Frontiers in drug delivery最新文献

{"title":"Antiparasitic triterpenic ester and ursolic acid lipid nanocapsule design, cytotoxicity, and permeability evaluation for oral delivery.","authors":"Laura Schioppa, Cecilia Bohns Michalowski, Lucia Mamede, Romano Terrasi, Marie-France Hérent, Giulio G Muccioli, Raphaël Frédérick, Michel Frederich, Ana Beloqui, Joelle Quetin-Leclercq","doi":"10.3389/fddev.2026.1846904","DOIUrl":"10.3389/fddev.2026.1846904","url":null,"abstract":"<p><strong>Introduction: </strong>Ursolic acid (UA), the antimalarial triterpenic mixture 8TTE (containing C-27 feruloyl and coumaroyl esters of ursane and oleane skeletons), and the semi-synthetic antitrypanosomal derivative ursolic acid O-phenyl propionate (UAOPP) exhibit high lipophilicity, which may limit their oral bioavailability. This study aimed to develop lipid nanocapsules (LNCs) to improve the solubility, intestinal permeability, and antiparasitic activity of these triterpenic compounds for potential oral delivery.</p><p><strong>Methods: </strong>LNCs formulations containing UA, 8TTE, and UAOPP were prepared and evaluated. A sensitive UPLCx{2013}MS method was developed and validated for selected triterpenes quantification during transport studies across Caco-2 cell monolayers [limit of detection (LOD): 2 nM; limit of quantification (LOQ): 25 nM]. Cytotoxicity and permeability studies were conducted on Caco-2 cells to assess formulation safety and intestinal transport. <i>In vitro</i> antiparasitic activity of free and formulated compounds was evaluated against <i>Plasmodium falciparum</i> and <i>Trypanosoma brucei brucei</i> (Tbb).</p><p><strong>Results and discussion: </strong>The formulations were non-toxic to Caco-2 cells at concentrations up to 2 mg/mL. Permeability studies demonstrated enhanced transport for the formulated triterpenic esters, with permeability increases of up to 2.68-fold, shifting their classification from poorly absorbed to moderately absorbed compounds in humans [apparent permeability coefficient (Papp) > 1 × 10^-6 cm/s]. Free UA showed the highest Papp value (4.95 × 10^-6 cm/s ± 1.29 × 10^-7), but caused epithelial integrity disruption after 2 h of incubation and during the following 48 h, whereas formulated UA induced minimal integrity loss at the same concentration. In antiparasitic assays, blank LNCs exhibited maximum non-toxic concentrations of 165 μg/mL against <i>P. falciparum</i> and 65 μg/mL against Tbb. At these maximum concentrations, formulated UA and 8TTE showed enhanced antiplasmodial activity; however, blank LNCs produced comparable effects. In contrast, UAOPP-loaded LNCs showed significantly improved antitrypanosomal activity by approximately 20% at 2.15 μM (cell viability: 38.20% ± 5.41) compared with free UAOPP (20.38% ± 8.80). These findings suggest that LNCs represent promising oral delivery systems for lipophilic triterpenes. Further in vivo pharmacokinetic and efficacy studies are needed to confirm their therapeutic potential.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1846904"},"PeriodicalIF":4.4,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13272439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148280173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphosulindac (OXT-328) restores the suppressed corneal sensitivity in rabbits with dry eye disease: therapeutic implications.","authors":"Wei Huang, Ziyi Wen, Konstantinos Tourmouzis, Liqun Huang, Sanford M Goldstein, Ernest Natke, Robert Honkanen, Basil Rigas","doi":"10.3389/fddev.2026.1778440","DOIUrl":"10.3389/fddev.2026.1778440","url":null,"abstract":"<p><strong>Background: </strong>The symptoms of dry eye disease (DED) result from activation of ocular sensory nerves and constitute the dominant component of its clinical presentation. We assessed the effect of phosphosulindac (PS), a small molecule efficacious in the treatment of DED in preclinical models, on corneal sensitivity (CS).</p><p><strong>Methods: </strong>CS was determined with a Cochet-Bonnet esthesiometer in New Zealand white (NZW) and Dutch-belted black (DBB) rabbits. DED was induced by Concanavalin A injections into the rabbits' lacrimal glands. Changes in CS, tear osmolarity, tear break up time (TBUT) and Schirmer tear test were measured before and after DED induction. PS in various formulations (emulsions, nanoparticles and hydrogels) and other ocular drugs were applied in eye drop form to normal rabbits and those with DED.</p><p><strong>Results: </strong>nduction of DED caused a decrease in the CS, TBUT time as measured by fluorescein dye, in tear production as measured by Schirmer's tear test and an increase in tear osmolarity. PS markedly restored the suppressed CS in dry eyes. The effect was immediate, fully reversible, lasted ∼26 h and appeared dissociated from its anti-inflammatory properties. The most efficacious formulation was a Carbopol-based hydrogel; cyclodextrin-based and emulsion formulations were also effective. The most optimal dose of PS was 0.2% and the optimal pH was 6.2. None of 7 compounds structurally related to PS affected CS nor did cyclosporine, lifitegrast and artificial tears. PS does not have an anesthetic effect on the cornea. In normal eyes, PS suppressed CS and this effect was concentration-, formulation-, and pH-dependent. Two non-steroidal anti-inflammatory drugs (NSAIDs), ketorolac and bromfenac, and lidocaine suppressed CS in normal but not in dry eyes.</p><p><strong>Conclusion: </strong>PS restores the suppressed CS in dry eyes possiblely by a direct effect on corneal nerves. This effect appears unique to PS, distinct from all tested compounds including the two currently approved drugs for DED. PS, in addition to affecting CS of DED, may improve its symptoms and merits further evaluation for the treatment of DED.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1778440"},"PeriodicalIF":4.4,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13272426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148280130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The fourth controlled release society workshop on oral peptide administration.","authors":"David J Brayden, Stephen T Buckley, Andrew L Lewis","doi":"10.3389/fddev.2026.1860678","DOIUrl":"10.3389/fddev.2026.1860678","url":null,"abstract":"<p><p>The Controlled Release Society (CRS, www.controlledrelease.org) held its fourth iteration of research and development in oral peptide administration on 14 July 2025 in Philadelphia (United States), entitled \"Recent advances in oral peptide delivery: from molecule to market.\" The previous versions were held in 2008, 2014, and 2023 (online), so it is a topic of continuing interest to drug delivery scientists as several oral peptide products have been released in the market over the period despite the enormous technical and commercial challenges involved. The workshop was co-sponsored by Frontiers in Drug Delivery, Novo Nordisk, Johnson and Johnson, Merck, Protagonist Therapeutics, Quotient Sciences, Genentech (Roche), and Bristol-Myers Squibb. It consisted of nine talks and two roundtable sessions. The overall aim of the workshop was to provide an update on the current clinical oral peptide programmes, address mechanistic progress on permeation enhancers, and evaluate the limitations of preclinical bioassays and animal models.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1860678"},"PeriodicalIF":4.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13266291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148266972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A two-tier protection strategy for oral delivery of GLP-1 peptides: lipid-based formulation combined with enteric capsules.","authors":"Camille Dumont, Vanessa Gonzalez, Paula Klatt, Sandrine Picco, Delphine Nombret, Marine Agisson, Euengla Uku, Thibault Saurel, Vincent Jannin","doi":"10.3389/fddev.2026.1770094","DOIUrl":"10.3389/fddev.2026.1770094","url":null,"abstract":"<p><strong>Introduction: </strong>Oral delivery of peptides is a promising alternative to invasive injectable therapies, offering improved patient adherence and convenience. Glucagon-like peptide-1 (GLP-1) analogs, in particular, are highly effective for the management of type 2 diabetes mellitus and obesity, yet their oral bioavailability remains limited by enzymatic degradation and poor intestinal permeability.</p><p><strong>Methods: </strong>In this study, we aimed to design a lipid-based formulation (LBF) of the model GLP-1 analog exenatide (EXE) in its hydrophobic ion-paired (HIP) form, incorporating permeation-enhancing excipients, and evaluate its performance in enteric capsule systems.</p><p><strong>Results and discussion: </strong>EXE-HIP was prepared with sodium docusate (1:4 molar ratio), which increased lipophilicity (log P = 0.9 ± 0.2 vs. -2.9 ± 0.3 for EXE) and markedly improved solubility in lipid excipients, especially in Labrafac™ MC60, a known promoter of intestinal permeability. An optimized LBF composed of 85% Labrafac™ MC60, 10% Kolliphor® RH40, and 5% propylene glycol was developed, with a final particle size of 106 nm, and it was loaded with 6 mg/g solubilized EXE (HIP form) and 20 mg/g of sodium caprate (complementary permeation enhancer). The formulation exhibited significant protection against α-chymotrypsin-mediated degradation, which is consistent with sequestration of EXE-HIP within lipid droplets that limit enzymatic access. Short-term stability studies highlighted formulation-dependent degradation behavior, with higher impurity formation observed for solubilized EXE-HIP than for suspended EXE acetate, particularly at room temperature. To further support oral delivery, customized gelatin/HPMC-AS enteric capsules were engineered to provide a complementary two-tier protection strategy: (i) protecting the peptide and lipid phase from gastric enzymatic degradation and preventing premature dilution in gastric fluids that could displace the peptide from its protective lipid environment, while (ii) ensuring coordinated release of both EXE-HIP and the permeation enhancers at the intestinal absorption site. These capsules met the USP delayed release requirements. Overall, this work presents a promising proof-of-concept oral delivery platform that combines HIP chemistry, lipid-based formulation, and ready-to-use enteric capsule technology to enhance <i>in vitro</i> enzymatic protection of peptide therapeutics, thereby laying the groundwork for future studies to assess bioavailability and therapeutic efficacy <i>in vivo</i>.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1770094"},"PeriodicalIF":4.4,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13236653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148201136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variability in the circulation of cerebrospinal fluid: causes and clinical implications for intraventricular drug delivery.","authors":"Herbert H Engelhard, Olivier Balédent, Matthew T Borzage, Lydia Andrews-Jones, Thomas M Feldsien, Didier R Lefebvre","doi":"10.3389/fddev.2026.1735474","DOIUrl":"10.3389/fddev.2026.1735474","url":null,"abstract":"<p><p>Understanding the many factors affecting the circulation of cerebrospinal fluid (CSF) is important for the treatment of neurological diseases, especially when considering macromolecular pharmaceuticals designed to be delivered directly into the ventricles of the brain. CSF production, pressure, flow, and absorption are tightly linked to the maintenance of brain homeostasis and function. Vascular pulsations help propel CSF through the ventricular system and subarachnoid space, with additional contributions made locally from the coordinated beating of ependymal cilia. Along with the anatomic configuration of the CSF pathways, these are critical determinants for moving therapeutic molecules and vectors to specific regions of the central nervous system (CNS) and their eventual clearance. The advent of phase contrast MRI has revolutionized the understanding of fluid flow in the human CNS, which is affected by circadian rhythm, age, molecular factors, and diseases, to name but a few. In this review, the basic principles and recent advances critical for understanding the considerable variability of CSF circulation are examined, considering differences that are encountered between healthy individuals and due to disease states. While the emphasis is on human data, illustrative comparisons with laboratory animals are made to enable translation of preclinical data to clinical use. This literature review is intended to be applicable to a wide variety of therapeutic agents, from drugs and macromolecules to adeno-associated virus (AAV) capsids, that are intended for intraventricular delivery.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1735474"},"PeriodicalIF":4.4,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13201979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral delivery of biologics: from barrier-limited formulation to active convective transport.","authors":"Sarfaraz K Niazi","doi":"10.3389/fddev.2026.1783113","DOIUrl":"10.3389/fddev.2026.1783113","url":null,"abstract":"<p><p>Biologic therapeutics have transformed the treatment of chronic and life-threatening diseases, yet their clinical use depends almost entirely on parenteral administration. Oral delivery is the preferred route for patients, but it remains challenging for proteins, peptides, and other macromolecules. The gastrointestinal tract blocks their absorption through size exclusion at tight junctions, the hydrophobic lipid bilayer of enterocytes, restricted receptor-mediated uptake, and enzymatic degradation in the lumen and at the brush border. Decades of work on formulation strategies and chemical permeation enhancers have yielded only modest, inconsistent gains. For most biologics, absolute oral bioavailability stays below 1% under physiological conditions. These limitations have prompted a shift from passive transport strategies to active, force-based delivery. Over the past decade, ingestible device platforms have advanced along a clear developmental sequence: early microneedle systems established feasibility in animals, mucus-clearing robotic capsules and liquid-injection auto-injectors extended the approach to liquid biologics in large-animal models, and self-pressurized convective capsules introduced an excipient-driven mechanism requiring no moving parts. This progression culminated in the first Phase 1 human study, which showed that device-based oral delivery of a full-length IgG antibody can match the bioavailability of subcutaneous injection. That result confirms that mechanical bypass of gastrointestinal barriers is achievable in humans and sets a reference point for the field. This review traces the development of active oral biologic delivery systems from early preclinical work to clinical supply, with a focus on convective, force-enabled approaches using self-pressurized capsule technologies. We describe the gastrointestinal barriers that passive strategies cannot overcome, compare device-based platforms by mechanism and evidence, and examine the physical and engineering principles underlying self-pressurized capsule design. We also propose criteria for selecting candidate drugs and address safety, regulatory classification, and manufacturing requirements. The analysis places convective oral delivery within the broader class of force-based platforms and identifies what each system requires to advance.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1783113"},"PeriodicalIF":4.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13180902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analytical similarity as the primary determinant of monoclonal antibody development: toward evidence-efficient regulatory frameworks.","authors":"Sarfaraz K Niazi","doi":"10.3389/fddev.2026.1801236","DOIUrl":"10.3389/fddev.2026.1801236","url":null,"abstract":"<p><p>Monoclonal antibodies (mAbs) constitute the most rapidly expanding and therapeutically impactful class of biological medicines, driven by their exceptional target specificity, modular engineering capabilities, predictable pharmacokinetics facilitated by neonatal Fc receptor (FcRn) recycling, and favorable safety profiles attributable to mechanism-based pharmacology. As foundational patents on blockbuster antibody therapeutics expire, biosimilar antibodies have become a vital mechanism to enhance global accessibility, improve healthcare sustainability, and promote market competition. Simultaneously, regulatory agencies worldwide are substantially restructuring development expectations to emphasize analytical precision, mechanistic understanding, human-relevant methodologies, and ethical nonclinical practices aligned with the 3Rs principles of replacement, reduction, and refinement. This comprehensive review analyzes the convergence of innovator and biosimilar antibody development toward an analytics-first comparability paradigm, mechanism-based safety assessment, and targeted clinical confirmation based on residual uncertainty rather than prescriptive requirements. It systematically incorporates regulatory positions from the United States Food and Drug Administration (FDA), European Medicines Agency (EMA), World Health Organization (WHO), Japan's Pharmaceuticals and Medical Devices Agency (PMDA), Health Canada, and the International Council for Harmonisation (ICH), together with contemporary peer-reviewed research literature. Focus is given to the FDA Modernization Act 2.0, which abolished statutory mandates for animal testing, and recent FDA draft guidance-which are provisional and open to revision pending finalization-addressing streamlined nonclinical safety studies for monospecific antibodies and science-based approaches to waiving comparative clinical efficacy studies (CES). The scientific boundaries distinguishing products amenable to streamlined development from those requiring tailored approaches are delineated, including the exclusion of polyclonal antibody preparations from biosimilar frameworks and the analytical complexities associated with conjugated antibodies and multispecific constructs. Important limitations of analytics-first approaches are also addressed, including scenarios involving heightened immunogenicity risk, novel targets with limited clinical experience, or insufficiently validated pharmacodynamic markers. These developments are examined alongside counterarguments and residual areas of regulatory skepticism. While the trajectory of regulatory reform appears to favor evidence-efficient, science-driven models for antibody development, this review explicitly distinguishes between established regulatory consensus, emerging draft guidance positions, and the author's scholarly interpretation, recognizing that the pace and scope of regulatory change remain subject to ongoing deliberation.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1801236"},"PeriodicalIF":4.4,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanoparticle-mediated mRNA delivery for cancer, autoimmunity, and genetic diseases: a rapid review.","authors":"Okechukwu Paul-Chima Ugwu, Fabian C Ogenyi, Mariam Basajja, Chinyere N Ugwu, Mundu M Mustafa, Michael Ben Okon","doi":"10.3389/fddev.2026.1793322","DOIUrl":"10.3389/fddev.2026.1793322","url":null,"abstract":"<p><strong>Introduction: </strong>Messenger RNA (mRNA) therapeutics have advanced from experimental platforms to clinical application, driven largely by the success of lipid nanoparticle (LNP)-based COVID-19 vaccines. Building on this progress, nanoparticle-mediated mRNA delivery is being extended to non-infectious indications, including oncology, autoimmune disorders, and inherited diseases. However, challenges such as extrahepatic targeting, endosomal escape, repeat-dose immunogenicity, thermostability, and scalable manufacturing remain significant barriers to translation.</p><p><strong>Methods: </strong>A rapid review of peer-reviewed studies and registered clinical trials published between January 2020 and October 2025 was conducted. Searches were performed in PubMed, Scopus, Web of Science Core Collection, and ClinicalTrials.gov using combined terms related to RNA modality and nanoparticle delivery. Eligible studies focused on non-viral nanoparticle platforms for therapeutic, non-infectious mRNA delivery, including applications in protein replacement, genome editing, and immune modulation. Screening yielded 15 studies for inclusion.</p><p><strong>Results: </strong>LNPs remain the most clinically advanced platform for therapeutic mRNA delivery. At the same time, polymeric, peptide-based, exosome-inspired, and hybrid nanoparticle systems are expanding the delivery landscape. Emerging RNA formats, including self-amplifying RNA and circular RNA, show potential to prolong expression at lower doses. Clinically, individualized mRNA neoantigen therapy (mRNA-4157/V940) combined with pembrolizumab reduced recurrence risk by approximately 49% in high-risk melanoma in the KEYNOTE-942 phase 2b trial, supporting phase 3 development. In cystic fibrosis, inhaled CFTR mRNA (ARCT-032) advanced to phase 2 after early phase 1 data demonstrated safety and tolerability.</p><p><strong>Discussion: </strong>Evidence for non-viral nanoparticle-mediated mRNA therapeutics is strong in preclinical research and increasingly promising in clinical applications beyond vaccinology. While LNPs dominate current translation, alternative carriers and improved RNA formats may broaden tissue targeting and therapeutic durability. Advances in biodegradable ionisable lipids, organ-selective LNPs, and lyophilised or solid formulations are being developed to address persistent delivery and manufacturing constraints. As the field matures, regulatory and policy frameworks will need to align with therapeutic endpoints and support long-term safety monitoring.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1793322"},"PeriodicalIF":4.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13079284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147700403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating the complexity of oral peptide delivery: challenges and strategies to enhance oral bioavailability.","authors":"Noor-Ul-Ain Khalid, Edgardo Rivera-Delgado, Thomas von Erlach","doi":"10.3389/fddev.2026.1809842","DOIUrl":"10.3389/fddev.2026.1809842","url":null,"abstract":"<p><p>Peptide therapeutics have emerged as a rapidly expanding drug class capable of modulating highly specific and previously inaccessible molecular targets. Maximizing the clinical and commercial potential of therapeutics, particularly in chronic indications, requires patient-friendly routes of administration with oral delivery often being preferred for its non-invasive nature. Peptides, however, often exhibit unfavorable physicochemical properties for epithelial permeability, paired with high polarity, charge, molecular size, and proteolytic instability. These factors collectively result in low and often insufficient systemic bioavailability. Recent advances in peptide chemistry have shifted the landscape of oral delivery. Structural modifications that enhance potency, metabolic stability, and half-life have enabled therapeutic efficacy even at low single-digit oral bioavailability, as demonstrated by clinically successful and late-stage candidates. Consequently, the central challenge is no longer feasibility, but optimization through designing formulation strategies that are mechanistically aligned with the physicochemical and pharmacokinetic properties of individual peptides. This review examines the key scientific barriers to oral peptide absorption and evaluates emerging strategies to address them, focusing on three interconnected domains: (1) functional excipients to overcome biological barriers; (2) translation of liquid prototypes into robust solid dosage formulations; and (3) integration of <i>in vitro</i>, <i>in vivo</i>, and computational tools to improve predictive accuracy and accelerate development. Collectively, these approaches outline a framework for data-driven optimization and potential route to de-risk translation of oral peptide therapeutics.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1809842"},"PeriodicalIF":4.4,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13055606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral delivery of peptides and proteins: pharmacokinetic boundaries, negative selection, and route triage.","authors":"Sarfaraz K Niazi","doi":"10.3389/fddev.2026.1776167","DOIUrl":"10.3389/fddev.2026.1776167","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"6 ","pages":"1776167"},"PeriodicalIF":4.4,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13047097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147624868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}