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Optimization of miniaturized in vitro assay for the evaluation of drug absorption

Terrmin

HT25

Beskrivning

Aim
To explore the impact of different parameters and conditions on the drug absorption in the established miniaturized in vitro permeation assay, and optimize the assay based on the acquired results.

Background
Lipid-based formulations (LBFs) is one of the commonly used strategies to overcome the low aqueous solubility issue of many active pharmaceutical ingredients (APIs). By incorporating the drug into a mixture of lipid, surfactants and co-solvents, the solubility gets improved and potentially with higher bioavailability as a result. Lipolysis is the standard assay to study the digestion and the drug release of LBFs and to rank the performance. However, the results from the lipolysis assay could fail to predict the rank order of drug absorption from animal studies. One possible reason is the lack of an absorptive receiver in such assays. In our lab, we have developed the enabling absorption (ENA) device, which consists of a donor and a receiver chamber, separated by an artificial membrane or cell membrane. It allows us to investigate the digestion and permeation simultaneously, with good in vitro in vivo correlation (IVIVC) when compared to the LBF studies in pigs and dogs. On top of this, effort was made to develop a miniaturized version of ENA to obtain higher throughput by consuming less materials. In this project we will continue the exploration of different parameters and condition of the smaller version of digestion-permeation assay, with a focus of replacing the animal derived materials with animal-free materials, implementing 3R principles (reduce, refine and replace). The results will be compared with the data from previous in vitro studies and reference in vivo data.

Methods
• Formulation preparation
o Select the drug substance and LBFs in this study, determine the solubility (if needed), prepare the formulation based on the established protocol.
• Digestion-permeation assay
o The experiment will be carried out in the miniaturized setup with modifications from previous version. An alternative is to use µDISS profiler for real time measurement.
• Drug quantification
o Drug release and permeation in µDISS profiler will be measured by UV in real time.
o Drug release and permeation in the miniaturized digestion-permeation device will be measured by HPLC-UV.

The task
The task of the student is to explore the impact of different parameters (assembly, stirring speed) and conditions (buffer, sinking agent) of the permeation assay on drug permeation. A literature study is needed before the start of the experiment. All experimental measurements will be performed in replicates (n?3). The student will use the established protocols, and potentially modify/update the protocol with the supervisors.
Expected results
• Acquire the permeation profile of selected formulations using the permeation setup. Explain how different setups affect the result of ranking orders.
• Contribute to the implementation of 3Rs principles by using animal-free agent to replace animal derived materials.

Huvudområde

Läkemedelsutveckling

Ämne

Läkemedelsformulering och Molekylär galenisk farmaci

Typ

Laborativ studie

Företag

Uppsala University

Ort/Plats

Uppsala

Handledarens namn

Lingxiao Li, Christel Bergström

Handledarens e-post

christel.bergstrom@uu.se

Institution

Institutionen för farmaci

Program

Masterprogram i läkemedelsutveckling

Kurs

Degree project in Drug Discovery and Development 45 c - 3FK044

Omfattning/hp

45hp