Physical and barrier changes in gastrointestinal mucus induced by the permeation enhancer sodium 8-[(2-hydroxybenzoyl)amino]octanoate (SNAC)

J. S. Mortensen, S. S.R. Bohr, S. Harloff-Helleberg, N. S. Hatzakis, L. Saaby, H. M. Nielsen*

*Corresponding author for this work

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Abstract

Drug delivery systems (DDS) for oral delivery of peptide drugs contain excipients that facilitate and enhance absorption. However, little knowledge exists on how DDS excipients such as permeation enhancers interact with the gastrointestinal mucus barrier. This study aimed to investigate interactions of the permeation enhancer sodium 8-[(2-hydroxybenzoyl)amino]octanoate (SNAC) with ex vivo porcine intestinal mucus (PIM), ex vivo porcine gastric mucus (PGM), as well as with in vitro biosimilar mucus (BM) by profiling their physical and barrier properties upon exposure to SNAC. Bulk mucus permeability studies using the peptides cyclosporine A and vancomycin, ovalbumin as a model protein, as well as fluorescein-isothiocyanate dextrans (FDs) of different molecular weights and different surface charges were conducted in parallel to mucus retention force studies using a texture analyzer, rheological studies, cryo-scanning electron microscopy (cryo-SEM), and single particle tracking of fluorescence-labelled nanoparticles to investigate the effects of the SNAC-mucus interaction. The exposure of SNAC to PIM increased the mucus retention force, storage modulus, viscosity, increased nanoparticle confinement within PIM as well as decreased the permeation of cyclosporine A and ovalbumin through PIM. Surprisingly, the viscosity of PGM and the permeation of cyclosporine A and ovalbumin through PGM was unaffected by the presence of SNAC, thus the effect of SNAC depended on the regional site that mucus was collected from. In the absence of SNAC, the permeation of different molecular weight and differently charged FDs through PIM was comparable to that through BM. However, while bulk permeation of neither of the FDs through PIM was affected by SNAC, the presence of SNAC decreased the permeation of FD4 and increased the permeation of FD150 kDa through BM. Additionally, and in contrast to observations in PIM, nanoparticle confinement within BM remained unaffected by the presence of SNAC. In conclusion, the present study showed that SNAC altered the physical and barrier properties of PIM, but not of PGM. The effects of SNAC in PIM were not observed in the BM in vitro model. Altogether, the study highlights the need for further understanding how permeation enhancers influence the mucus barrier and illustrates that the selected mucus model for such studies should be chosen with care.

Original languageEnglish
JournalJournal of Controlled Release
Volume352
Pages (from-to)163-178
Number of pages16
ISSN0168-3659
DOIs
Publication statusPublished - 2022

Bibliographical note

Funding Information:
The Department of Experimental Medicine (University of Copenhagen, UCPH) are greatly acknowledged for providing pig intestines. Laboratory technician Karina Vissing, scholar student Sylvester Petersen and Master student Lasse Krog (Department of Pharmacy, UCPH) are acknowledged for their help with mucus collection. The Novo Nordisk Foundation is acknowledged for funding the project (Grand Challenge Program NNF16OC0021948 through the Center for Biopharmaceuticals and Biobarriers in Drug Delivery (BioDelivery), UCPH). Additionally, this work was supported by the Lundbeck Foundation (project no. R303-2018-2968 ). Further, the Innovative Medicines Initiative Joint Undertaking ( European Union's Seventh Framework program FP7/2007-2013 and EFPIA: 115363 ) and the Carlsberg Foundation are acknowledged for support.

Funding Information:
The Department of Experimental Medicine (University of Copenhagen, UCPH) are greatly acknowledged for providing pig intestines. Laboratory technician Karina Vissing, scholar student Sylvester Petersen and Master student Lasse Krog (Department of Pharmacy, UCPH) are acknowledged for their help with mucus collection. The Novo Nordisk Foundation is acknowledged for funding the project (Grand Challenge Program NNF16OC0021948 through the Center for Biopharmaceuticals and Biobarriers in Drug Delivery (BioDelivery), UCPH). Additionally, this work was supported by the Lundbeck Foundation (project no. R303-2018-2968). Further, the Innovative Medicines Initiative Joint Undertaking (European Union's Seventh Framework program FP7/2007-2013 and EFPIA: 115363) and the Carlsberg Foundation are acknowledged for support.

Publisher Copyright:
© 2022 The Authors

Keywords

  • Ex vivo porcine gastric mucus
  • Ex vivo porcine intestinal mucus
  • Mucus retention force
  • Permeability
  • Permeation enhancer
  • Rheology
  • Salcaprozate sodium
  • Single particle tracking

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