Pharmaceutical Research最新文献

{"title":"Effects of Liver Surgery on Drug Transporters in the Liver and Remote Organs.","authors":"Reza Mehvar","doi":"10.1007/s11095-025-03901-8","DOIUrl":"https://doi.org/10.1007/s11095-025-03901-8","url":null,"abstract":"<p><p>Alterations in drug transporters in acute liver failure and chronic liver diseases, such as cirrhosis, have been reviewed before. However, there is a lack of comprehensive reviews on how liver surgery, including transplantation and partial hepatectomy, affects drug transporters. Because ischemia-reperfusion (IR) injury is a hallmark of liver transplantation and most other surgical procedures of the liver, this review focuses on the effects of IR injury, in addition to liver resection, on the expression and function of transporters in the liver and remote organs. Most of the reported studies in this area are carried out in animal models of liver surgeries, with relatively limited data in humans. The results indicate that the effects of IR injury and partial hepatectomy on drug transporters are complex and depend on many variables, such as the species, length and type of ischemia, reperfusion time, and the extent of liver resection. However, for a few major transporters, clear trends have emerged based on both animal and human studies. A major trend is that warm (normothermic) hepatic IR injury or liver transplantation causes overexpression of P-glycoprotein in the liver and remote organs, affecting the pharmacokinetics of substrate drugs. Another observed trend is the relocalization of the liver MRP2/Mrp2 from the canalicular membranes to the cytoplasmic area, reducing the function of the transporter even in the absence of a change in its protein. Alterations in transporter function, such as P-glycoprotein, may significantly impact the pharmacokinetics and pharmacodynamics of drugs in patients undergoing liver surgeries.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754029","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":"Investigating Zinc Migration from Rigid Needle Shield to Drug Formulation in Needle Tip of Pre-filled Syringe.","authors":"Guangli Hu, Chengbei Li, Kaitlin Wang, Yongchao Su, William Forrest, Jeffrey Givand, Dario Ferreira Sanchez, Margie Olbinado, Matthias Wagner, Christian Grünzweig, Vladimir Novak","doi":"10.1007/s11095-025-03888-2","DOIUrl":"https://doi.org/10.1007/s11095-025-03888-2","url":null,"abstract":"<p><strong>Objective: </strong>This study investigates the underexplored mechanisms of needle clogging in pre-filled syringes (PFSs), focusing on zinc (Zn) ions, which have been reported to promote protein gelation and increase formulation viscosity. We present direct evidence of Zn migration from the rigid needle shield (RNS) into drug products, aiming to elucidate the migration pathways and the role of Zn in clogging.</p><p><strong>Methods: </strong>Pre-filled syringes containing a therapeutic monoclonal antibody (mAb) were stored at 5°C and subjected to stress conditions at 40°C for up to six months. Inductively coupled plasma mass spectrometry (ICP-MS) measured metal ion levels, while synchrotron-based X-ray phase-contrast computed tomography (SR-XPCT) and X-ray fluorescence (SR-XRF) provided in situ visualization of Zn distribution in dry materials under stress.</p><p><strong>Results: </strong>We found that Zn leaches from the RNS into the drug formulation during liquid-RNS contact. ICP-MS revealed higher Zn levels, along with aluminum and titanium, in clogged needles compared to clean ones. SR-XRF identified Zn hot spots within the dried drug product, while SR-XPCT displayed 3D visualization of Zn particle accumulation at the needle tip. Notably, Zn migration accelerated at 40°C, with minimal detection at 5°C, indicating the significant influence of temperature.</p><p><strong>Conclusions: </strong>This study offers the first experimental evidence of Zn migration from the RNS into drug formulations within staked-in-needle PFSs. While Zn is not solely responsible for needle clogging, its presence in both RNS and the drug suggests a contributory role. These insights can inform strategies for improving PFS performance and reliability.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744135","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":"Development of Candesartan Cilexetil-sodium Carbonate Anhydrate-mesoporous Silica Solid Dispersion in Polymer-free System.","authors":"Jeong Sun Sohn, Jae-Seon Kim, Jin-Seok Choi","doi":"10.1007/s11095-025-03897-1","DOIUrl":"https://doi.org/10.1007/s11095-025-03897-1","url":null,"abstract":"<p><strong>Purpose: </strong>Candesartan cilexetil (CDST) is used to treat hypertension; the drug belongs to the Biopharmaceutics Classification System (BCS class II) due to its low solubility in aqueous solutions. The commercial product, Atacand®Tab, contains 16 mg of CDST in a small tablet weighing approximately 130 mg. This study developed a polymer-free system by using a CDST solid dispersion (SD) of sodium carbonate anhydrate and mesoporous silica.</p><p><strong>Methods: </strong>The SD formulation was developed to ensure solubilization and stability of CDST using a solvent evaporation method.</p><p><strong>Results: </strong>The dissolution (%) of CDST in the optimal formulation (SD1) at 60 min in pH1.2 medium, pH4.0 buffer, distilled water (DW), and pH6.8 buffer without polysorbate 20 increased by 35.2-, 45.5-, 34.4-, and 28.1-fold compared to that of Atacand®Tab and by 63.4-, 37.5-, 1.7-, and 46.9-fold, respectively, compared to the physical mixture (PM1). The dissolution of SD1 formulation was over 98% in DW and pH6.8 buffer after 60 min. The physicochemical properties of the SD1 formulation changed the melting point, drug-excipient interaction, and crystallinity of CDST. Additionally, the stability of SD1 formulation for 12 months was secured.</p><p><strong>Conclusions: </strong>The SD1 formulation improved the dissolution of CDST and secured stability by changes in its physicochemical properties.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732746","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":"Dual-modified Liposomes Encapsulating Nucleic Acids (pApoE2 or pGFP) for Transport Studies Across a Hydrocortisone-enhanced In Vitro Blood-brain Barrier Model for CNS Therapeutic Screening.","authors":"Chinenye Edith Muolokwu, Avinash Gothwal, Takahisa Kanekiyo, Jagdish Singh","doi":"10.1007/s11095-025-03900-9","DOIUrl":"https://doi.org/10.1007/s11095-025-03900-9","url":null,"abstract":"<p><strong>Purpose: </strong>The study assessed dual-modified liposomes for delivering pApoE2 and pGFP across an in vitro blood-brain barrier (BBB) model supplemented with hydrocortisone (HC), evaluating their transfection efficiency in neuronal cells across the BBB and the impact of hydrocortisone on BBB integrity.</p><p><strong>Methods: </strong>An in vitro BBB model was developed using brain endothelial cells (bEnd.3) co-cultured with primary astrocytes in a transwell system. Hydrocortisone's effect on BBB integrity was assessed via transepithelial electrical resistance (TEER), permeability and transport studies. Liposomes, modified with cell-penetrating peptide-RDP and Transferrin, encapsulating pApoE2 or pGFP-chitosan polyplex, were evaluated for neuronal cell transfection after crossing the BBB.</p><p><strong>Results: </strong>The BBB models supplemented with 150 nM HC showed a significant increase in TEER values compared to monolayers (p < 0.0001) and co-culture BBB models without HC supplementation (p < 0.01), indicating enhanced BBB integrity. Permeability assays demonstrated reduced sodium fluorescein translocation across the 150 nM hydrocortisone-supplemented BBB models compared to monolayers (p < 0.001) and co-culture models without HC supplementation (p < 0.05). Liposomes exhibited good characteristics and efficient encapsulation of pApoE2 or pGFP-chitosan polyplex, and successfully crossed the developed BBB model. Dual-modified liposomes (RDP-T_f) achieved significantly greater transfection efficiency of pApoE2 and pGFP in neuronal cells (p < 0.0001) compared to single-modified (RDP or T_f) and plain liposomes.</p><p><strong>Conclusions: </strong>Hydrocortisone enhanced the BBB properties of the in vitro model, making it more representative of the in vivo BBB. Dual-modified liposomes demonstrated superior efficacy in delivering genetic materials across the BBB, providing a promising approach for therapeutic interventions in neurodegenerative diseases like Alzheimer's.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732747","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":"Effect of Colour and Surface Properties of Solid Pharmaceutical Dosage Forms on Light Reflection in Solar Spectral Range.","authors":"Elżbieta Mickoś, Anna Banyś, Magdalena Hartman-Petrycka, Żaneta Gortat-Stanisławska, Sławomir Wilczyński","doi":"10.1007/s11095-025-03896-2","DOIUrl":"https://doi.org/10.1007/s11095-025-03896-2","url":null,"abstract":"<p><strong>Objective: </strong>The objective of the present study was to undertake a comparative analysis of the effect of colour, score line, embossing or printing on the surface of selected solid oral pharmaceutical dosage forms on the reflectance properties in the range of ultraviolet A, visible and near infrared radiation from 335 to 2500 nm. This analysis was carried out using the value of directional hemispherical reflectance as a parameter indicating the resistance of the pharmaceutical dosage form to solar radiation through reflection mechanism. Reflected radiation has no physical or chemical effects.</p><p><strong>Methods: </strong>Directional hemispherical reflectance (DHR) was used in analysis. Quantitative assessment of the reflected radiation by the sample allows the determination of how much radiation is absorbed or transmitted by the tested object, thus allowing the assessment of the interaction strength of specific spectral ranges.</p><p><strong>Results: </strong>External parameters of the pharmaceutical dosage form, such as colour, score lines, embossing, or imprints, can determine interactions of medicinal product with electromagnetic radiation.</p><p><strong>Conclusions: </strong>These findings have practical implications for pharmaceutical formulation. The results suggest that colour and surface texture should be considered when developing photostable pharmaceutical products.</p><p><strong>Highlights: </strong>• Electromagnetic radiation affect on stability of medicinal product. • Reflected radiation does not cause physical and chemical effects. • Colour and structural elements of solid pharmaceutical dosage form determine reflective properties. • Directional hemispherical reflectance (reflectance) as a measurer of exposure to radiation.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732748","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":"Influence of Milling Parameters on Crystal Morphology, Thermal Behavior, and Dissolution of Mesalamine Nanocrystals.","authors":"Sakshi Kunjir, Prajakta Pathare, Sonam Sharma, Jyoti Deoriya, Subramanian Natesan, Rajkumar Malayandi","doi":"10.1007/s11095-025-03891-7","DOIUrl":"https://doi.org/10.1007/s11095-025-03891-7","url":null,"abstract":"<p><strong>Purpose: </strong>The low aqueous solubility limits the therapeutic potential of both new and existing drug molecules. Mesalamine (MES), a primary therapeutic agent for inflammatory bowel diseases, has low aqueous solubility and incomplete dissolution in the colon; hence, it requires a high administered dose (maximum daily dose of 4.8 g/day). This study attempts to improve the dissolution velocity and solubility by designing MES nanocrystals.</p><p><strong>Methods: </strong>MES nanocrystals were prepared using the dry ball milling (BM) process. MES nanocrystals (NCs) were prepared using Soluplus as stabilizer, and milling parameters were optimized to obtain the desirable particle size and other pharmaceutical attributes.</p><p><strong>Results: </strong>The prepared MES NCs were characterized to understand the influence of key milling parameters like time, speed, and stabilizer concentration. Variations in these parameters resulted in diverse morphologies, including rectangular bars, elongated hexagons, spheroids, and plates. Batch 29 (40/1/400) exhibited a plate-like crystal habit with a particle size of 435 nm and a PDI of 0.39, demonstrating an improved dissolution efficacy (84% in 60 min). Spectroscopic, microscopic, and thermal analyses confirmed the influence of ball milling on solubility, dissolution rate, particle size, and crystal habits.</p><p><strong>Conclusion: </strong>The study outcomes could be useful for the successful scale-up and commercialization of drug products based on the dry BM platform technology.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699199","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":"Correction: \"Simultaneous Pharmacokinetic Modeling of Gentamicin, Tobramycin and Vancomycin Clearance From Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration\".","authors":"R F De Cock, K Allegaert, J M Brussee, C M Sherwin, H Mulla, M de Hoog, J N van den Anker, M Danhof, C A Knibbe","doi":"10.1007/s11095-025-03895-3","DOIUrl":"https://doi.org/10.1007/s11095-025-03895-3","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691198","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":"Dissolution Profiles Comparison Using Various Model Independent Statistical Approaches: Can We Increase Chance of Similarity?","authors":"Rajkumar Boddu, Karthik Parsa, Priyansh Pandya, Sivacharan Kollipara","doi":"10.1007/s11095-025-03892-6","DOIUrl":"https://doi.org/10.1007/s11095-025-03892-6","url":null,"abstract":"<p><strong>Purpose: </strong>In vitro dissolution testing is a critical quality attribute for solid dosage forms. Apart from similarity factor (f2), other alternatives namely model independent and dependent methods are suggested by regulatory agencies. Current manuscript attempts to compare various model independent approaches on dissolution similarity.</p><p><strong>Methods: </strong>Dissolution data with various degrees of variability (10-20%, 40-50%, 70-80%) are compared using similarity factor f2 (estimated, expected, bias corrected with percentile & BCa intervals) and novel approaches such as EDNE, SE, T2EQ, and MSD. Further, a flow chart is proposed to assist selection of suitable methodology.</p><p><strong>Results: </strong>The expected f2 was stringent as compared to other f2 types and the Bca confidence intervals approach increased chance of acceptance as compared to conventional f2 bootstrap. Further, EDNE results synchronized with f2 analysis. Outcome from SE, T2EQ approaches depends on value of equivalence margin. MSD approach was most stringent as compared to others. Finally, a decision tree has been proposed to facilitate the selection of appropriate methodology for similarity analysis with consideration of regulatory perspectives.</p><p><strong>Conclusions: </strong>Overall, various model independent approaches are compared for dissolution similarity analysis. This comprehensive guidance will assist formulation and biopharmaceutics scientists to enhance the success rate of similarity while ensuring regulatory compliance and thus helps to achieve drug product with consistent performance.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659876","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":"IVPT Data Challenges in the Real World: Outliers, Anomalous and Aberrant Data: Examples.","authors":"Paul A Lehman","doi":"10.1007/s11095-025-03893-5","DOIUrl":"10.1007/s11095-025-03893-5","url":null,"abstract":"<p><strong>Background: </strong>The in vitro permeation test (IVPT) is a sensitive and robust model system that has been vital in elucidating the fundamental parameters surrounding the absorption of both therapeutic agents and industrial chemicals through skin. Unlike most clinical bioequivalence study designs, the IVPT method allows for the evaluation of multiple replicates (skin sections) from the same donor (\"subject\") at the same time. Though this should provide an advantage for a better characterization of the topical permeation kinetics within a donor, it also comes with the likelihood that any given skin replicate within the same donor, may demonstrate an unusual or anomalous absorption profile. These are often described as 'outliers', those sections demonstrating a substantial difference in percutaneous absorption kinetics to the other replicates.</p><p><strong>Methods: </strong>A retrospective analysis of data from the authors' archives has been screened with the objective of finding and addressing a number of questions regarding skin section and donor data outliers, anomalous data, missing data and the establishment of a representative J_max.</p><p><strong>Conclusion: </strong>When the IVPT method has been properly designed and performed, outliers reflect anomalies in the donor's skin and donor population rather than as an artifact of the IVPT method. Identification and statistical confirmation approaches help to differentiate anomalous data from the core data set. In addition, missing data, and determining a representative J_max, confound the accurate determination of BE for topical formulations.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1089-1099"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144650121","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":"First-in-Class Clinically Investigated Oral Factor D Inhibitors for the Treatment of Complement-Mediated Diseases.","authors":"Venkat R Gadhachanda, Jason A Wiles, Steven D Podos, David Boyer, Jane Thanassi, Dhara Patel, Yongsen Zhao, Lijuan Wang, Mingjun Huang","doi":"10.1007/s11095-025-03882-8","DOIUrl":"10.1007/s11095-025-03882-8","url":null,"abstract":"<p><strong>Objective: </strong>The goal of the study was to discover small molecular inhibitors of complement factor D (FD), an essential protease for activation of the alternative pathway (AP) of complement, that possess the characteristics for clinical investigation in complement-mediated diseases such as paroxysmal nocturnal hemoglobinuria (PNH).</p><p><strong>Methods: </strong>Compounds were synthesized and tested in vitro for potency, selectivity, and metabolic stability. The optimized compounds were subjected further to a panel of in vitro tests for primary and secondary pharmacology including inhibitory effects on FD, different complement pathways and disease models, as well as to pharmacokinetic and pharmacodynamic evaluations in animals.</p><p><strong>Results: </strong>Following multiple rounds of optimization, danicopan and later vermicopan were chosen as candidates for clinical investigation. Both compounds demonstrated potent and selective inhibitory effects on FD and AP, suitable pharmacokinetic characteristics for oral dosing, and efficacy in PNH in vitro disease models. In addition to enhanced in vitro potency, vemircopan exhibited lower clearance and higher bioavailability in animal studies compared with danicopan.</p><p><strong>Conclusion: </strong>Preclinical evaluations of danicopan and vermicopan provided rationales to conduct clinical studies in complement-mediated diseases. Recently, danicopan was approved as an add-on therapy to the C5 inhibitors ravulizumab or eculizumab for the treatment of extravascular hemolysis in patients with PNH.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1119-1131"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497664","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}