Enabling oral delivery of peptides by designing phospholipid complexes for self-emulsifying drug delivery systems

Prof. Dr. A. Müllertz1), University of Copenhagen/Denmark

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1.

Prof. Dr. Anette MüllertzDepartment of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen/Denmark

People involved

Venkatasubramanian Ramakrishnan (PhD fellow sponsored by the PRC) - University of Copenhagen, Denmark (venkatasubramanian.ramakrishnan@sund.ku.dk)

Abstract

Oral delivery of peptides is desired in many therapeutic regimes but is challenged by the physical-chemical properties of the peptides, resulting in low absorption. Low gastric pH and proteases distributed in the entire gastro-intestinal tract can degrade orally administrated peptides.1)2)3) Tight junctions connecting the enterocytes in the small intestine impede the uptake of peptides, necessitating the use of permeation enhancers in the formulation. One possible way of increasing peptide absorption after oral dosing is by lipophilizing the peptides and subsequent incorporation of the complexes into self-emulsifying drug delivery systems (SEDDS) as a final delivery system.4)5) The SEDDS can be designed and functionalized as to have the desired properties, that are inclusion of permeation enhancers, protection of the peptide from proteolysis, delay of digestion of the lipids, and mucoadhesive properties. In this project lipophilic peptide complexes using natural phospholipids or mono-acyl phospholipids will be developed and these complexes will be incorporated into SEDDS. This project further includes identification of the ideal complexing agent (phospholipids or mono-acyl phospholipids) for relevant peptides and optimization of the SEDDS to achieve the desired drug delivery profile. Selected SEDDS will be tested in animal models (rats), both for assessing the mechanism behind peptide absorption and for evaluating the pharmaco-kinetics after oral dosing.

The overall aim of the project is to increase the oral bioavailability of selected peptides by complexing them with phospholipids and mono-acyl phospholipids, respectively, and subsequent incorporation of the complex into self-emulsifying drug delivery systems

Benefit for the community

This project will lead to an increased understanding of how to enable oral peptide delivery, which ultimately will be of benefit to patients.

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References:
1.
Li P, Tan A, Prestidge CA, Nielsen HM, Müllertz A, 2014
Self-nanoemulsifying drug delivery systems for oral insulin delivery: in vitro and in vivo evaluations of enteric coating and drug loading
Int. J. Pharm. 477, 390–398
2.
Welling SH, Hubálek F, Jacobsen J, Brayden DJ, Rahbek UL, Buckley ST, 2014
The role of citric acid in oral peptide and protein formulations: Relationship between calcium chelation and proteolysis inhibition
Eur. J. Pharm. Biopharm. 86, 544–551
3.
Li P, Nielsen HM, Fano M, Müllertz A, 2013
Preparation and characterization of insulin-surfactant complexes for loading into lipid-based drug delivery systems
J. Pharm. Sci. 102, 2689–2698
4.
Liu J, Hirschberger C, Fanø M, Mu H, Müllertz A, 2020
Evaluation of self-emulsifying drug delivery systems for oral insulin delivery using an in vitro model simulating the intestinal proteolysis
Eur. J. Pharm. Sci. 147, 105272
5.
Liu J, Werner U, Funke M, Besenius M, Saaby L, Fanø M, Mu H, Müllertz A, 2019
SEDDS for intestinal absorption of insulin: Application of Caco-2 and Caco-2/HT29 co-culture monolayers and intra-jejunal instillation in rats
Int. J. Pharm. 560, 377-384
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