Pharmaceutical Research最新文献

{"title":"Utility of Relative Activity Factors to Determine Fraction Glucuronidation and Clearance of Icenticaftor in Humans.","authors":"Mitesh Patel, Sahil Shaikh, Felix Huth, Sujal Deshmukh","doi":"10.1007/s11095-026-04136-x","DOIUrl":"10.1007/s11095-026-04136-x","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study is to quantify the contribution of individual UDP-glucuronosyl transferase (UGT) enzymes involved in the glucuronidation of icenticaftor, which is primarily glucuronidated in the human liver to two distinct glucuronide metabolites that are ultimately excreted in the urine.</p><p><strong>Methods: </strong>The formation of icenticaftor-glucuronide in recombinant UGT systems was scaled with relative activity factor (RAF) of involved UGT enzymes to determine the fraction glucuronidation in human liver.</p><p><strong>Results: </strong>Scaling of the glucuronidation activity of UGT enzymes in recombinant UGT systems demonstrated that hepatic UGT1A9 contributed to about two-third of the overall icenticaftor glucuronidation while the remaining was accounted by UGT2B7. Moreover, the predicted UGT-mediated clearance of icenticaftor, upon scaling the intrinsic clearance (CL_int) with RAF, correlates well with that estimated in humans.</p><p><strong>Conclusion: </strong>Collectively, current data are indicative of the utility of activity-based scalars to predict fraction glucuronidation and clearance of icenticaftor in the clinic. UGT1A9 is identified as the major UGT enzyme in the glucuronidation of icenticaftor in human liver.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2751-2759"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148318710","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":"Meta-Analysis and Physiologically-Based Modeling of the Pharmacokinetics and Pharmacodynamics of Dexamethasone in Horses.","authors":"Ruihong Yu, Pierre-Louis Toutain, Carl Ekstrand, William J Jusko","doi":"10.1007/s11095-026-04120-5","DOIUrl":"10.1007/s11095-026-04120-5","url":null,"abstract":"<p><strong>Purpose: </strong>Dexamethasone (DEX) is widely used in equine practice for its potent anti-inflammatory effects and diverse studies have examined its pharmacology in horses. We integrated all available pharmacokinetic (PK) and pharmacodynamic (PD) data from 12 studies to quantify DEX disposition and endocrine effects in horses.</p><p><strong>Methods: </strong>DEX concentrations in blood, urine and synovial fluid, plus cortisol (CTS) and glucose (GLU) in plasma, following various administration routes (intravenous (IV), intramuscular (IM), intra-articular, oral) were available from original studies or digitized from literature. A minimal physiologically-based PK model and linked indirect response PD models were applied.</p><p><strong>Results: </strong>The mean clearance of DEX was 344 mL/h/kg via hepatic metabolism (98%) and renal excretion (2%). Due to nonlinear tissue binding, DEX generally exhibited a prolonged terminal phase in plasma, maintaining concentrations above a designated plasma threshold of 5 pg/mL for 67 h following 0.05 mg/kg IV dose. Dosing input parameters of DEX varied markedly across dosing routes and prodrug formulations (alcohol, isonicotinate, phosphate), with bioavailability ranging 37 ~ 100%. Oral and pro-drug doses produced rapid absorption, except for IM DEX-isonicotinate that exhibited slow (flip-flop) availability. Adrenal suppression with an IC₅₀ of 0.038 ng/mL and plasma GLU increases with an EC₅₀ of 0.79 ng/mL were observed that commonly persisted for 2 ~ 4 days after single dose.</p><p><strong>Conclusions: </strong>This meta-analysis utilized a mechanistic and physiologically-based modeling framework to provide global perspectives that may promote the rational use of DEX in equine medicine and support evidence-based regulatory decisions.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2733-2750"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283985","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":"Hydrogel-Mediated Delivery of Drug Nanocarriers in the Oedematous Postoperative Brain.","authors":"Noel Benton, Wenbo Zhan","doi":"10.1007/s11095-026-04155-8","DOIUrl":"10.1007/s11095-026-04155-8","url":null,"abstract":"<p><p>PURPOSE AND OBJECTIVES: Hydrogel-nanocarrier systems have emerged as a clinically implementable strategy to reduce glioblastoma recurrence following surgery. Despite demonstrated feasibility, the influence of intrinsic tissue and nanocarrier properties on delivery outcomes remains insufficiently understood. This study aims to quantify their individual effects on delivery performance.</p><p><strong>Methods: </strong>A mathematical model is applied to simulate hydrogel-mediated nanocarrier delivery to the oedematous postoperative brain. Simulations are conducted in a realistic 3-D brain geometry rebuilt from medical imaging data. Nine factors are investigated, including drug release rate, nanocarrier diffusivity, blood drainage rate, partitioning at the cell membrane and within cells, drug loading dose, oedema severity, blood pressure, and tissue permeability.</p><p><strong>Results: </strong>The modelling reveals distinct responses of delivery outcomes to each factor. Optimal ranges are identified that maximise drug availability and/or improve distribution volume and uniformity. The results suggest that drug delivery is controlled predominantly by drug release and elimination rather than transport.</p><p><strong>Conclusions: </strong>These findings enhance understanding of the coupled interactions between drug transport and brain tissue in the post-operative environment and provide a quantitative reference for the optimisation of hydrogel-nanocarrier delivery systems to improve inhibition of glioblastoma recurrence.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2507-2528"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148448705","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":"Biomedical Large Language Models and Prompt Engineering for Causality Assessment of Individual Case Safety Reports in Pharmacovigilance.","authors":"Nicole Sonne Heckmann, Despoina Georgia Papoutsi, Maria Antonietta Barbieri, Vera Battini, Søren Norlin Mølgaard, Simon Ørum Schmidt, Lars Melskens, Maurizio Sessa","doi":"10.1007/s11095-026-04121-4","DOIUrl":"10.1007/s11095-026-04121-4","url":null,"abstract":"<p><strong>Background: </strong>Biomedical Large Language Models (LLMs) combined with prompt engineering offer domain-specific reasoning, yet their application to individual-level causality assessment remains unexplored. This study evaluated five combinations of biomedical LLMs, prompting strategies, and causality algorithms by comparing their agreement with two human expert evaluators.</p><p><strong>Research design and methods: </strong>A total of 150 Individual Case Safety Reports (ICSRs) were analyzed: 140 reports from Food and Drug Administration Adverse Event Reporting System (FAERS), and 10 myocarditis/pericarditis ICSRs from Vaccine AERS (VAERS). Assessments were conducted using the Naranjo and WHO-UMC algorithms. Biomedical LLMs tested included TinyLlama 1.1B, Medicine LLaMA-3 8B, and MedLLaMA v20, combined with Chain-of-Thought (CoT) or Decomposition prompting. Agreement was measured using Gwet's Agreement Coefficient 1 (AC1) and percentage agreement, alongside performance metrics and qualitative error analysis.</p><p><strong>Results: </strong>The Medicine LLaMA-3 8B-Naranjo-CoT combination achieved the highest agreement with human assessors for the final classification of causality (64%). Biomedical LLMs demonstrated low inter-rater agreement on critical items of causality assessment such as identification of listed AE, temporal plausibility, alternative causes, and objective evidence of AEs. Frequent model failures included irrelevant responses.</p><p><strong>Conclusions: </strong>Biomedical LLMs showed improved performance over general purpose models previously tested but remain suboptimal for reliable causality assessment of ICSRs.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2761-2774"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006241","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":"Impurities and Potential Immunogenicity Associated With Follow-on and Compounded Glucagon-like Peptide-1 Receptor Agonists.","authors":"Katharina L Kopp, Kasper Lamberth, Ole Schelde, Anne Kjærgaard Øgendahl, Magdalena Wojcieszek, Jesper Emil Mogensen, Henrik Sune Ramírez-Andersen, Christina Lene Schneider, Arne Staby, Morten Hach","doi":"10.1007/s11095-026-04146-9","DOIUrl":"10.1007/s11095-026-04146-9","url":null,"abstract":"<p><strong>Purpose: </strong>To assess impurity profiles/potential immunogenicity of multiple samples of follow-on or compounded products for two glucagon-like peptide-1 receptor agonists (GLP-1 RAs): semaglutide and liraglutide.</p><p><strong>Methods: </strong>Major histocompatibility complex-II-associated peptide proteomics assay (MAPPs), liquid chromatography-mass spectrometry analysis, photostability testing, and fibrillation assay were performed.</p><p><strong>Results: </strong>For semaglutide and liraglutide, various potentially immunogenic peptides (distinct number/distribution vs originators) were presented on impurity-stimulated monocyte-derived dendritic cells from healthy donors. The follow-on drug substance and follow-on or compounded products had distinct impurity profiles (amino acid deletions/additions and unidentified impurities) versus the originators. Significant disparity in strength, impurity sum, and high-molecular-weight protein level were observed between compounded semaglutide and originator products when exposed to light. The liraglutide follow-ons had reduced physical stability versus the originator.</p><p><strong>Conclusions: </strong>The tested peptide impurities pose increased immunogenicity potential. Follow-on or compounded products also had different impurity profiles, which could be affected by the sourcing of the active pharmaceutical ingredient, manufacturing process, and degradation during storage. The distinct impurity profiles of follow-on and compounded products could lead to an undesirable immune response in patients. These results underscore the importance of in vitro immunogenicity assays/clinical immunogenicity studies for GLP-1 RA follow-on or compounded products.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2861-2886"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148631294","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":"Injectable in-situ Forming Lipid Liquid Crystal for Long-acting Fluocinolone Release in Posterior Ocular Therapy: In-vitro and In-vivo Evaluations.","authors":"Malihe Karimi, Mojtaba Abrishami, Mehdi Farzadnia, Hossein Kamali, Bizhan Malaekeh-Nikouei","doi":"10.1007/s11095-026-04141-0","DOIUrl":"10.1007/s11095-026-04141-0","url":null,"abstract":"<p><strong>Objective: </strong>Intravitreal injection is a preferred route for targeted drug delivery to the posterior eye. However, commercial non-biodegradable polymeric implants for fluocinolone acetonide (FA) often necessitate surgical removal after long-term release, reducing patient compliance and increase surgical risks. Biodegradable polymeric implants also typically exhibit an initial burst release. This study explores the development of an innovative biodegradable in-situ forming lipid liquid crystal (ISF-LLC) formulation for sustained FA delivery over two months via a single intravitreal injection without burst release.</p><p><strong>Methods: </strong>The optimized formulation, developed using Design of Experiment software, comprised phosphatidylcholine and sorbitan monooleate (PC: SMO 30/70 w/w%) with N-methyl-2-pyrrolidone (NMP 30w/w%).</p><p><strong>Results: </strong>The ISF-LLC formulation exhibited pseudoplastic behavior, excellent syringeability, stability, and a hexagonal crystalline structure. In-vivo pharmacokinetic analysis in rabbit vitreous humor revealed a slow, controlled release rate of 0.49 ± 0.01 μg/day over 60 days (within the clinical range 0.2-0.6 μg/day), with no burst release during the first 7 days (0.22 ± 0.01 μg/day). The vitreal half-life was 22.80 ± 0.51 days, and FA was undetectable systemically. Quantitative histopathology showed no significant differences in retinal thickness (203-209 μm vs. 203 ± 2 μm, p > 0.05) or inflammatory cell count (1-3 vs. 1.3 ± 0.6 cells/field, p > 0.05) between treated and control groups. No retinal damage or systemic toxicity was observed.</p><p><strong>Conclusions: </strong>The injectable biodegradable ISF-LLC formulation is a promising controlled-release, long-acting platform for intravitreal drug delivery, eliminating initial burst release and need for surgical removal, thereby improving patient outcomes in ocular therapy.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2775-2793"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148318698","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":"Sustained Intra-Articular Delivery of Triple Therapeutics Using a Phase-Transition Phospholipid-Based Gel for Effective Treatment of Gouty Arthritis.","authors":"Sirui Ma, Jing Yang, Ao Li, Qing Lin, Tao Gong","doi":"10.1007/s11095-026-04134-z","DOIUrl":"10.1007/s11095-026-04134-z","url":null,"abstract":"<p><strong>Purpose: </strong>This study developed a coordinated-delivery phospholipid-based gel for therapeutics with distinct physicochemical properties to overcome the limitations of current monotherapies for gouty arthritis (GA), achieving synergistic therapeutic effects.</p><p><strong>Methods: </strong>A phospholipid phase-transition gel (RMU-Gel) was prepared via a stirring method to co-encapsulate three agents with distinct physicochemical properties-resveratrol (Res), meloxicam (Melx), and uricase (URE). The study evaluated its in vitro release behavior, in vivo pharmacokinetics, the synergistic effects of Res and Melx, pharmacodynamics in a rat model of gouty arthritis, as well as the preliminary safety and biodegradability of the drug-loaded phospholipid gel.</p><p><strong>Results: </strong>In vitro release results showed that RMU-Gel enabled a slow and prolonged release of the drugs in the release medium. The combination of resveratrol and meloxicam significantly enhanced anti-inflammatory and antioxidant responses. In the rat model, a single dose of RMU-Gel provided therapeutic effects lasting over 7 days, outperforming repeated injections of drug suspensions, with excellent safety and biodegradability.</p><p><strong>Conclusion: </strong>RMU-Gel offers a simple yet powerful platform for the coordinated co-delivery of physicochemically diverse agents. Specifically, the major breakthrough of this study is the successful co-encapsulation and sustained co-release of three therapeutics with markedly different physicochemical properties within a single phospholipid gel system, thereby preserving their multi-pathway therapeutic synergy. This provides a promising multifunctional strategy for efficient management of gouty arthritis.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2795-2809"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361951","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":"In Vitro-In Vivo Correlation (IVIVC) in Transdermal Drug Delivery Systems: Models, Regulatory Perspectives and Translational Challenges.","authors":"Uday Sankar Chakrabarty, Amrita Chakraborty, Mainak Mal, Dibya Sinha","doi":"10.1007/s11095-026-04181-6","DOIUrl":"10.1007/s11095-026-04181-6","url":null,"abstract":"<p><p>Transdermal drug delivery systems (TDDS) represent a clinically established yet mechanistically complex platform for systemic drug administration, offering advantages such as avoidance of hepatic first-pass metabolism, sustained drug input and improved patient adherence. However, their development and regulatory evaluation remain challenging due to the physiological variability of the skin barrier, site-dependent absorption and formulation-skin interactions. In vitro-in vivo correlation (IVIVC) has therefore emerged as a critical translational framework for linking in vitro permeation characteristics with systemic pharmacokinetic outcomes and thereby supporting formulation optimization, regulatory decision-making and reduction of repetitive clinical studies. This review provides a comprehensive and integrative analysis of IVIVC in TDDS, encompassing experimental methodologies, mechanistic modelling strategies, regulatory perspectives and translational challenges. Emphasis is placed on the limitations of classical empirical correlations when applied to transdermal systems, where lag time, cutaneous depot formation and nonlinear absorption frequently violate traditional IVIVC assumptions. Mechanistic and physiologically based pharmacokinetic (PBPK) approaches are highlighted as more robust alternatives capable of incorporating skin physiology, variability and formulation-specific effects. Evidence from successful and unsuccessful case studies demonstrates that predictive IVIVC is achievable but strongly dependent on methodological standardisation, model validity and physiological representation. Regulatory frameworks currently regard IVIVC primarily as a supportive tool; however, increasing integration with Quality-by-Design (QbD) principles, model-informed drug development (MIDD) and advanced experimental platforms indicates growing acceptance. The review ultimately reframes IVIVC for TDDS as a continuum of translational strategies rather than a binary outcome and identifies key knowledge gaps whose resolution will be essential for advancing predictive, regulatorily trusted IVIVC models for next-generation transdermal therapeutics.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2589-2606"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713337","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":"Variance-Consistent Covariate Modeling from Posterior Summaries in Population Pharmacokinetics.","authors":"Junya Ooka, Mizuki Uno, Yuta Nakamaru, Yiran Song, Mengqi Fang, Kanako So, Tomoko Kita, Fumiyoshi Yamashita","doi":"10.1007/s11095-026-04143-y","DOIUrl":"10.1007/s11095-026-04143-y","url":null,"abstract":"<p><strong>Purpose: </strong>Systematic covariate modeling in nonlinear mixed-effects (NLME) analysis is computationally intensive due to repeated refitting to concentration-time data. Although empirical Bayes estimates (EBEs) facilitate screening, η-shrinkage attenuates between-subject variability and distorts covariance structures, leading to shrinkage bias. We propose a variance-consistent framework enabling covariate modeling from a single base-model fit.</p><p><strong>Methods: </strong>The proposed approach incorporates subject-specific posterior means and covariances from an NLME base model. A variance-matching penalty enforces consistency between the total between-subject covariance (model-explained and unexplained) and the base model estimates, preserving the covariance structure without refitting. Performance was compared with EBE regression, two-stage Bayesian estimation, and NLME covariate modeling. Stepwise covariate selection was evaluated using likelihood ratio tests, with the resulting structure compared against the NLME-identified structure as the gold-standard reference.</p><p><strong>Results: </strong>Under substantial η-shrinkage of approximately 30%, EBE regression and two-stage Bayesian estimation attenuated covariate-effect parameter estimates. The proposed method provided unbiased estimates, mitigating shrinkage bias and recovering covariate-effect parameter estimates obtained with NLME. It also reproduced NLME-based stepwise covariate selection with high computational scalability by avoiding repeated refitting to time-course data.</p><p><strong>Conclusions: </strong>Variance-consistent posterior-based covariate modeling provides a statistically coherent and computationally scalable framework for systematic covariate identification in population PKPD analysis.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2711-2720"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148423173","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":"Spray Dried Lysozyme Microspheres: Morphological Evolution and Enzymatic Activity Retention.","authors":"Mengyuan Li, Shen Yan, Shengyu Zhang, Xiao Dong Chen, Winston Duo Wu","doi":"10.1007/s11095-026-04144-x","DOIUrl":"10.1007/s11095-026-04144-x","url":null,"abstract":"<p><strong>Purpose: </strong>Conventional spray drying often produces heterogeneous enzyme powders because of broad droplet size distributions and complex turbulent flow fields, limiting mechanistic understanding of particle formation and quantitative structure-activity analysis. This study aimed to fabricate uniform lysozyme microspheres and clarify how formulation and drying conditions govern their microstructure and enzymatic activity.</p><p><strong>Methods: </strong>A micro-fluidic jet spray dryer was used to prepare highly uniform pure lysozyme and excipient-containing lysozyme microspheres. The effects of carbohydrate excipients and drying temperature on particle morphology, secondary structure, surface composition, and enzymatic activity were systematically evaluated.</p><p><strong>Results: </strong>Pure spray-dried lysozyme microspheres showed a highly uniform single-hole bowl-like morphology with smooth surfaces. However, drying-induced thermal and shear stresses reduced α-helix content and caused activity loss. Carbohydrate excipients altered the structural evolution pathways. Surface elemental analysis indicated lysozyme enrichment in most formulations, except those containing dextran T40. Mannitol crystallization induced phase separation, lysozyme unfolding, and inactivation. Trehalose preserved conformational stability through a hydrogen-bonded glassy matrix, whereas dextran T40 mainly suppressed lysozyme aggregation through steric hindrance.</p><p><strong>Conclusions: </strong>This work establishes a formulation properties/process-microstructure-enzymatic activity relationship in a uniform microsphere system, supporting the rational design of performance-predictable spray-dried enzyme powders.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2941-2956"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361968","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}