REVIEW article
Front. Drug Saf. Regul.
Sec. Substance-Based Medical Devices
Oral absorption of high molecular weight Polyethylene Glycols: mechanistic, safety and regulatory insights
University of Milan, Milan, Italy
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Abstract
The gastrointestinal absorption of macromolecules represents a major challenge in both drug development and regulatory evaluation, as the intestinal barrier is highly effective in limiting the systemic uptake of large molecules. Nevertheless, understanding the mechanisms that govern macromolecule permeability is essential for assessing the safety, efficacy profile, and regulatory qualification of substance-based healthcare products. Polyethylene glycols (PEGs) represent a useful reference system for understanding the physiological limits of macromolecule absorption and for supporting evidence-based regulatory decision-making. Indeed, PEGs are widely used as excipients and active ingredients in numerous healthcare products due to their chemical stability, low immunogenicity, and good tolerability; however, their therapeutic use is strongly influenced by their gastrointestinal absorption. Low-molecular-weight (MW) PEGs (200–600 g/mol) can be absorbed through the gastrointestinal mucosa and therefore are effective probes for testing GI functionality. On the contrary, high-MW PEGs (e.g., PEG 3350 and PEG 4000), are negligible absorbed, acting as osmotic laxatives. Under Regulation (EU) 2017/745, they are classified as Class IIb substance-based medical devices. This review critically analyzes the current evidence on the gastrointestinal fate of PEGs with different molecular weights and discusses their relevance for the interpretation of macromolecule absorption. The overall evidence is particularly relevant for the regulatory qualification of PEG-containing healthcare products.
Summary
Keywords
Gastrointestinal absorption, MDR Rule 21 classification, medical devices, Osmotic laxatives, Polyethylene glycols (PEG 3350/4000), Safety assessment of high-MW PEGs
Received
09 April 2026
Accepted
13 July 2026
Copyright
© 2026 Gennari, Azari, Casiraghi and Musazzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Chiara Grazia Milena Gennari
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.