Intestinal permeation enhancers to improve oral bioavailability of macromolecules: reasons for low efficacy in humans

ABSTRACT

Introduction

Intestinal permeation enhancers (PEs) are substances that transiently alter the intestinal epithelial barrier to facilitate permeation of macromolecules with low oral bioavailability (BA). While a number of PEs have progressed to clinical testing in conventional formulations with macromolecules, there has been only low single digit increases in oral BA, irrespective of whether the drug met primary or secondary clinical endpoints.

Areas covered

This article considers the causes of sub-optimal BA of macromolecules from PE dosage forms and suggests approaches that may improve performance in humans.

Expert opinion

Permeation enhancement is most effective when the PE is co-localized with the macromolecule at the epithelial surface. Conditions in the GI tract impede optimal co-localization. Novel delivery systems that limit dilution and spreading of the PE and macromolecule in the small intestine have attempted to replicate promising enhancement efficacy observed in static drug delivery models.

KEYWORDS:

• Intestinal permeability
• oral peptide delivery
• intestinal permeation enhancers
• intestinal epithelium
• oral bioavailability

Article highlights

• Intestinal PEs are currently the most common approach to enable oral delivery of macromolecules in clinical trials.

• PEs are most effective for delivery of small stable macromolecules that have a long plasma half-life.

• PEs are broadly categorized based on mode of action as either transcellular (acting via complexation on mild mucosal aberration) or paracellular (acting via direct interaction with the TJ or through endogenous intracellular signaling mechanisms), or a combination of both.

• Safety concerns related to modulation of intestinal barrier integrity have not yet emerged as a drawback for the narrow selection of PEs that have progressed to clinical trials.

• Conditions in the small intestine and standard dosage form designs limit the optimal co-localization of PE and macromolecule at the intestinal wall, and maybe why there is persistence of low and variable BA in humans.

• A number of devices have been designed to promote optimal co-localization at the intestinal wall.

This box summarizes the key points contained in the article.

Declaration of interest

D Brayden acts as consultants to Pharma researching oral peptides. Past collaborative research in D Brayden’s lab has been funded by Sanofi and Novo-Nordisk. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

D Brayden is funded by the Science Foundation Ireland (SFI) CÚRAM Centre for Medical Devices, grant number 13/RC/2073, by the SFI BiOrbic Centre for Bioeconomy, grant number 16/RC/3889, and by the EU Regional Development Fund.