In depth mechanistic biopharmaceutical investigation of oral phospholipid-based formulations for poorly soluble drugs

Prof. Dr. Martin Brandl1) and Dr. Ann-Christin Jacobsen1) – University of Southern Denmark, Odense/Denmark

+ Show more

1.

Professor Dr. Martin Brandl and Dr. Ann-Christin JacobsenUniversity of Southern Denmark, Department of Physics, Chemistry and Pharmacy, Campusvej 55, 5230 Odense M, Denmark

People involved

Dr. Ann-Christin Jacobsen  (Postdoc sponsored by the PRC) - University of Southern Denmark, Odense/Denmark

Dr. Paulina Skupin-Mruglaska (collaborator) - Poznan University of Medical Sciences (see PRC project of Dr. Skupin-Mrugalska)

Abstract

The biopharmaceutical behavior of phospholipid-based enabling formulations of poorly soluble drugs is complex due to the gastrointestinal processing of phospholipids (e.g., enzymatic breakdown)1) and the formation of nano-sized structures (e.g., liposomes and mixed micelles)2). Typically, enabling formulations also induce supersaturation, which further increases complexity.

Experimental evidence indicates that drug solubilized by nano-sized structures and molecularly dissolved drug contribute to oral absorption in different ways: The molecularly dissolved drug determines rate and extent of oral absorption and nano-sized structures may act as a reservoir. Traditional biopharmaceutical tools cannot resolve the distribution of the drug between the molecularly dissolved state and drug associated with nano-sized structures nor the related kinetics.

In this project, a biopharmaceutical approach that can resolve how the drug is distributed between different phases and which nano-sized structures evolve during gastrointestinal processing of phospholipid-based enabling formulations will be established (Figure 1)

Figure 1. Schematic overview of the proposed biopharmaceutical characterization approach to obtain an in-depth mechanistic understanding of the performance of phospholipid-based oral formulations.

The approach is based on in vitro lipolysis to mimic the gastrointestinal processing1)3) in combination with two innovative tools: (1) microdialysis sampling to determine the molecularly dissolved drug4) and (2) field flow fractionation (AF4/MALLS)2) to resolve the ultrastructural pattern of co-existing colloidal states during lipolysis.

Benefit for the community

A biopharmaceutical approach will be established that combines in vitro lipolysis, microdialysis sampling and AF4-MALLS. This combination is expected to help formulation experts to gain an in-depth mechanistic understanding of the behavior of phospholipid-based enabling formulations in the gastrointestinal tract. Thereby, hopefully, future development of phospholipid-based enabling formulations can be facilitated.

Visit the supervisors lab

Contact to Drug Transport & Delivery at the University of Southern Denmark.

Prof. Martin Brandl and Dr. Ann-Christin Jacobsen.

References:
1.
Parmentier J, Thomas N, Muellertz A, Fricker G, Rades T, 2012
Exploring the fate of liposomes in the intestine by dynamic in vitro lipolysis
Int. J. Pharm. 437, 253-263
2.
Elvang PA, Jacobsen AC, Bauer-Brandl A, Stein PC, Brandl M, 2018
Co-existing colloidal phases in artificial intestinal fluids assessed by AF4/MALLS and DLS: A systematic study into cholate & (lyso-) phospholipid blends, incorporating celecoxib as a model drug
Eur. J. Pharm. Sci. 120, 61-72
3.
Jacobsen AC, Kabedev A, Sinko PD, Palm JE, Bergström CAS, Teleki A, 2022
Intrinsic lipolysis rate for systematic design of lipid-based formulations
Drug Delivery Transl. Res.
4.
Holzem FL, Schaffland JP, Brandl M, Bauer-Brandl A, Stillhart C, 2022
Microdialysis and nanofiltration allow to distinguish molecularly dissolved from colloid-associated drug concentrations during biomimetic dissolution testing of supersaturating formulations
Eur. J. Pharm. Sci. 174, 106166
Publications derived from the project:
1.
Czajkowski M, Jacobsen AC, Bauer-Brandl A, Brandl M, Skupin-Mrugalska P, 2023
Hydrogenated phospholipid, a promising excipient in amorphous solid dispersions of fenofibrate for oral delivery: Preparation and in-vitro biopharmaceutical characterization
Int. J. Pharm. 644, 123294
previous project
next project