Pharmaceutical Research最新文献

{"title":"Development and Optimization of Sorafenib Nanosuspension By High-pressure Homogenization for Improved Oral Bioavailability.","authors":"Ho-Ik Choi, Alam Zeb, Kyung-Won Kim, Jeong-Su Ryu, Ha-Yeon Noh, Se-Yun Kim, Min-Ju Kim, Fawad Ali Shah, Najam Us Sahar, Wondong Kim, Jin-Ki Kim","doi":"10.1007/s11095-026-04195-0","DOIUrl":"https://doi.org/10.1007/s11095-026-04195-0","url":null,"abstract":"<p><strong>Purpose: </strong>Sorafenib (SRF) is a multi-kinase inhibitor approved for the treatment of hepatocellular, advanced renal cell, and differentiated thyroid carcinomas. However, oral bioavailability of SRF is excessively low and variable due to its poor aqueous solubility. Herein, we developed and optimized sorafenib nanosuspensions (SRF-NS) by using different hydrophilic polymers and surfactants for improving its dissolution and oral bioavailability.</p><p><strong>Methods: </strong>SRF-NS were prepared by high-pressure homogenization technique, and were optimized by varying the type and ratio of stabilizers and surfactants, and pressure and number of homogenization cycles. SRF-NS with optimal physicochemical properties were further characterized for surface morphology, physical stability, crystallinity, in vitro dissolution, and in vivo pharmacokinetics.</p><p><strong>Results: </strong>SRF-NS with SRF/hydroxypropyl cellulose EXF/Tween 80/sodium lauryl sulfate at weight ratios of 10/5/2/1 showed the smallest particle size (~ 328 nm) and low polydispersity index (< 0.3). The optimized SRF-NS exhibited significantly improved dissolution in simulated gastric fluid and simulated intestinal fluid compared with bulk SRF powder. Furthermore, SRF-NS displayed enhanced oral bioavailability in rats with 1.54- and 1.63-times higher C_max and AUC_last, respectively, compared to SRF powder.</p><p><strong>Conclusion: </strong>NS with reduced particle size and increased solubility could be a promising formulation for enhancing oral bioavailability of SRF.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970681","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":"Preclinical Pharmacokinetic and Pharmacological Profiling of B339, a Novel SARM1 Inhibitor for the Treatment of Vincristine-induced Peripheral Neuropathy.","authors":"Aaditi Karnik, Girish Siddanagouda Hosmani, Sonam Dolma, Aditi Gangopadhyay, Amit Lalwani, Ramesh Babu Boga, D Sriram, Punna Rao Ravi, Abhijeet R Joshi","doi":"10.1007/s11095-026-04198-x","DOIUrl":"https://doi.org/10.1007/s11095-026-04198-x","url":null,"abstract":"<p><strong>Purpose: </strong>Despite the extensive knowledge about the role of Sterile α and TIR motif-containing protein-1 (SARM1) inhibition in the prevention of axonal degeneration, very few pharmacological inhibitors of SARM1 have been discovered and tested in preclinical models, with limited knowledge about their pharmacokinetic properties.</p><p><strong>Methods: </strong>In this study, a thioamide small-molecule library was screened against SARM1 via structure-guided molecular docking and the inhibitory activity of the resulting hits was further evaluated using High Performance Liquid Chromatography (HPLC) based in vitro NADase assay. In vitro drug metabolism and in vivo pharmacokinetic studies were performed for the best candidate, and the compound was tested in a preclinical mouse model of vincristine-induced peripheral neuropathy (VIPN).</p><p><strong>Results: </strong>A benzothioamide derivative, B339, emerged as a potent SARM1 inhibitor (IC₅₀ 7.215 μM) through our in silico and in vitro screening. The compound exhibited absolute bioavailability of 53% when administered through intraperitoneal (IP) route but appear to have rapid clearance. In a mouse model of VIPN, B339 (30 mg/kg IP) demonstrated prevention of thermal and mechanical allodynia, and motor impairment, improved sensory and motor nerve conduction, and prevented axonal degeneration.</p><p><strong>Conclusions: </strong>The study provided discovery and in-depth pharmacokinetic characterization of a novel SARM1 inhibitor, B339, and demonstrated its pharmacological potential for the treatment of VIPN.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970638","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":"CFD-Enabled Deep Insert Nasal Delivery for Precision Sinus Targeting.","authors":"Weixiao Wang, Rui Ma, Chengwen Zhong, Yuxiang Zhao, Sha Liu","doi":"10.1007/s11095-026-04191-4","DOIUrl":"https://doi.org/10.1007/s11095-026-04191-4","url":null,"abstract":"<p><p>Traditional nasal spray delivery suffers from poor targeting, with most particles depositing in anterior nasal regions, leading to insufficient therapeutic effects, higher dosage requirements, and increased side effect risks. This study quantitatively evaluated nasal spray performance and assessed the benefits of deep versus shallow insertion. A standardized three-dimensional healthy nasal cavity model and computational fluid dynamics were employed, combining the Reynolds-averaged Navier-Stokes k- <math><mi>ω</mi></math> turbulence model with a two-way coupled discrete phase model. Key spray parameters including injection velocity, cone angle, particle releasing position, injection direction, particle size distribution, insertion depth, and respiratory flow rate, were systematically investigated through 1144 test cases. Target regions were defined based on the clinical importance of the frontal, maxillary, ethmoid, and sphenoid sinus ostia. Deep insertion posterior to the nasal valve markedly enhanced drug transport to sinus targets. Compared with shallow insertion, deep delivery increased total target deposition efficiency from 4.4% to 44.9% and reduced sensitivity to operational errors, with coefficients of variation decreasing by at least 60%. The primary mechanism of improvement was the reduction of ineffective anterior deposition. Deep nasal spray delivery significantly improves drug targeting to the sinuses and enhances robustness against user operational variability. Strategies that increase delivery depth show strong potential to improve therapeutic effectiveness, reduce required dosages, and lower side effect risks for nasal and sinus conditions.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955955","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":"Employing General-Purpose and Biomedical Large Language Models with Advanced Prompt Engineering for Pharmacoepidemiologic Study Design.","authors":"Xinyao Zhang, Nicole Sonne Heckmann, Manuela Del Castillo Suero, Francesco Paolo Speca, Maurizio Sessa","doi":"10.1007/s11095-026-04190-5","DOIUrl":"https://doi.org/10.1007/s11095-026-04190-5","url":null,"abstract":"<p><strong>Background: </strong>The potential of large language models (LLMs) to automate and support pharmacoepidemiologic study design is an emerging area of interest, yet their reliability remains insufficiently characterized. General-purpose LLMs often display inaccuracies, while the comparative performance of specialized biomedical LLMs in this domain remains unknown.</p><p><strong>Methods: </strong>This study evaluated general-purpose LLMs (GPT-4o and DeepSeek-R1) versus biomedically fine-tuned LLMs (QuantFactory/Bio-Medical-Llama-3-8B-GGUF and Irathernotsay/qwen2-1.5B-medical_qa-Finetune) using 46 protocols (2018-2024) from the HMA-EMA Catalogue and Sentinel System. Performance was assessed across relevance, logic of justification, and ontology-code agreement across multiple coding systems using Least-to-Most (LTM) and Active Prompting strategies.</p><p><strong>Results: </strong>GPT-4o and DeepSeek-R1 paired with LTM prompting achieved the highest relevance and logic of justification scores, with GPT-4o-LTM reaching a median relevance score of 4 in 8 of 9 questions for HMA-EMA protocols. Biomedical LLMs showed lower relevance overall and frequently generated insufficient justification. All LLMs demonstrated limited proficiency in ontology-code mapping.</p><p><strong>Conclusion: </strong>Off-the-shelf general-purpose LLMs currently offered more reliable support for pharmacoepidemiologic study design than the smaller biomedical LLMs evaluated. In the model-controlled comparison (GPT-4o with Least-to-Most versus Active prompting), prompt strategy did not significantly affect performance (paired p = 0.93), and prompt comparisons are therefore reported descriptively. Because the two model groups also differed in scale and instruction-tuning, this contrast should be interpreted as a comparison of readily deployable options rather than of biomedical specialization alone.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955993","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":"A Rate-Weighted Framework for Diffusion, Swelling, and Erosion in Monolithic Polymeric Devices: Geometry-Unified Analytical Forms and a priori Mechanism Weights from Polymer-Solvent Thermodynamics.","authors":"Pitt Supaphol","doi":"10.1007/s11095-026-04182-5","DOIUrl":"https://doi.org/10.1007/s11095-026-04182-5","url":null,"abstract":"<p><strong>Purpose: </strong>Mathematical descriptions of bioactive release invoke Fickian diffusion, Case II swelling, and surface erosion, yet each is usually treated in isolation. This work unifies the three within one analytical skeleton for homogeneously loaded monolithic devices of canonical geometry - slabs, cylinders, and spheres - excluding compressed tablets, osmotic systems, and reservoir devices, grounding their coefficients in polymer-solvent thermodynamics.</p><p><strong>Methods: </strong>Eigenfunction series give the diffusion solutions and short-time √t asymptotics; moving-boundary kinematics give polynomial swelling and erosion laws. Coefficients are linked to Hansen-van Krevelen solubility parameters and the Flory-Huggins χ. The mechanisms are coupled as a multiplicative product form and an additive Dirichlet mixture whose weights are fixed a priori by each mechanism's characteristic rate - the leading Laplacian eigenvalue for diffusion, the front-traversal rate for the moving fronts - termed Thermodynamic Rate Decomposition (TRD). Validation comprises an exponent consistency check and fit-free tests against a propranolol-HPMC cylinder, an etofylline-PEO slab, and the published sphere case.</p><p><strong>Results: </strong>Power-law fitting returns Fickian exponents of 0.50, 0.46, and 0.45 for slab, cylinder, and sphere (consensus 0.50, 0.45, 0.43) and a slab Case II exponent of 1.00. With no parameter fitted to the release curve, predictions reproduce both measured profiles to within about 13% RMSE and assign the dominant mechanism correctly. Weights move by at most 0.03 under an independent moment-based definition.</p><p><strong>Conclusion: </strong>Geometry enters through one integer index n  <math><mo>∈</mo></math>  {1, 2, 3}, giving compact, thermodynamically traceable equations that support a priori mechanism assignment and first-pass quantitative analysis within this device class.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880499","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":"An Orthogonal Framework for Higher-Order Structural and In Vitro Functional Comparability of Chemically Synthesized Liraglutide Relative to an rDNA-Origin Reference Product.","authors":"Yangming Tang, Mengmeng Bai, Xiaojie Lu, Xinhui Xing","doi":"10.1007/s11095-026-04178-1","DOIUrl":"https://doi.org/10.1007/s11095-026-04178-1","url":null,"abstract":"<p><strong>Purpose: </strong>Synthetic peptide test products referencing recombinant-origin products present unique regulatory challenges in demonstrating higher-order structural (HOS) comparability beyond primary sequence sameness. Liraglutide, a lipidated glucagon-like peptide-1 (GLP-1) receptor agonist with defined self-association behavior, represents an important model for such assessments.</p><p><strong>Methods: </strong>A head-to-head comparability study was performed between a chemically synthesized liraglutide product and its recombinant reference listed drug (RLD). An orthogonal analytical framework integrating spectroscopic, biophysical, nuclear magnetic resonance (NMR)-based, and in vitro functional methods was applied to assess secondary structure, supramolecular assembly, aggregation propensity, molecular conformational fingerprints, and biological activity.</p><p><strong>Results: </strong>The test products and RLD demonstrated highly comparable structural and functional profiles across all evaluated dimensions. Secondary structural characteristics, NMR fingerprints, and spatial conformational features were highly consistent. Solution-state analyses showed comparable diffusion behavior and a dominant low-oligomeric assembly, with apparent aggregation numbers close to the hexamer-to-heptamer range and without evidence of abnormal aggregation or fibrillation. Functional studies further confirmed comparable GLP-1 receptor activity and stability profiles.</p><p><strong>Conclusions: </strong>Orthogonal structural and functional characterization can substantially reduce residual uncertainty for synthetic peptide generics referencing recombinant products and provides a practical framework for comparability assessment of complex peptide drugs.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880955","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":"Transnasal Administration of Surfactant Aerosol to the Lungs of Infants Using Direct Interfaces - Lessons Learned from Computational Fluid Dynamics.","authors":"Hasan Jubaer, Dale Farkas, Caleb Dalton, Mohammad A M Momin, Michael Hindle, Worth Longest","doi":"10.1007/s11095-026-04186-1","DOIUrl":"https://doi.org/10.1007/s11095-026-04186-1","url":null,"abstract":"<p><strong>Purpose: </strong>Direct-to-infant (D2I) transnasal aerosol surfactant therapy (AST) offers a promising non-invasive alternative for treating neonatal respiratory distress syndrome (RDS). However, achieving high lung delivery efficiency with dry powder inhalers (DPIs) requires careful optimization of complex fluid-particle interactions. This study used computational fluid dynamics (CFD) to optimize an Infant Air‑Jet Dry Powder Aerosol Delivery System (iDP‑ADS) and derive transferable design principles.</p><p><strong>Methods: </strong>A CFD model of the iDP‑ADS coupled to a 31‑week preterm nose‑throat geometry was validated against in vitro measurements. Sensitivity analyses evaluated modeling assumptions (steady‑state vs. transient, monodisperse vs. polydisperse) and critical design parameters influencing aerosol delivery, such as upstream air volume, interface geometry, temporal aerosol emission profiles, and actuation flow rates.</p><p><strong>Results: </strong>The CFD model demonstrated strong in vitro agreement (2.8% mean absolute difference). Regarding modeling: standard simplifications, particularly steady-state approximations, overpredicted lung transmission (~24%), establishing the necessity of high-fidelity transient simulations with polydisperse aerosols. Regarding aerosol delivery: integrating an upstream air volume created \"hydrodynamic shielding,\" reducing relative interface losses by up to 50%. A 10 mm diffusive path length and 20° (inward and downward) prong alignment balanced jet dissipation while minimizing nasal deposition. Front-loading of aerosol emission prevented entrapment of 10-14% of the dose in anatomical dead space. An optimal system-specific actuation flow rate of 3 L/min achieved ~53.5% aerosol lung transmission, balancing aerosolization efficiency against turbulence-driven transport losses.</p><p><strong>Conclusions: </strong>High-efficiency transnasal AST requires balancing often competing aerosol generation physics, transport behavior, and clinical constraints. This study highlights CFD as a vital design tool, providing key lessons to inform future modeling and practical interface development.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881171","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":"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}