to enhance bioavailability. Validated physiological relevant bioadhesion test methods are requested. The methods seek to evaluate whether a new vehicle has suitable bioadhesive properties or whether varying the dose of API or composition of polymers will affect the bioadhesive properties. The project aims at in vitro in vivo correlation of oromucosal bioadhesivness of selected polymers with different physico-chemical properties (charge, molecular size, chemical structure) in in order to select a few in vitro methods to future rational and fast development of oromucosal bioadhesive drug delivery systems. Initially, an application to authorities for study of human in vivo oromucosal bioadhesiveness must be written. Next, the work will comprise preparation and characterisation of solid formulations (e.g. ordered mixture, spray dried particles, compacts), applying qualitative and quantitative in vitro bioadhesion methods (e.g. zeta potential, tensile strength, rheology, retention, tubidity) based on theories of electrostatic interaction, wetting, diffusion and interpenetration.
The project may be in cooperation with a PhD students already working within this subject.

Keywords: in vitro in vivo correlation, oromucosal drug delivery, polymers, bioadhesive dosage forms, bioadhesion methods, mucin
Supervisors: Jette Jacobsen and ph.d. student

Oromucosal drug delivery – evaluation of predicative in vitro permeability models
Administration of drugs directly into the oral cavity is an attractive route for both local therapy and systemic delivery of drugs which inherently exhibit variable bioavailability after oral dosing, or low bioavailability due to high first-pass metabolism in the gastro-intestinal tract, liver or skin. Further, this route allows fast on-sett of drug action compared to the oral route.
Current research focus on development of in vitro oromucosal models based on a cell culture and a side-by-side diffusion chamber applying animal oromucosal tissue to evaluate buccal drug absorption. Next, the formulations will be tested in an in vivo bioavailability study, and the predictability of the developed in vitro models will be evaluated. Finally, the overall project aims at in vitro in vivo correlations. The project is in cooperation with a PhD students already working within this subject.
The work may comprise development of physiological relevant transport media based on analysis of collected human saliva, selection of bioadhesive excipients and preparation of formulations (e.g. bioadhesive tablet, in situ gel, chewing gum, liquid) hereof, followed by studies of erosion/bioadhesion, drug release, toxicity, in vitro permeability using the developed in vitro models, and possible bioavailability study in animals in collaboration with industrial partner.
The work could also focus on evaluation of excipients (flavours, emulsifiers, absorption enhancers) and texture of medicated chewing gum in collaboration with industrial partner.

Keywords: oromucosal drug delivery, permeability, physiological relevant transport media, mucin, bioadhesive dosage forms, cell culture, side-by-side diffusion chamber, bioavailability
Supervisors: Jette Jacobsen and ph.d. student.

The effect of surfactants on oral absorption of poorly water-soluble drugs
For many poorly soluble drugs aqueous solubility is known to be the limiting factor for absorption and therefore limiting factor for bioavailability. Addition of surfactants to solid dosage forms is one of several techniques to increase the drug dissolution and solubility in the GI tract. This approach overcomes low aqueous solubility by solubilising the drugs in surfactant micelles thereby increasing the total amount of drug in solution. However, there are many in vitro examples of surfactants increasing the total solubility but decreasing the permeability of a drug. Theoretically decrease in permeability should decrease bioavailability but in many cases an increased bioavailability is observed in vivo. The objective of this project is to shed some light upon this apparent paradox between the drugs solubility, permeability and bioavailability. Techniques such ITC, HPLC, UV and fluorescence spectroscopy will be employed to examine the drug in solution and the artificial PAMPA membrane or the Caco-2 cell model will be employed for studies of permeation and absorption. Surfactants with well known physico-chemical properties will be used to test a mechanistic model already in development. The project is in cooperation with the pharmaceutical industry and a PhD student already working within this subject.

Keywords: Drug solubility, Permeation and Absorption
Supervisors: Jette Jacobsen, Anette Müllertz, Peter Madelung (Ph.D. Student)

Dosage forms for the elderly under POLYPHARMACY regimens
The elderly often are afflicted by a number of conditions each requiring one or more drugs in different schedules. To make things more complicated, aging is often associated with loss of mechanical (“cannot pick up the tablet or open the packaging”) and mental function (“cannot remember if the red ones are once or twice daily, was it morning or evening?”). On top of this, many of those patients have difficulties with the sheer number of tablets and capsules they need to swallow and with the amount of water required to wash them down.
In this set of projects, strategies are developed to overcome or alleviate the obstacles. There are many aspects to be addressed: formulation, information gathering, behavior of the patients and so on. There is overlap between this and the project “Easy to swallow formulations for children”.

Keywords: dosage form, formulation, polypharmacy
Supervisors: Daniel Bar-Shalom and Jette Jacobsen

Oromucosal drug delivery using bioadhesive liposomes or liquids for alleviation of xerostomia
Bioadhesive drug delivery systems have gained considerable interest as a means to prolong the residence time of active pharmaceutical ingredients (API) in the oral cavity. These projects will focus on bioadhesive formulations as carrier for excipents to alleviate xerostomia (dry mouth), which can be a very disabling state of health. Xerostomia can be due to e.g. use of medicine or illness (Sjögrens syndrome, radiation therapy). A simple aqueous liquid formulation without bioadhesive excipents is non-efficient due to short retention time in the mouth. Further, commercial available products (i.e. artificial saliva substitutes) have drawbacks; they require frequent application and some are percieved as “sticky” by users. There is a need for new products with improved and prolonged effect since 10-20 % of otherwise healthy adults report a feeling of dry mouth and many medicated persons complain about dry mouth as a side-effect of their medication. The number of dry mouth persons is considerable higher for oromucosal disorders. Dry mouth and oromucosal disorders may lead to other, more severe disorders.
One project focus on liposones as delivery system. Liposomes are small lipid vesicles covered by a bilayer of phospholipids, cholesterol, and a smaller amount of other components. They can be used as biocompatible carriers of both lipophilic and hydrophilic APIs. The project aims at designing and characterizing bioadhesive liposomes for treatment of xerostomia. The work may comprise preparation and characterisation of simple liposomes containing water or a wetting agent, screening bioadhesive excipients for liposomes, testing liposomes with bioadhesive excipients using qualitative and quantitative bioadhesion methods based on theories of electrostatic interaction or wetting.
Another project will examine the factors important to prolonge adhesion of wetting agent in xerostomia focusing on the effect of presence or absence of mucin. The work may comprise preparation and characterisation of solid or liquid bioadhesive formulations, development of in vitro methods for spreadability, studies of bioadhesiveness (retention time and force), and hydration rate.
Methods to be used in both projects could be HPLC, retention model with porcine buccal mucosa, tensile strength, rheology, zeta potential, turbidity, ect. 
Keywords: oromucosal, liposome, drug delivery, bioadhesive, xerostomia
Supervisors: Jette Jacobsen and Huiling Mu (liposome project) or Daniel Bar-Shalom (effect of mucin). Both projects are in collaboration with an external specialist in oromucosal medicine and pathology

Easy to swallow formulations for children
Paediatric patients often cannot swallow the dosage forms they need to take because they are not available in age-specific versions. The problem is exponentially amplified in cases where the child’s condition requires multiple medicines.
Medicines for children are often prepared magisterially. Preparing magisterial combination formulations is problematic as it is difficult to rule out interactions between the different drugs and/or excipients present in the final product.
In this set of projects, strategies are developed to: (a) avoid interactions, (b) effectively mask the taste of the medicines and (c) develop age appropriate dosage forms. There is overlap between this and the project “Dosage forms for the elderly under POLYPHARMACY regimens”.

Keywords: dosage form, paediatric patients, polypharmacy
Supervisors: Daniel Bar-Shalom and Jette Jacobsen

Drug absorption mechanisms – effect of solubilisation in bile and excipients.
Prior to intestinal absorption, poorly soluble drugs are kept solubilised in the intestinal lumen by in micelles formed by components from the bile (bile salts and phospholipids) and administered excipients. We have developed models to simulate the solubilisation of drugs in the small intestine, but now we want to improve our model to also simulate the absorption by use of either cell culture models or intestinal tissue. The Drug should be solubilised in simulated intestinal fluids, composed in a way that it is compatible with the barrier membrane to be used. Barrier membranes can be intestinal tissue mounted in a side-by-side diffusion chamber (i.e. Ussing chamber) or using mucus producing cell culture models (e.g. co-culture of Caco-2 and HT-29 cells). The project aims at studying I) effect of fasted or fed state inclusive degree of digestion of a lipid-based formulation on intestinal absorption of poorly soluble drugs or II) effect of excipients on barrier properties of the mucus layer and/or epithelium. The work may comprise drug solubility studies in physiological relevant transport media, formulation and characterisation of lipid-based formulations, lipolysis of excipents or formulations, toxicity assays, and transport studies of excipients and active pharmaceutical ingredients (API) in tissue based- and cell culture model, quantification of API (scintillation, HPLC-UV, spectrophotometry), and development of methods to measure thickness of mucus.

Keywords: oral drug delivery, permeability, physiological relevant transport media, fed or fasted state, mucus, cell culture, side-by-side diffusion chamber
Supervisors: Jette Jacobsen, Anette Müllertz