{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T11:19:36Z","timestamp":1787915976653,"version":"build-2784847793"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Drug Saf. Regul."],"abstract":"<jats:p>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 (lMW) PEGs (200\u2013600 g\/mol) can be absorbed through the gastrointestinal mucosa and therefore are effective probes for testing gastrointestinal functionality. On the contrary, high-MW (hMW) PEGs (e.g., polyethylene glycol 3350 and PEG 4000), are negligible absorbed, acting as osmotic laxatives. Under Regulation (EU) 2017\/745, hMW PEGs 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.<\/jats:p>","DOI":"10.3389\/fdsfr.2026.1851318","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T11:01:51Z","timestamp":1787914911000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Oral absorption of high molecular weight polyethylene glycols: mechanistic, safety and regulatory insights"],"prefix":"10.3389","volume":"6","author":[{"given":"Chiara G. 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