Journal
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
Volume 170, Issue -, Pages 70-76Publisher
ELSEVIER
DOI: 10.1016/j.ejpb.2021.11.010
Keywords
Oral drug delivery; Intestinal permeation enhancers; Pre-clinical intestinal models; protein delivery; absorption enhancers; oral delivery; oral protein delivery; Caco-2; phenylpiperazine; sodium deoxycholate
Categories
Funding
- National Science Foundation [1807983]
- National Institutes of Health [DP2-HD098860]
- Direct For Mathematical & Physical Scien
- Division Of Materials Research [1807983] Funding Source: National Science Foundation
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Decades of research on oral peptide drugs have led to clinically successful formulations, often utilizing permeation enhancers to facilitate absorption in the intestines. This study examined the effects of two permeation enhancers on the transport of macromolecules of varying sizes, highlighting their potential to improve the absorption of proteins.
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.
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