Oral delivery of peptides and proteins: pharmacokinetic boundaries, negative selection, and route triage.

Oral delivery of peptides and proteins has been pursued for over a century due to its noninvasive nature. Despite sustained innovation across multiple technological generations-such as enteric coatings, enzyme inhibitors, permeation enhancers, nanoparticles, and ingestible devices-most oral peptide programs have failed to achieve regulatory or commercial success. The recent approval of oral semaglutide has renewed enthusiasm but introduced a substantial risk of conceptual over-extrapolation. This review critically examines the pharmacokinetic, pharmacodynamic, regulatory, and economic foundations of oral peptide delivery. Three recurrent failure modes explain the historical record: (1) exposure infeasibility when low bioavailability combines with short elimination half-life, preventing accumulation regardless of formulation sophistication; (2) variability-driven regulatory failure when coefficients of variation exceed thresholds compatible with bioequivalence requirements; and (3) dose escalation leading to gastrointestinal toxicity and prohibitive manufacturing costs before therapeutic efficacy is achieved. Oral semaglutide is analyzed as a boundary case rather than a platform validation. Its success reflects a rare alignment of properties: an exceptionally long half-life (∼168 h), high potency, wide therapeutic window, and time-integrated pharmacodynamics that accommodate low and variable absorption. Most peptides lack this constellation. Oral octreotide, approved under restricted maintenance-only labeling, is another boundary case that illustrates these constraints. Emerging macrocyclic peptides (MK-0616, JNJ-77242113) and small molecule GLP-1 agonists (orforglipron) may reshape the competitive landscape. To prevent predictable failure, this review proposes a negative-selection framework that identifies peptides unsuitable for classical oral delivery at an early stage. For excluded molecules, a route-triage strategy directs candidates toward pulmonary, nasal, buccal, or long-acting injectable delivery. Device-mediated swallowed injection systems differ from oral absorption and are evaluated as combination products governed by device reliability rather than pharmacokinetic enhancement. The fundamental conclusion is that the success of oral delivery depends on molecular pharmacology, not on formulation technology. Oral delivery should be pursued when pharmacology permits and abandoned when it does not-a prerequisite for sustainable advancement in the field.