Intestinal Permeation Enhancers for Oral Delivery.....pdf (1.58 MB)

Intestinal permeation enhancers for oral delivery of macromolecules: A comparison between salcaprozate sodium (SNAC) and sodium caprate (C10)

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journal contribution
posted on 16.07.2021, 16:03 by Caroline Twarog, Sarinj Fattah, Joanne Heade, Sam Maher, Elias Fattal, David J Brayden
Salcaprozate sodium (SNAC) and sodium caprate (C10) are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules. Their effects on intestinal epithelia were studied for over 30 years, yet there is still debate over their mechanisms of action. C10 acts via openings of epithelial tight junctions and/or membrane perturbation, while for decades SNAC was thought to increase passive transcellular permeation across small intestinal epithelia based on increased lipophilicity arising from noncovalent macromolecule complexation. More recently, an additional mechanism for SNAC associated with a pH-elevating, monomer-inducing, and pepsin-inhibiting effect in the stomach for oral delivery of semaglutide was advocated. Comparing the two surfactants, we found equivocal evidence for discrete mechanisms at the level of epithelial interactions in the small intestine, especially at the high doses used in vivo. Evidence that one agent is more efficacious compared to the other is not convincing, with tablets containing these PEs inducing single-digit highly variable increases in oral bioavailability of payloads in human trials, although this may be adequate for potent macromolecules. Regarding safety, SNAC has generally regarded as safe (GRAS) status and is Food and Drug Administration (FDA)-approved as a medical food (Eligen®-Vitamin B12, Emisphere, Roseland, NJ, USA), whereas C10 has a long history of use in man, and has food additive status. Evidence for co-absorption of microorganisms in the presence of either SNAC or C10 has not emerged from clinical trials to date, and long-term effects from repeat dosing beyond six months have yet to be assessed. Since there are no obvious scientific reasons to prefer SNAC over C10 in orally delivering a poorly permeable macromolecule, then formulation, manufacturing, and commercial considerations are the key drivers in decision-making.

Funding

Science Foundation Ireland Grant 13/RC/2073, the CÚRAM Center for Medical Devices

EU Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie Grant agreement No 666010

French National Agency of Research and Technology, CIFRE grant number: 2016/0439

Sanofi Pharma

History

Comments

The original article is available at https://www.mdpi.com

Published Citation

Twarog C, Fattah S, Heade J, Maher S, Fattal E, Brayden DJ. Intestinal permeation enhancers for oral delivery of macromolecules: a comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C10). Pharmaceutics. 2019;11(2):78.

Publication Date

13 February 2019

PubMed ID

30781867

Department/Unit

  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Chemistry and Pharmaceutical Sciences
  • Respiratory Medicine

Publisher

MDPI AG

Version

  • Published Version (Version of Record)