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Fein KC, Gleeson JP, Newby AN, et al. Intestinal permeation enhancers enable oral delivery of macromolecules up to 70 kDa in size. Eur J Pharm Biopharm. 2021;170:70-76doi: 10.1016/j.ejpb.2021.11.010.
Fein, K. C., Gleeson, J. P., Newby, A. N., & Whitehead, K. A. (2022). Intestinal permeation enhancers enable oral delivery of macromolecules up to 70 kDa in size. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 17070-76. https://doi.org/10.1016/j.ejpb.2021.11.010
Fein, Katherine C, et al. "Intestinal permeation enhancers enable oral delivery of macromolecules up to 70 kDa in size." European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V vol. 170 (2022): 70-76. doi: https://doi.org/10.1016/j.ejpb.2021.11.010
Fein KC, Gleeson JP, Newby AN, Whitehead KA. Intestinal permeation enhancers enable oral delivery of macromolecules up to 70 kDa in size. Eur J Pharm Biopharm. 2022 Jan;170:70-76. doi: 10.1016/j.ejpb.2021.11.010. Epub 2021 Dec 05. PMID: 34879228.
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Eur J Pharm Biopharm. 2022 Jan;170:70-76. doi: 10.1016/j.ejpb.2021.11.010. Epub 2021 Dec 05.

Intestinal permeation enhancers enable oral delivery of macromolecules up to 70 kDa in size.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V

Katherine C Fein, John P Gleeson, Alexandra N Newby, Kathryn A Whitehead

Affiliations

  1. Department of Chemical Engineering, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, United States.
  2. Department of Chemical Engineering, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, United States; Department of Biomedical Engineering, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, United States. Electronic address: [email protected].

PMID: 34879228 DOI: 10.1016/j.ejpb.2021.11.010

Abstract

The decades-long effort to deliver peptide drugs orally has resulted in several clinically successful formulations. These formulations are enabled by the inclusion of permeation enhancers that facilitate the intestinal absorption of peptides. Thus far, these oral peptide drugs have been limited to peptides less than 5 kDa, and it is unclear whether there is an upper bound of protein size that can be delivered with permeation enhancers. In this work, we examined two permeation enhancers, 1-phenylpiperazine (PPZ) and sodium deoxycholate (SDC), for their ability to increase intestinal transport of a model macromolecule (FITC-Dextran) as a function of its size. Specifically, the permeability of dextrans with molecular weights of 4, 10, 40, and 70 kDa was assessed in an in vitro and in vivo model of the intestine. In Caco-2 monolayers, both PPZ and SDC significantly increased the permeability of only FD4 and FD10. However, in mice, PPZ and SDC behaved differently. While SDC improved the absorption of all tested sizes of dextrans, PPZ was effective only for FD4 and FD10. This work is the first report of PPZ as a permeation enhancer in vivo, and it highlights the ability of permeation enhancers to improve the absorption of macromolecules across a broad range of sizes relevant for protein drugs.

Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Keywords: Caco-2; Intestinal permeation enhancers; Oral drug delivery; Pre-clinical intestinal models; absorption enhancers; oral delivery; oral protein delivery; phenylpiperazine; protein delivery; sodium deoxycholate

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