Pharmaceutical Research最新文献

{"title":"Syn-Anti Conformational Equilibrium of Indomethacin: A Combined NOESY and Quantum Chemical Study.","authors":"Aleksey Kovalev, Konstantin Belov, Yoshio Barrera, Savaş Kaya, Ilya Khodov","doi":"10.1007/s11095-026-04162-9","DOIUrl":"10.1007/s11095-026-04162-9","url":null,"abstract":"<p><strong>Purpose: </strong>To elucidate the conformational equilibrium of Indomethacin in solution and to establish its relationship with solvent environment and solid-state polymorphism.</p><p><strong>Methods: </strong>A combined experimental-computational approach was employed. One- and two-dimensional NOESY NMR spectroscopy were used to quantify cross-relaxation rates and derive conformation-sensitive internuclear distances in DMSO-d6 and CDCl3. Conformer populations were determined using the initial rate approximation and isolated spin-pair approximation. Quantum-chemical calculations based on Density Functional Theory (B3LYP-D3(BJ)/def2-TZVP, SMD solvation model) were performed to evaluate conformer energetics and solvent effects.</p><p><strong>Results: </strong>Two conformer families, syn- and anti-, were identified as key structural motifs governing indomethacin behavior. InDMSO-d6, the syn-conformer dominates (80.8%), whereas in CDCl3 the equilibrium shifts toward nearly equal populations (51.5% syn, 48.5% anti), revealing a strong solvent-dependent effect. Experimentally derived NOESY distances showed excellent agreement with computed geometries. DFT calculations confirmed the energetic preference of syn-type conformers while demonstrating significant solvent-induced changes in relative stability. Importantly, a direct correlation between solution-phase conformational equilibrium and known polymorphic forms was established.</p><p><strong>Conclusion: </strong>This study demonstrates that solvent-controlled conformational equilibria play a probable role in determining the solid-state forms of indomethacin. The integrated NOESY-DFT methodology provides a robust and quantitative framework for conformational analysis and offers a predictive tool for rational design and optimization of pharmaceutical solid forms.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3317-3332"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148631297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Brain Distribution of a Purine-Derived Neuroprotective Agent after Intranasal Administration in Neonatal Rats with Hypoxic-Ischemic Brain Injury.","authors":"Auriane Maïza, Clemence Disdier, Amalia Tsintzou, Anvi Laetitia Nguyen, Alain Pruvost, Frederic Théodoro, Zexi Zang, Bingqing Wang, Nassima Oumata, Hervé Galons, Barbara S Stonestreet, Aloïse Mabondzo, Xiaodi F Chen","doi":"10.1007/s11095-026-04163-8","DOIUrl":"10.1007/s11095-026-04163-8","url":null,"abstract":"<p><strong>Purpose: </strong>Hypoxic-ischemic (HI) brain injury results in death and lifelong disabilities in newborns. Pharmaceutical agents are not available to treat HI brain injury. We reported that intraperitoneal (IP) BRT_002 is neuroprotective after HI in neonatal rodents. We examined whether intranasal (IN) BRT_002 provides adequate exposure by measuring plasma/brain PK, brain distribution, brain-to-plasma ratios, and hemispheric volume loss after HI, and compared results to our published findings after IP administration.</p><p><strong>Methods: </strong>Metabolic stability of BRT_002 and its metabolite BRT_001 was examined in rat and human liver microsomes. Postnatal day P7 sham or HI-exposed rats given IN BRT_002 (30 mg/kg) had plasma and ipsilateral brain BRT_002/BRT_001 quantified by LC-MS/MS at 1, 2, 6, and 24 h along with PK parameters (C_max, AUC_tot, t_1/2) and brain-to-plasma ratios derived. IN BRT_002 was given at 0, 24, and 48 h after HI to a separate group with hemispheric volume loss (P10, Nissl) and sex determined.</p><p><strong>Results: </strong>IN BRT_002 resulted in lower plasma and brain exposure (lower C_max and AUC_tot) with minimal levels at 24 h compared to IP administration in Sham and HI animals. Brain BRT_001 exposure increased slightly with limited effects on elimination kinetics after HI. Plasma PK did not show effects by sex, but sex affected select brain/injury determinations. IN BRT_002 did not reduce HI hemispheric volume loss.</p><p><strong>Conclusion: </strong>IN BRT_002 administration produced limited brain exposure to BRT_001 and did not provide neuroprotection after HI. These findings emphasize the importance of PK-guided validation for brain exposures, targets, and neuroprotection when drugs are given by the IN route.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3173-3191"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Controlled Release of the IL-1R Antagonist, Anakinra, from Microgels with an Extended Intra-articular Residence Time.","authors":"Ruben J Trujillo, Sara Lok, Lawrence J Bonassar, David Putnam","doi":"10.1007/s11095-026-04196-z","DOIUrl":"10.1007/s11095-026-04196-z","url":null,"abstract":"<p><strong>Purpose: </strong>To establish intra-articularly injected microgel compositions that can control the rate of release of anakinra, a protein-based IL-1R antagonist, at therapeutically relevant concentrations for an extended period of time.</p><p><strong>Methods: </strong>Uptake and release of the IL-1Ra from microgels was tuned by simple post-synthesis modifications via the addition of calcium chloride after protein loading, or conjugation of small molecules to existing microgels to study the effects of negative (unmodified), positive (dimethylethylenediamine, agmatine), polar (ethanolamine), and non-polar (phenethylamine) side chains on protein delivery.</p><p><strong>Results: </strong>Microgels modified with phenethylamine enhanced the loading capacity of the IL-1Ra to 242%. Both calcium-treated and small molecule-modified microgels had a decrease in initial burst release from the microgel matrix, and both extended the release of IL-1Ra from 6 h for unmodified microgels to over 60 days within the active therapeutic index of the drug. Microgels persist in the joint space for at least 8 weeks, and follow a bi-exponential decay curve with a ß half-life of 93.2 days.</p><p><strong>Conclusions: </strong>These findings demonstrate the application of simple post-synthesis modifications for improved drug delivery via polyanionic microgels, and support the potential use of poly(acrylic acid) microgels as intra-articular drug delivery vehicles for osteoarthritis treatment.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2967-2988"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Federated Estimation of Population Pharmacokinetic Models with Exact Equivalence to Pooled-Data Analysis.","authors":"Yuta Nakamaru, Mizuki Uno, Yiran Song, Kanako So, Tomoko Kita, Fumiyoshi Yamashita","doi":"10.1007/s11095-026-04203-3","DOIUrl":"10.1007/s11095-026-04203-3","url":null,"abstract":"<p><strong>Purpose: </strong>Population pharmacokinetic (PopPK) analysis relies on nonlinear mixed-effects modeling of pooled data; however, sharing subject-level data across sites is often restricted. This study develops a federated framework that exactly recovers the global objective function corresponding to centralized pooled-data analysis, thereby yielding identical parameter estimates without sharing subject-level data.</p><p><strong>Methods: </strong>Each site computes its local contributions to the global objective function and corresponding gradients. A central server aggregates these quantities to reconstruct the global objective function and gradient at each parameter value. Performance was evaluated using simulations of a one-compartment oral model under two multi-site scenarios: heterogeneous sparse sampling and between-site heterogeneity in covariate distribution. Federated estimation was compared with centralized pooled-data estimation, independent site-specific estimation, and weighted combination of site-specific estimates and variances. Parameter uncertainty was assessed using bootstrap resampling.</p><p><strong>Results: </strong>Across scenarios, federated estimation yielded parameter estimates and bootstrap confidence intervals that closely matched with those from centralized pooled-data estimation for fixed effects, between-subject variability, and residual error. In contrast, independent site-specific estimation showed deviations under certain conditions, and weighted pooling of site-specific estimates did not reproduce centralized variance estimates.</p><p><strong>Conclusions: </strong>The proposed federated framework enables mathematically equivalent PopPK estimation without sharing subject-level data.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2957-2966"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amorphous Solid Dispersions in Non-Oral Drug Delivery: A Critical Review Bridging Mechanistic Advantages and Gaps in Translational Evidence.","authors":"Bruno Vincenzo Fiod Riccio, Aline Franciane Leão, Ana Beatriz Klosowski, Fernanda Isadora Boni, Leonardo Miziara Barboza Ferreira, Maurício Palmeira Chaves de Souza, Priscileila Colerato Ferrari, Marlus Chorilli","doi":"10.1007/s11095-026-04200-6","DOIUrl":"10.1007/s11095-026-04200-6","url":null,"abstract":"<p><strong>Background: </strong>Non-oral drug delivery routes, including cutaneous, transdermal, pulmonary, ophthalmic, parenteral, vaginal, and rectal administration, are essential for both local and systemic therapies but impose route-specific constraints on drug dissolution, retention, permeation, clearance, and exposure. Amorphous solid dispersions (ASDs),extensively investigated for oral delivery, may improve the performance of poorly water-soluble drugs by stabilizing high-energy amorphous states, increasing apparent solubility, and promoting transient supersaturation. However, their translation into non-oral dosage forms remains fragmented and largely preclinical.</p><p><strong>Objective: </strong>This review critically examines the potential, limitations, and translational challenges of ASDs for non-oral drug delivery, with emphasis on the physicochemical, biopharmaceutical, pharmaceutical, and route-dependent determinants governing their performance.</p><p><strong>Scope: </strong>Key aspects discussed include drug-polymer interactions, molecular mobility, phase behavior, water uptake, crystallization, interactions with secondary pharmaceutical bases, and route-specific pharmacokinetic/pharmacodynamic relationships. Current evidence is examined across dermal, transdermal, pulmonary, ophthalmic, vaginal, rectal, and parenteral delivery systems. Parenteral administration is considered a special case encompassing sterile suspensions, reconstitutable systems, microneedles, implants, and depot-forming formulations. Recent technological advances, patent and industrial landscapes, and the potential extension of ASD principles to peptides, proteins, biologics, and other complex molecular entities are also addressed. ASDs are further positioned in relation to alternative and complementary solubility-enhancing technologies, including nanoparticles, nanocrystals, cocrystals, cyclodextrins, micelles, lipid-based systems, emulsions, solvents, and cosolvents.</p><p><strong>Conclusions: </strong>ASDs off er a promising but still underdeveloped strategy for improving non-oral delivery of poorly soluble drugs. Their successful translation will depend not only on achieving and maintaining favorable amorphousstates and supersaturation, but also on converting these physicochemical advantages into route-specific drug exposure, therapeutic benefit, formulation stability, manufacturability, and clinically meaningful outcomes.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3057-3081"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights into Membrane- and Release-Controlled Drug Permeation from Ketoprofen-Lidocaine Eutectic Fluids.","authors":"Masahiro Sugino, Yui Igarashi, Suzuka Shiina, Shou Nakadate, Yutaka Inoue, Tetsuya Watanabe","doi":"10.1007/s11095-026-04150-z","DOIUrl":"10.1007/s11095-026-04150-z","url":null,"abstract":"<p><strong>Purpose: </strong>Eutectic fluids (EFs) are liquid pharmaceutical systems formed through intermolecular interactions between their components. This study aims to clarify the mechanistic basis of membrane- and release-controlled drug permeation from the ketoprofen-lidocaine (KP-LD) EFs by characterizing their physicochemical properties and molecular interactions.</p><p><strong>Methods: </strong>Two types of liquid EFs were prepared by mixing and heating KP with LD. The prepared EFs were characterized using thermodynamic, rheological, and NMR-based analyses to obtain parameters related to phase behavior, viscosity, molecular dynamics, and molecular diffusion. Silicone membrane permeation behavior was evaluated to elucidate how these physicochemical properties influence membrane‑controlled and release‑controlled drug permeation.</p><p><strong>Results: </strong>Differential scanning calorimetry indicated the absence of detectable crystallinity, and the mixtures appeared to form a homogeneous liquid phase. Rheological analysis revealed a Newtonian flow behavior, and the viscosity of EF_A (KP:LD = 1:1) was markedly lower than that of EF_B (KP:LD = 2:1). Permeation studies showed KP permeation was membrane-controlled, whereas LD permeation was release-controlled within the EFs, allowing for the calculation of its diffusion coefficient. Analyses of ¹H-¹H NOESY and DOSY suggested close spatial proximity and weak intermolecular interactions, indicating cooperative molecular dynamics between KP and LD.</p><p><strong>Conclusion: </strong>EFs examined in this study can accommodate a high drug content and function as reservoirs of active pharmaceutical ingredients. In particular, EF_A exhibited unique physicochemical and permeation properties that are not observed in aqueous solutions or conventional formulations, suggesting its potential as a novel EF system for transdermal drug delivery.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3233-3243"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Domain Knowledge Constrained Symbolic Regression for Optimising Dermal Drug Formulations.","authors":"Yu Zhang, Xilu Wang, Dimitrios Tsaoulidis, Tao Chen","doi":"10.1007/s11095-026-04170-9","DOIUrl":"10.1007/s11095-026-04170-9","url":null,"abstract":"<p><strong>Purpose: </strong>Interpretable dynamic models that remain physically admissible under extrapolation are essential for dermal formulation optimisation. Mechanistic models are often labour-intensive to derive, whereas unconstrained data-driven models may violate physical constraints and degrade beyond observed conditions.</p><p><strong>Methods: </strong>We developed a domain knowledge constrained symbolic regression (DKC-SR) framework to discover compact, interpretable dynamic models for cumulative release directly from time-series experiments. Domain knowledge was embedded through a restricted operator set and feasibility constraints over the bounded optimisation domain. Candidate expressions were evaluated by numerically solving the dynamic differential equations and selected using an information-criterion trade-off across a level-wise set of complexity-controlled models. The final surrogate was coupled with the covariance matrix adaptation evolution strategy for formulation optimisation.</p><p><strong>Results: </strong>In an ibuprofen formulation case study, the selected model provided a formulation ranking that, combined with experimental validation, guided the optimiser to a narrow high-performing region; a representative optimum was experimentally confirmed to exceed the historical best. Although the surrogate was more reliable for ranking and optimisation guidance than for exact quantitative calibration, it remained physically admissible and numerically stable across the design space.</p><p><strong>Conclusions: </strong>DKC-SR provides a compact, interpretable, and optimisation-ready route to modelling dermal release under bounded design constraints.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3393-3410"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Microbiome Associations with Tacrolimus Pharmacokinetics in Adult Hematopoietic Cell Transplantation Using Population Pharmacokinetic and Machine Learning.","authors":"Moataz E Mohamed, Shen Cheng, Christopher Staley, Armin Rashidi, Najla El Jurdi, Shernan G Holtan, Pamala A Jacobson","doi":"10.1007/s11095-026-04152-x","DOIUrl":"10.1007/s11095-026-04152-x","url":null,"abstract":"<p><strong>Purpose: </strong>Tacrolimus (TAC) is known for its high pharmacokinetic variability which cannot be fully explained by pharmacogenomic (PGx) and clinical variables. We identified gut microbiome associated with TAC pharmacokinetic variability in allogeneic hematopoietic cell transplant (HCT) recipients.</p><p><strong>Methods: </strong>In this observational study, metagenomic shotgun sequencing was used to analyze stool microbiome collected within ± 10 days from time of first oral TAC trough at steady state. TAC steady state concentrations (222 IV continuous infusion and 436 oral troughs) were modeled to estimate TAC clearance (CL) and oral bioavailability (F) using nonlinear mixed effects modeling. The effect of clinical covariates, PGx variants and concomitant medications on CL and F were evaluated. Machine learning was used to identify bacterial species associated with variability in F and CL. The identified species were incorporated into the final model, and simulations were conducted to estimate their clinical relevance on oral TAC troughs.</p><p><strong>Results: </strong>TAC population CL was 6.91 L/h and population F was 64.4%. TAC CL was increased in those with CYP3A5*1 genotype and reduced with voriconazole use and if estimated glomerular filtration rate < 60 ml/min/1.73 m². TAC F increased with laxative use and decreased with corticosteroid use. Limosilactobacillus fermentum had the strongest positive effect on oral TAC troughs while Bacteroides uniformis had the strongest negative effect.</p><p><strong>Conclusion: </strong>Gut microbiome contributes to the inter-patient variability in TAC CL and oral F.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3125-3144"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis and Characterization of Anti-CTLA4 Peptide Conjugated Gemcitabine Prodrug Nanoparticles for Targeted Lung Cancer Chemoimmunotherapy.","authors":"Soumyadeep Chattopadhyay, Sakuntala Gayen, Souvik Roy","doi":"10.1007/s11095-026-04147-8","DOIUrl":"10.1007/s11095-026-04147-8","url":null,"abstract":"<p><strong>Objective: </strong>Lung cancer continues to be a major contributor to global cancer mortality due to extensive tumor heterogeneity, drug resistance, and limited efficacy of conventional therapies. To address these limitations, the present study aimed on rational design and development of anti-CTLA4 peptide-conjugated gemcitabine prodrug nanoparticles (PD-NPs) for targeted lung cancer chemoimmunotherapy.</p><p><strong>Method: </strong>PD-NPs was synthesized by conjugating an anti-CTLA4 peptide (ARHPSWYRPFEGCG), a cathepsin B cleavable linker (FRRG) to the free amino group of gemcitabine via a single step amide bond formation, enabling the formation of stable self-assemble PD-NPs. In-silico evaluation was carried out by molecular docking study, while physicochemical properties were confirmed through different spectroscopical analyses. In-vitro studies, including cell viability, clonogenic, scratch, and apoptosis assay by flow cytometry were performed in A549 and NCI-H460 cell lines. In-vivo toxicity and biodistribution study were conducted to determine therapeutic doses. Subsequently chemoimmunotherapeutic efficacy of PD-NPs was evaluated in B16-F10 induced lung tumor mice model.</p><p><strong>Results: </strong>PD-NPs exhibited a zeta potential of ± 34.4 mV, an average particle size of 229.8 ± 2.1 nm, and polydispersity index 0.2, suggesting a stable and monodisperse formulation. In vitro studies demonstrated potent cytotoxic effect, suppression of clonogenicity, inhibition of cellular migration, apoptosis induction, and inhibition of carcinogenic protein expression. In vivo treatment resulted in significant tumor regression, restoration of lung tissue architecture, activating CD8 expression, and altering TNF-α expression following PD-NPs treatment.</p><p><strong>Conclusion: </strong>Overall, these findings highlight the therapeutic potential of enzyme responsive, anti-CTLA4 peptide conjugated gemcitabine prodrug nanoparticles as a promising strategy for targeted lung cancer chemoimmunotherapy.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3193-3219"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148397269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semaglutide Bioavailability: Limitations, Formulation Innovation and Future Opportunities.","authors":"Shahin Vahora, Vishal Shah, Bhavesh Patel","doi":"10.1007/s11095-026-04185-2","DOIUrl":"10.1007/s11095-026-04185-2","url":null,"abstract":"<p><p>Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, improved the type 2 diabetes mellitus treatment and obesity by its glucose-lowering and weight loss effects. Although the subcutaneous route provides high bioavailability and stable pharmacokinetics, the development of oral semaglutide makes a significant advancement in peptide therapeutics. However, oral delivery remains limited by an absolute bioavailability of only approximately 0.4-1% under optimized fasting conditions with restricted water intake, whereas systemic exposure is essentially absent in the fed state because plasma semaglutide concentrations remain below the limit of quantification. This extremely low exposure reflects peptide degradation within the gastrointestinal tract, poor epithelial permeability, gastric physiological constraints, and presystemic metabolism. The combination with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) helps in gastric absorption by increasing the local gastric microenvironmental pH, thereby reducing acid-induced peptide unfolding, suppressing pepsin activation, maintaining semaglutide predominantly in its absorbable monomeric form by limiting oligomer formation, and enhancing transcellular uptake. But the oral form of semaglutide is constrained by narrow dose limits, considerable pharmacokinetic variability that, despite large fluctuations in individual absorption, produces relatively stable steady-state exposure because semaglutide's approximately one-week half-life and extensive albumin binding buffer day-to-day differences in absorption. This review examines semaglutide pharmacokinetics, focusing on mechanistic challenges to oral bioavailability and formulation approaches to address this. We assess emerging methods such as nanotechnology-based formulations, other permeation enhancers, enzyme inhibitors and device-based delivery systems for their abilities to improve absorption and efficacy. Furthermore, clinical efficacy and patient adherence as well as research opportunities are considered. Continual development of these technologies may emerge as a solution to enhance bioavailability, decrease dosing frequency and expand the range of uses of oral peptide therapies.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2989-3010"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}