Pharmaceutical Research最新文献

{"title":"Crystallization Inhibition and Solid-State Stability in High Drug Loaded Amorphous Drug-Polymer Dispersions Above the Overlap Concentration.","authors":"Sichen Song, Ronald A Siegel","doi":"10.1007/s11095-026-04167-4","DOIUrl":"10.1007/s11095-026-04167-4","url":null,"abstract":"<p><p>Amorphous solid dispersions (ASDs) have been shown to be an effective formulation strategy for improving apparent solubility, dissolution rate, and hence oral bioavailability of poorly aqueous soluble drugs. In this perspective, we review recent progress in understanding the role of polymer concentration, particularly the overlap concentration, c*, in governing crystallization of high drug loaded ASDs. The overlap concentration, c*, is a threshold above which adjacent polymer coils start to contact. Recent work has shown that when polymer concentration is below c*, the presence of the continuous polymer-free amorphous drug domain allows crystallization to proceed similarly to neat drug, resulting in limited inhibition. Above c*, formation of a homogeneous polymer rich matrix suppresses crystallization, primarily by delaying the first nucleation event. Representative case studies demonstrate the generality of this framework across diverse drug-polymer systems, although limitations arise for sufficiently high molecular weight polymers. Overall, the c*-guided rheological approach provides a mechanistic basis for rational polymer selection and optimization in high drug loaded, and therefore reduced overall volume, ASD formulations.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2491-2501"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669526","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":"Innovative Production of Diclofenac Sodium-Loaded Solid Lipid Nanoparticles by Membrane Nanoprecipitation: Evaluation of Encapsulation Efficiency and Photoprotection Ability.","authors":"Fabio Bazzarelli, Giuseppina Ioele, Martina Chieffallo, Lidietta Giorno, Antonio Garofalo, Alessio Fuoco, Emma Piacentini","doi":"10.1007/s11095-026-04139-8","DOIUrl":"10.1007/s11095-026-04139-8","url":null,"abstract":"<p><strong>Purpose: </strong>The stability of diclofenac sodium (DS) in liquid formulation is influenced by environmental factors such as temperature, humidity and light. The encapsulation of this drug in solid lipid nanoparticles (SLNs) can offer a useful strategy to protect it from degradation. The present study shows the potential of membrane nanoprecipitation (MN) as a productive and advantageous method for the formulation of cocoa butter-based SLNs to improve the photostability of DS.</p><p><strong>Methods: </strong>Conventional batch nanoprecipitation and MN were explored by varying the formulation parameters and process conditions to obtain SLNs.</p><p><strong>Results: </strong>The MN produced SLNs with an average size of 421 ± 14 nm, a high encapsulation efficiency of 95 ± 3.2%, and a drug loading of 8.8 ± 0.2%, when an acetate buffer at pH 4.1 was used as the non-solvent phase. Chemical characterization of the proposed formulation was performed by DSC and FTIR analyses. The efficacy of SLNs in preserving DS stability was investigated under simulated sunlight exposure, demonstrating a residual drug concentration of 90% after 3.34 min with respect to the aqueous solution that showed the same concentration value after 0.072 min.</p><p><strong>Conclusions: </strong>Overall, MN represents a suitable and sustainable process for the continuous production of light-stable drug-loaded SLNs.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2843-2859"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148284070","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":"Initial Exploration on the Application of the MoCMC Approach for Determining In Vitro Product Comparability.","authors":"Marilyn N Martinez, David G Longstaff","doi":"10.1007/s11095-026-04128-x","DOIUrl":"10.1007/s11095-026-04128-x","url":null,"abstract":"<p><strong>Purpose: </strong>To provide an initial assessment of the Matrix of Chemistry, Manufacturing and Control (MoCMC) approach for evaluating product physicochemical (Q3) similarity as part of the bioequivalence assessment of products containing non-systemically absorbed drugs.</p><p><strong>Methodology: </strong>Each Q3 parameter was expressed as the radius of a polygon using a mathematical formula that converted each specified reference Q3 parameter mean to a value of \"5\". That formula was applied to the corresponding individual test and reference product Q3 parameters, and the areas of the resulting treatment polygons were determined. The ratio of product area/outer area [Matrix Comparability Index (MCI)] was calculated where each side of the outer polygon had a radius of \"10\". When generated across multiple lots per treatment, the MCI values were statistically compared. Both actual (from our previously published investigation) and hypothetical MCI values were used to characterize the performance of the MoCMC across a range of situations.</p><p><strong>Results: </strong>The influence of any individual Q3 parameter decreased as the number of radii increased. The ability to identify statistically significant product differences decreased as variability of either test or reference MCI values increased. Nevertheless, by combining statistical analysis with a comparison of the spread of test and reference MCI values, the MoCMC identified product differences previously not detected by in vitro dissolution profiles alone.</p><p><strong>Conclusions: </strong>The MoCMC can serve as a tool for comparing products containing non-systemically absorbed drugs. However, statistical refinements are needed when applying this approach to an evaluation of product bioequivalence. The latter is under development.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2911-2922"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339499","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 Newly Designed Antibody-drug Conjugate Targeting B7-H3 Demonstrates Enhanced Therapeutic Efficacy Across a Spectrum of Cancers.","authors":"Jing Qian, Xinyu Zhu, Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Qiaohong Zheng, Jincheng Wang, Feng Yu, Lei Nie, Qinjie Weng","doi":"10.1007/s11095-026-04076-6","DOIUrl":"10.1007/s11095-026-04076-6","url":null,"abstract":"<p><strong>Introduction: </strong>The development of antibody-drug conjugates (ADCs) has accelerated due to their tumor-targeting precision. However, challenges in optimizing the target-linker-payload combination often lead to attrition from safety or efficacy issues, highlighting the need for ADCs with an improved therapeutic index. This study presents a newly designed B7-H3-targeted ADC, BR112, and demonstrates its superior preclinical efficacy across multiple models.</p><p><strong>Methods: </strong>BR112 comprises a humanized anti-B7-H3 antibody (112-59) conjugated to the microtubule inhibitor MMAE via a Pyridazinedione-valine-citrulline-p-aminobenzyl (PD-VC-PAB) linker with a drug-to-antibody ratio (DAR) of 4.15. The binding affinity and internalization profile of 112-59 were evaluated across multiple cell lines. In vitro cytotoxicity and in vivo antitumor efficacy were assessed in multiple cancer cell lines and three xenograft models. Pharmacokinetics of BR112 were analyzed in cynomolgus monkeys.</p><p><strong>Results: </strong>The antibody 112-59 exhibited high binding affinity for human B7-H3 (Kd = 5.28 nM), with potent cell-binding (EC50 ≈ 1 nM) and superior internalization across multiple cancer cell lines, exceeding the performance of antibodies used in clinical-stage comparator ADCs (MGC018 and DS-7300). Consequently, BR112 demonstrated potent cytotoxicity in vitro, with IC50 values ranging from femtomolar to nanomolar. In vivo, BR112 induced complete tumor regression in xenograft models (HCC1954, HCC1806, Calu-6) at doses of 3-10 mg/kg, outperforming both MGC018 and DS-7300. Pharmacokinetic studies in cynomolgus monkeys showed dose-proportional exposure and minimal MMAE release, confirming linker stability.</p><p><strong>Conclusion: </strong>This study positions BR112 as a promising therapeutic candidate with enhanced efficacy and a stable pharmacokinetic profile for the treatment of B7-H3-expressing solid tumors.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2641-2653"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265278","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":"Leveraging Carnitine-functionalized Lipid Nanocarrier based Targeted Delivery of A1874 PROTAC for Glioblastoma.","authors":"Himaxi Patel, Xiang Chen, Afsin Malik, Kareena S Poonai, Zhe-Sheng Chen, Sei Higuchi, Ketan Patel","doi":"10.1007/s11095-026-04130-3","DOIUrl":"10.1007/s11095-026-04130-3","url":null,"abstract":"<p><strong>Purpose: </strong>Glioblastoma(GBM) is highly aggressive and therapeutically refractory brain malignancy. Despite maximal intervention, patient prognosis remains dismal. A major obstacle in its management is the limited permeation of therapeutic agents across the blood-brain barrier(BBB), further intensified by resistance to standard chemotherapy such as temozolomide(TMZ). Proteolysis-targeting chimeras(PROTACs), offer new opportunities by enabling selective degradation of oncogenic proteins. A1874, a heterobifunctional molecule, has demonstrated potent, selective degradation of oncogenic driver-BRD4 in pancreatic, breast, and colon cancer. BRD4 drives GBM cell proliferation, survival, and resistance to therapy; therefore, we investigated the therapeutic potential of A1874 in brain cancer.</p><p><strong>Methods: </strong>Herein, we developed brain-targeted self-nanoemulsifying drug delivery system, termed PRONano, designed to enhance the targeted delivery of A1874. The system is functionalized with Palmitoyl-DL-carnitine chloride(PC) to facilitate transport across the BBB. Physicochemical characterization was performed to assess particle size. In-vitro cytotoxicity, qualitative and quantitative cellular uptake was analyzed. Mechanistic validation was conducted using western blot and qPCR, while 3D spheroid assay was employed to assess efficacy in tumor-mimicking microenvironment.</p><p><strong>Results: </strong>PRONano exhibited nanoscale particle size and significantly enhanced intracellular uptake of A1874. Formulation exhibited enhanced cytotoxicity in temozolomide-sensitive and resistant GBM cells. Effective BRD4 protein degradation was identified in the Western blot. PRONano significantly inhibited 3-D spheroid tumor growth suggesting better penetration and efficacy in tumor-like microenvironment.</p><p><strong>Conclusions: </strong>PRONano is brain-targeted, rationally designed nanoformulation which can overcome major A1874 delivery constraints. This strategy augmented PROTAC delivery and therapeutic potential in GBM, supporting future preclinical development.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2829-2842"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369045","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":"Stimulus-Responsive Polymeric Carriers for Gene Delivery: Balancing Endosomal Escape with Nucleic Acid Release.","authors":"Kenneth Hulugalla, Alexander W Fortenberry, Dilusha J de Silva, Thomas Werfel","doi":"10.1007/s11095-026-04173-6","DOIUrl":"10.1007/s11095-026-04173-6","url":null,"abstract":"<p><strong>Background: </strong>Polymeric carriers for nucleic acid delivery must overcome two sequential intracellular barriers: escape from the endosome and release of the cargo into the cytosol. These steps are typically treated as independent design problems and optimized separately.</p><p><strong>Objective: </strong>This review argues that escape and release are coupled through the same electrostatic and pH-dependent interactions, creating a fundamental tradeoff . The cationic charge that enables a polymer to destabilize endosomal membranes also tightens its grip on the nucleic acid payload, so conditions favoring escape simultaneously inhibit release.</p><p><strong>Methods: </strong>We trace this tradeoff across the major strategy classes in the polymeric delivery literature, evaluating each by where and when its trigger acts relative to the escape event. We further assess the assay toolkit for measuring escape and release, and the translational variables that shift the balance in vivo.</p><p><strong>Results: </strong>pH-responsive polymers tune the activation zone for membrane destabilization but cannot decouple escape from binding, since both depend on the same protonation events. Charge-shifting polymers address release more directly by programming a loss of cationic character after endosomal entry. Non-pH triggers, including disulfide, thioketal, diselenide, and esterase-responsive chemistries, off er orthogonal release mechanisms but face spatial and temporal alignment constraints. Characteristic failure modes recur: premature release, redundant triggering, and kinetic misalignment. No existing assay measures endosomal disruption and cargo release state simultaneously, and translational variables including protein corona formation, cell-type-dependent endosomal acidifi cation, and PEG shielding shift the balance in ways in vitro screening does not capture.</p><p><strong>Conclusion: </strong>The tradeoff cannot be resolved by chemistry alone, meaning the responsive trigger considered in isolation. Its resolution requires coordination across spatial (architectural domain segregation), temporal (kinetic alignment of escape and release), and formulation-level (N/P ratio, PEG density, formation pH) design axes.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2553-2588"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689654","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":"Low Analytical Evaluation Threshold in Leachables Screening: Challenges, Potential Solutions and Alternative Approaches.","authors":"Petra Booij, Tarja Nurmi, Georg Pour, Jason Creasey, Ting Zhang, Julie Hash, Aeshna Amin, Cindy Duong, JoAnn Chen, Steven A Zdravkovic, Michael Helfrich, Tim Verdonck, Janine Müller, Alicja Sobańtka, Craig McKenzie, Mary Kate Bielinski","doi":"10.1007/s11095-026-04151-y","DOIUrl":"10.1007/s11095-026-04151-y","url":null,"abstract":"<p><p>Achieving the Analytical Evaluation Threshold (AET) for leachables is critical in quantification for patient safety evaluation but presents challenges for drug products with large dosing volumes or complex matrices. This paper reviews these challenges, presents industry perspectives, and proposes scientifically justified approaches to ensure patient safety where the AET is not analytically achievable. An industry-wide survey conducted by the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium among 23 member companies identified common hurdles and alternative approaches used in leachables risk assessments. Findings were supplemented with case studies and a review of current analytical and regulatory strategies. The survey identified large dosing volumes (74% respondents) and matrix complexity (68% respondents) as the primary drivers for unachievable AETs. Matrix complexity was shown to significantly impact achievable limits of quantification (LOQs), with reported LOQs ranging from < 10 parts per billion (ppb) in simple aqueous solutions to > 100 ppb in complex matrices like protein-based or lipid-based formulations. Key analytical difficulties included identifying unknown leachables, background interference, and differentiating true leachables from analytical artifacts. When conventional screening methods cannot meet the AET, a robust, scientifically rationalized alternative approach is essential. Recommendations include implementing targeted leachable studies for enhanced sensitivity, using simulation studies to predict leachable profiles without matrix interference, and applying predictive modelling. For therapies addressing life-threatening conditions, a risk-benefit analysis leveraging the \"less than lifetime\" (LTL) concept may justify higher thresholds. Demonstrating rigorous method development efforts and providing scientific justification for the chosen strategy is crucial for regulatory alignment and ensuring patient safety.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2623-2640"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713305","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":"In-vitro Assessment of Immediate Release Rivaroxaban Coated Fixed Dose Combination Tablets with Extended Release Molnupiravir for the Management of Coagulopathy Associated with COVID.","authors":"Abu Mohiuddin, Sumanta Mondal, Koustav Dutta, Santanu Kaity","doi":"10.1007/s11095-026-04107-2","DOIUrl":"10.1007/s11095-026-04107-2","url":null,"abstract":"<p><strong>Purpose: </strong>Coagulopathy associated with SARS-CoV-2 infection leads to the formation of abnormal blood clots even in tiny blood vessels, which can lead to severe life-threatening conditions like organ damage, heart attack, and stroke. The objective of this study was to develop a solid oral fixed-dose combination (FDC) of molnupiravir (MPV) as an extended-release core (MPV-XR) with rivaroxaban (RIV) active coating for the management of viral infections with coagulopathy-related complications. While MPV-XR helps reduce viral infection along with daily pill burden, RIV simultaneously minimises coagulopathy-related complications.</p><p><strong>Method: </strong>We strategically selected the manufacturing process of RIV active coating on MPV-XR core tablets as an efficient, fast, and cost-effective method for large-scale formulation manufacturing. Both the MPV-XR core and the RIV-coated MPV-XR finished dosage form were characterised by various instrumental and pharmacopoeial studies.</p><p><strong>Results: </strong>The composition of the P2 batch was found to be the optimum for the MPV-XR core tablet, and the RIV coating with 5% w/w solid content showed the best active-coated tablets with the minimum unit-to-unit content variation (AV, 5.5%). A scale-up batch was executed to evaluate the impact of batch magnification on product quality.</p><p><strong>Conclusion: </strong>FDC of MPV-XR with RIV coating was manufactured, and appropriate characterisation was performed. The scale-up batch samples also showed promising quality in terms of drug content and drug release. Thus, the novel formulation approach showed proven quality characteristics for specific use in coagulopathy associated with SARS-CoV-2 infection. However, detailed clinical study needs to be conducted before its large scale manufacturing and commercialization.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2887-2910"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308946","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":"Reassessing and Updating Regulatory Standards on the Declaration of Storage Conditions in the Product Information of Medicinal Products: An Evidence-Based Proposal under EMA Guidance.","authors":"Helena Pericão, Henrique Cavaco, Miguel Dias, Luís Sarmento, Mário Magalhães, Bernardo Filipe, Herivelto Vieira, João Rita, Pedro Gonçalves, Matilde Vaz, Beatriz Coimbra, Beatriz Monteiro, Beatriz Gomes, Cátia Josué, Ecaterina Fuior, Lara Penso, Maria Ferreira, Maria Leonor Forjaz, Rodrigo Neves, Sofia Azevedo, Constança Lopes, Sofia Rosário, Rita Leal, Pia Erjavec, Felipe Lima, Rui Loureiro, Gracinda M M Sanches-Fernandes","doi":"10.1007/s11095-026-04122-3","DOIUrl":"10.1007/s11095-026-04122-3","url":null,"abstract":"<p><strong>Purpose: </strong>The European Medicines Agency (EMA) guideline Declaration of Storage Conditions in the Product Information of Medicinal Products (CPMP/QWP/609/96/Rev.2) was last revised in 2007. Since then, advances in stability science, increased climatic variability, and evolving regulatory expectations have highlighted limitations in the framework, particularly the use of vague descriptors such as \"room temperature\" or \"no special storage conditions.\" This work reassesses the scientific and regulatory basis for storage statements, integrating current understanding of mean kinetic temperature (MKT), climate-related risks, and developments in ICH and WHO guidance, and proposes a harmonized revision (Rev.3).</p><p><strong>Methods: </strong>A structured analysis of regulatory and scientific principles was conducted, incorporating MKT, climate-related risks, and developments in ICH and WHO guidance. These elements informed a revised framework and model storage statements, including a decision table linking stability outcomes to label statements.</p><p><strong>Results: </strong>The proposed update introduces explicit temperature-based statements, strengthens the linkage between stability data and label wording, clarifies requirements for moisture- and light-sensitive products, expands guidance for sterile and reconstituted preparations, and provides contingency instructions for temperature excursions. A decision table mapping stability outcomes to label statements is included to support regulatory implementation.</p><p><strong>Conclusion: </strong>This revision provides an updated synthesis of EMA, ICH, and WHO requirements, translating regulatory principles into clear storage statements and contingency guidance. It offers a more precise framework reducing ambiguity, supports justification of storage conditions through stability data and MKT-informed risk assessment, aiming to improve understanding among patients and healthcare professionals, strengthening real-world product quality and contributing to future EMA guideline development.</p><p><strong>Highlights: </strong>Identifies scientific and regulatory limitations in current \"no special storage conditions\" terminology; Links ICH stability guidelines and climatic variability to precise storage statements; Proposes harmonised core label phrases for room temperature, fridge, and freezer; Introduces contingency labelling for climate-related and cold-chain excursions.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2701-2709"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982803","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":"Dead-Space Microdomains as Explicit Barriers to Extracellular Drug Transport in Alzheimer's Disease.","authors":"Dimitrios Charemis, Dimitrios Lampropoulos, Yannis Dimakopoulos, Gregory Sivolapenko, Maria Hadjinicolaou","doi":"10.1007/s11095-026-04129-w","DOIUrl":"10.1007/s11095-026-04129-w","url":null,"abstract":"<p><strong>Objective: </strong>The impact of dead-space (DS) microdomains on cerebral drug penetration has been demonstrated experimentally; yet computational models typically capture their effects indirectly through effective tortuosity parameters. Here, we develop an anatomically grounded framework that systematically evaluates pharmaceutical diffusion within the central nervous system (CNS).</p><p><strong>Methods: </strong>A finite element (FE) model was developed with DS explicitly represented as impermeable obstructions in the extracellular space (ECS) - consistent with structural remodeling observed in Alzheimer's disease (AD). The model was calibrated by reproducing experimental diffusion timescales and subsequently applied to quantify the geometric contribution of DS to pharmaceutical transport.</p><p><strong>Results: </strong>Transport hindrance exhibited a strong dependence on molecular size. Within a representative ECS unit, the arrival of the <math><mrow><mn>0.5</mn> <msub><mi>c</mi> <mn>0</mn></msub> </mrow> </math> concentration contour at the venule was delayed by 11 s for Memantine, 14 s for Donepezil, and 80 s for Aducanumab. Spatial analyses revealed penetration delays that were not captured by domain-averaged uptake metrics. A Péclet number analysis confirmed that ECS transport for all three compounds remains diffusion-dominated under neurodegenerative conditions.</p><p><strong>Conclusions: </strong>The proposed framework provides a computationally efficient foundation for predictive multiphysics modeling in the human CNS and demonstrates how local ECS obstructions can lead to therapeutic hindrance in AD.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2683-2699"},"PeriodicalIF":4.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148212128","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}